key: cord-0698601-j2ygh4iq
authors: Fitting, Sylvia; McRae, MaryPeace; Hauser, Kurt F.
title: Opioid and neuroHIV Comorbidity – Current and Future Perspectives
date: 2020-09-02
journal: J Neuroimmune Pharmacol
DOI: 10.1007/s11481-020-09941-8
sha: 455517c6ee3099fbe8686f20231b0cbe8ee719b1
doc_id: 698601
cord_uid: j2ygh4iq

With the current national opioid crisis, it is critical to examine the mechanisms underlying pathophysiologic interactions between human immunodeficiency virus (HIV) and opioids in the central nervous system (CNS). Recent advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal opioid-HIV interactions with increasing clarity. However, despite the substantial new insight, the unique impact of opioids on the severity, progression, and prognosis of neuroHIV and HIV-associated neurocognitive disorders (HAND) are not fully understood. In this review, we explore, in detail, what is currently known about mechanisms underlying opioid interactions with HIV, with emphasis on individual HIV-1-expressed gene products at the molecular, cellular and systems levels. Furthermore, we review preclinical and clinical studies with a focus on key considerations when addressing questions of whether opioid-HIV interactive pathogenesis results in unique structural or functional deficits not seen with either disease alone. These considerations include, understanding the combined consequences of HIV-1 genetic variants, host variants, and μ-opioid receptor (MOR) and HIV chemokine co-receptor interactions on the comorbidity. Lastly, we present topics that need to be considered in the future to better understand the unique contributions of opioids to the pathophysiology of neuroHIV. [Figure: see text]

the constant rise in deaths involving opioids, the U.S. Government declared the opioid crisis/epidemic a public health emergency in 2017 (U.S. Department of Health and Human Services 2017). Injection drug use increases the likelihood of contracting human immunodeficiency virus (HIV) and drug abuse and HIV have long been described as interrelated epidemics (Swan 1997; Leshner 1998; Nath et al. 1999 Nath et al. , 2002 . Despite this understanding, opioid use disorder (OUD) and HIV remain a huge public health concern (Strathdee and Beyrer 2015; Peters et al. 2016) . In fact, the opioid crisis is seen as a major roadblock in several aspects of public health, including thwarting the goal of eliminating HIV within the next decade Lerner and Fauci 2019) .

OUD is also likely to exacerbate many negative aspects of the COVID-19 pandemic (Alexander et al. 2020; Becker and Fiellin 2020; NIDA 2020; Wakeman et al. 2020) . Not only are individuals with OUD more vulnerable to SARS-CoV-2 and liable to spread the infection, social-distancing practices create isolation, despair, and economic hardships, heightening opioid abuse (with inherent respiratory depression depending on the amount of tolerance developed) and the probability of overdose (Becker and Fiellin 2020; Wakeman et al. 2020) . By virtue of its greater safety profile and decreased likelihood for abuse (Bell and Strang 2020) , the use of buprenorphine via telemedicine has become advantageous for managing OUD during the COVID-19 pandemic (Leppla and Gross 2020; Samuels et al. 2020) but presents new challenges (Khatri and Perrone 2020) .

The current opioid crisis did not happen quickly; in fact, it has been described as occurring in three phases. The first phase began in the late 1990s with an increase in the number of prescription opioids. This led to overdose deaths that were attributable to natural and semisynthetic opioids, such as methadone (Kolodyny et al. 2015; CDC 2017) . The second phase began in 2010 in which heroin took the lead as the principal cause of overdose deaths. The most recent, third wave, began in 2013 in which highly potent synthetic opioids, such as fentanyl and its analogs became the main cause of mortality (Kolodyny et al. 2015; CDC 2017) . The entry of fentanyl and its analogs into the clandestine market has changed the dynamics of the opioid market in the U.S. The synthetic opioids, such as fentanyl, are several orders of magnitude more potent than morphine, easily smuggled, and frequently and inconsistently mixed with lower quality drugs increasing the probability of overdosing. According to the National Forensic Laboratory Information System of the U.S. Drug Enforcement Administration (DEA), fentanyl accounted for one-third of the illicit opioids seized in 2017 (UNODC 2019c) and has become a global problem (UNODC 2019b).

The effects of opioid abuse on the central nervous system (CNS) have been extensively examined. Immediate effects of opioids result in decreased levels of consciousness, sedation (Collett 1998; Thompson 2000; Indelicato and Portenoy 2002) , drowsiness, and sleep disturbances (Moore and Dimsdale 2002; Bourne and Mills 2004; Qureshi and Lee-Chiong 2004) . While acute opioid exposure can impair cognition in healthy subjects (Lawlor 2002; Ersek et al. 2004) , enduring cognitive and psychomotor deficits occur with chronic opioid use (Sjogren et al. 2000; Dublin et al. 2015; Roberts et al. 2018; Wollman et al. 2019; Serafini et al. 2020) , including altered pain perception (opioid-induced hyperalgesia), dysregulated reward/saliency processing, hyperkatifeia, and epigenetic changes, which can persist years following abstinence (Ersche et al. 2006; Browne et al. 2020) . The behavioral changes seen with long-term opioid use are accompanied by lasting structural and epigenetic (e.g., altered DNA methylation and expression of noncoding RNAs) alterations in brain regions implicated in mood, reward, and motivation (Upadhyay et al. 2010; Dublin et al. 2015; Volkow and Morales 2015; Koob and Volkow 2016; Serafini et al. 2020) .

Up to 90% of post-mortem tissues sampled from opiate abusers display brain edema (Buttner 2011) , astrogliosis and microgliosis especially in the hippocampus (Oehmichen et al. 1996) , white matter, and subcortical regions at autopsy (Tomlinson et al. 1999; Anthony et al. 2005; . The reactive gliosis is accompanied by increases in proinflammatory cytokines and inflammatory mediators, including TNF-α, IL-1β, and nitric oxide synthase (NOS) (Dyuizen and Lamash 2009) . Opiates especially drive the enhanced activation of heme-oxygenase, NOS, and cyclic GMP-dependent-protein kinase (Liang and Clark 2004) and production of reactive nitrogen species (RNS) such as peroxynitrite (Salvemini 2009) , and resultant nitrosative damage . Nitrosative damage is an important endpoint for opiate exposure (Pasternak et al. 1995; Liang and Clark 2004; Salvemini 2009) and key site of convergence for the oxidative stress accompanying HIV protein exposure McLane et al. 2018) .

For delayed heroin overdose death after a survival period of 5 h or more, studies report neurovascular disorders, hypoxic ischemic leukoencephalopathy, and region-specific atrophy with neuronal losses that can include the hippocampal formation, the cerebellar Purkinje cell layer and olivary nucleus (Protass 1971; Ginsberg et al. 1976; Gosztonyi et al. 1993) , as well as other areas (Buttner 2011; Cadet et al. 2014 ). Loss of neurons and synaptic connections is supported by postmortem reports of smaller mean relative volumes in various brain regions in individuals with OUD, including cortical areas (Danos et al. 1998; Pezawas et al. 1998) , the basal ganglia (Muller et al. 2015 (Muller et al. , 2019 , prefrontal cortex (Cadet et al. 2014) , and hypothalamus (Muller et al. 2018) . Interestingly, leukoencephalopathy, atrophy (Cadet et al. 2014) , and increased hyperphosphorylated tau-containing neurofibrillary tangles are reported with chronic opiate abuse compared to age-matched controls Anthony et al. 2010; Kovacs et al. 2015) . Glycogen synthase kinase 3 α or β (GSK-3α/β; the pan antibody used in this study does not discern α from β isoforms) and/or cyclin-dependent kinase-5 (Cdk-5) are increased in the frontal and temporal cortices, the locus coeruleus, and the hippocampus, respectively, and correlate with microgliosis (Anthony et al. 2010) . Further, more prolonged use increases the risk of accelerated age-related and even Alzheimer's-like pathological changes Anthony et al. 2010; Kovacs et al. 2015) and cognitive impairment (Gruber et al. 2007 ).

Moreover, heroin use is associated with symmetric T2 and fluid-attenuated inversion recovery (FLAIR) hyperintense white matter lesions of the CNS using magnetic resonance imaging (MRI), which coincide with increased microgliosis and inflammation at the same sites (Upadhyay et al. 2010; Bora et al. 2012; Qiu et al. 2013; Alaee et al. 2014; Li et al. 2016; Shrot et al. 2017) . Although a few studies have started to examine opiate-HIV interactions in white matter (see below), we predict that the interactive effects on myelin dysregulation will significantly worsen CNS outcomes.

Preclinical studies indicate opioid-induced neuroimmune signaling alter the saliency of opioid reward and physical dependence (Narita et al. 2006; Hutchinson et al. 2008 Hutchinson et al. , 2009 . Direct injections of astrocyte-conditioned medium containing cytokines into the nucleus accumbens (NAc) increase morphine conditioned place preference (Narita et al. 2006) . Drugs reported to selectively attenuate glial inflammation block morphine conditioned place preference and attenuate symptoms of opioid withdrawal (Narita et al. 2006; Hutchinson et al. 2009; Liu et al. 2010) . μ (MOR), δ (DOR), and κ (KOR) opioid receptors are expressed by subsets of astrocytes and microglia (Stiene- Martin and Hauser 1991; Eriksson et al. 1992; Stiene-Martin et al. 1993; Ruzicka et al. 1995; Gurwell et al. 1993; Turchan-Cholewo et al. 2008; Maduna et al. 2018) and are involved in opioid tolerance and dependence to varying degrees (Kieffer and Gaveriaux-Ruff 2002; Berger and Whistler 2010; Morgan and Christie 2011) . Despite some reports of morphine triggering immune activation via Toll-like receptor 4 (TLR4) (Terashvili et al. 2008; Hutchinson et al. 2010; Coller and Hutchinson 2012; Hutchinson et al. 2012; Theberge et al. 2013; Lacagnina et al. 2017 ) by binding to a myeloid differentiation protein-2 intermediary , this is contrary to the typical actions of opiates, which by themselves (and in the absence of a priming event such as HIV co-exposure) tend to suppress immune function (Eisenstein 2019) . A vast majority of the immune, antinociceptive, and other physiological effects of opioids are mediated by opioid receptors per se and not TLR4 (Hu et al. 2011; Fukagawa et al. 2013; Stevens et al. 2013; Mattioli et al. 2014; Eisenstein 2019) .

Overall, the findings indicate that immune signaling plays a critical role in the pathophysiology of OUD and associated physical dependence. How opioids effect neuroHIV, as well as how opioid abuse and dependence are altered by neuroHIV or whether opioid-HIV interactions result in a unique disease state are discussed.

People infected with HIV (PWH) with OUD have an increased incidence of neuroHIV and CNS complications (Bell et al. 1998; Nath et al. 1999 Nath et al. , 2000a Nath et al. , 2002 Anthony et al. 2008; Meyer et al. 2013; Smith et al. 2014) . Injection drug use increases the probability of contracting HIV ) and opioid drugs intrinsically alter the pathogenesis of HIV. PWH who develop intractable pain syndromes related to peripheral neuropathies often receive opioid drugs for treatment (Mirsattari et al. 1999; Denis et al. 2019) . PWH who misuse opioids are more likely to undertake risky sexual behavior and are less likely to adhere to combined antiretroviral (ARV) therapy (cART) regimens (Lemons et al. 2019) . Opioid receptors are widely expressed on immune cells and opioids can modulate immune function (Donahoe and Falek 1988; Plotnikoff 1988; Rouveix 1992; Adler et al. 1993; Carr and Serou 1995; Carr et al. 1996; Sheng et al. 1997; Banerjee et al. 2011; Purohit et al. 2012) , which typically (but not always) result in immune suppression (Wybran et al. 1979; McDonough et al. 1980 McDonough et al. , 1981 Donahoe and Falek 1988; Donahoe et al. 1991; Falek et al. 1991; Novick et al. 1991; Chao et al. 1996a; Peterson et al. 1998; Rogers and Peterson 2003; Stein et al. 2003; Roy et al. 2006; Rittner et al. 2008) . The "opiate cofactor hypothesis" proposes opioids contribute directly to the pathogenesis of acquired immune deficiency syndrome (AIDS) (Donahoe and Vlahov 1998) , in part, because MOR activation can increase HIV replication in immune cells (Peterson et al. 1990 (Peterson et al. , 1992 (Peterson et al. , 1993 (Peterson et al. , 1999 Ho et al. 2003) . Furthermore, MOR and HIV co-receptors, including both CCR5 Yuan et al. 2013; Arnatt et al. 2016 ) and CXCR4 (Pitcher et al. 2014) can interact via convergent downstream signaling and perhaps via direct molecular interactions (Rogers et al. 2000; Rogers and Peterson 2003; Steele et al. 2003; Chen et al. 2004; Song et al. 2011; Arnatt et al. 2016 ). MOR-CCR5 or CXCR4 interactions are highly contextual and can promote (Guo et al. 2002; Steele et al. 2003) or inhibit (Strazza et al. 2014 ) HIV expression, depending on the nature and duration of exposure (see Fig. 9 ; Berman et al. 2006 ) and cell type involved (Kim et al. 2018) . Depending on the outcome measure, Tat expression reduces morphine's efficacy and potency Hahn et al. 2016) . Antagonizing CCR5 with maraviroc reinstates morphine potency in an antinociceptive assay and restores physical dependence in Tat exposed, morphine-tolerant mice (Gonek et al. 2018) .

Epidemiological studies suggest OUD can increase AIDS progression (Donahoe and Vlahov 1998; Dronda et al. 2004; Meijerink et al. 2014 Meijerink et al. , 2015 . In the pre-cART era, opiate abuse was found to exacerbate HIV encephalitis (HIVE) (Bell et al. 1998 (Bell et al. , 2002 . In Indonesian injection heroin abusers who lacked access to cART, CD4 counts (a measure of HIV progression) were reduced compared to PWH not using heroin (Meijerink et al. 2014 ). However, with the introduction of cART, the clinical picture has significantly changed with a 50% decline in the rate of death from AIDS, reduced incidence of opportunistic infections and HIVE, and a 40-50% decrease in the incidence of HIV-associated dementia (HAD), the most severe form of HIV-associated neurocognitive disorders (HAND) (Maschke et al. 2000; McArthur et al. 2010; Saylor et al. 2016) . Nevertheless, chronic opiate exposure (which almost always is confounded by the use of other illicit and legal drugs) in PWH can worsen neuroHIV Bell et al. 2006; Anthony et al. 2008 ) and cognitive impairment (Rodriguez Salgado et al. 2006; Martin-Thormeyer and Paul 2009; Byrd et al. 2011; Smith et al. 2014; Martin et al. 2018; Rubin et al. 2018 ) despite cART, even though some studies fail to show that opioids worsen neuroHIV (Royal et al. 1991; Applebaum et al. 2010) or HAND (Martin et al. 2019) . Opiate exposure in cARTtreated PWH worsens CD4 counts and viral loads (Ryan et al. 2004) , neuropathology (including increased tauopathy; Smith et al. 2014) , CNS inflammation (Anthony et al. , 2008 Smith et al. 2014) , and neurocognition (Applebaum et al. 2009; Byrd et al. 2011; Meyer et al. 2013) including deficits in memory and working memory (Byrd et al. 2011) . Table 1 gives an overview on reported interactive effects of HIV and opioids in some of the clinical and preclinical CNS studies referenced in this review.

Although translational, "bench-to-bedside", research is important, reverse-translational approaches and multiple preclinical models are essential to better understand complex disease and improve established therapies (Singer 2019) . Evidence suggests that HIV compartmentalizes within the CNS early during the course of the infection establishing a separate reservoir harboring Bintact proviral" HIV (Churchill et al. 2016; Bruner et al. 2019 ) within resident neural cell populations (Bednar et al. 2015; Sturdevant et al. 2015; Veenhuis et al. 2019 ) and perivascular macrophages (Fischer-Smith et al. 2001; Burdo et al. 2013; Rappaport and Volsky 2015) . Preclinical studies assessing opioid interactions with HIV or viral proteins permit mechanistic understanding of how particular CNS cell types, including neurons, astroglia, and microglia are affected and contribute to accentuating effects of opiates on neuroHIV, which are discussed in detail below.

Prior reviews have outlined how opiate drugs likely exacerbate neuroHIV pathology in neurons and glia Hauser et al. 2012; Reddy et al. 2012; Hauser and Knapp 2014; Liu et al. 2016a; Murphy et al. 2019) including in the enteric nervous system (Galligan 2015; Meng et al. 2015) . Opioid-HIV pathophysiological interactions are complex and differ depending on the timing and duration of co-exposure, the pharmacology of the opioid drug involved, the cell types and brain regions targeted, host and viral genetics, and are highly contextual Knapp 2014, 2018) . A summary of the cellular and molecular interactions in various CNS cell types is also reviewed in detail in Table 2 .

Although the extent to which astroglia display productive infection is debated (Russell et al. 2017; Ko et al. 2019) , there is nevertheless considerable evidence of proviral integration in the CNS of PWH (Gorry et al. 2003; Churchill et al. 2009 ), infectious animal models (Eugenin et al. 2011) , and/or cultured human fetal astrocytes (Tornatore et al. 1994; Liu et al. 2004; Do et al. 2014; Narasipura et al. 2014; Li et al. 2015; Nath 2015; Li et al. 2020) . Integrated HIV sequences have been identified in astrocytes in HIV-infected CNS tissue by laser capture microdissection (Churchill et al. 2006) . Astroglia appear to infect via nonclassical, CD4-independent mechanisms, that can have the appearance of virologic synapses, adding to the debate Do et al. 2014; Li et al. 2015; Nath 2015; Al-Harthi et al. 2019; Li et al. 2020) .

Irrespective of whether they become infected, MOR-expressing, HIV or HIV protein-exposed astrocytes release greater amounts of inflammatory cytokines and dysfunction sufficient to harm bystander neurons upon treatment with opiates , 2008b Zou et al. 2011; El-Hage et al. 2014) . MOR-expressing subsets of glia, especially microglia and astroglia, are prominent in driving the interactive opioid and HIV neuropathogenesis Hauser and Knapp 2014; Liu et al. 2016a; Chilunda et al. 2019; Murphy et al. 2019) . When MOR is deleted from glia (astrocytes and microglia), morphine no longer increases the death of Tat-exposed striatal medium spiny neurons (MSNs) . Conversely, if MOR is deleted from MSNs, morphine exacerbates the neurotoxic effects of Tat in MSNs . The proinflammatory effects of Tat alone or in combination with morphine on glia are mediated through a Beclin-1-dependent autophagy pathway (Rodriguez et al. 2017; Lapierre et al. 2018) . Drugs with selective glial antiinflammatory activity (i.e., ibudilast or AV411) attenuated the deleterious effects of HIV and opiate exposure, including HIV-1 replication, cytokine release, and neurotoxicity in vitro ). Thus, the observed neuronal death is largely mediated by MOR-expressing glia , including astroglia , 2008b and microglia (Turchan-Cholewo et al. 2008; Bokhari et al. 2009; Turchan-Cholewo et al. 2009; Gupta et al. 2010) .

The direct contributions of astrocytes to opioid and HIV interactions have been discussed previously Hauser et al. 2012; Reddy et al. 2012; Hauser and Knapp 2014) . Subsets of astroglia can express MOR, DOR and KOR (Stiene- Martin and Hauser 1991; Eriksson et al. 1992; Ruzicka et al. 1995; Gurwell et al. 1996; Peterson et al. 1998; Stiene-Martin et al. 1998 , 2001 , as well as endogenous opioid peptides (Vilijn et al. 1988; Shinoda et al. 1989; Spruce et al. 1990; Hauser et al. 1990; Low et al. 1992 ). It appears that the 'early' events triggering the release of proinflammatory cytokines (i.e., TNF-α and IL-1β) from astroglia can be mediated by HIV Tat exposure alone , b, 2008a . Opioids enhance HIV-1-induced inflammation later during the inflammatory cascade by exacerbating the sustained release of CCL5 from astrocytes, which subsequently triggers the release of CCL2 thereby enhancing the recruitment and activation of macrophages/microglia (El-Hage et al. 2008a) (Fig. 1 ). This is caused by the morphine-dependent exacerbation of Tat-induced increases in intracellular calcium concentration ([Ca 2+ ] i ) in astroglia , which accelerates the trafficking of NF-κB p65 (RelA) subunits to the nucleus and sustained CCL2, CCL5, and IL-6 transcription in astrocytes (El-Hage et al. 2008b ).

Unlike in astrocytes, opiate and HIV interactions in microglia tend to be self-limiting (Turchan-Cholewo et al. 2009 ). Opiates initially trigger large increases in the production of proinflammatory cytokines (Hauser, unpublished) , reactive oxygen (ROS) and nitrogen (RNS) species (Turchan-Cholewo et al. 2009 ), and the release of glutamate (Gupta et al. 2010 ) and ATP (Sorrell and Hauser 2014) extracellularly in Tat-exposed microglia. The release of glutamate is mediated by the catalytic subunit of the cystine-glutamate antiporter x c − (xCT) (Gupta et al. 2010) . Interestingly, following acute increases in the release of cytokines (e.g., TNF-α; unpublished), morphine no longer increases Tatinduced cytokine levels at 24 h; instead, their levels are reduced by opiate-dependent proteasome inhibition. The proteasome inhibitor, MG115, mimics the effects of morphine in decreasing proteasome activity at 24 h and blocks TNFα, IL-6, and CCL2 release from microglia, but does not increase ROS or RNS production (Turchan-Cholewo et al. 2009 ). The ubiquitin proteasome system (UPS) is typically viewed as contributing to opiate tolerance and physical dependence by modulating MOR downregulation (Massaly et al. 2014; Caputi et al. 2019) , rather than MOR activity constraining the UPS. Thus, while HIV-exposed, MOR-expressing microglia show a burst of ROS and proinflammatory cytokine production in response to morphine, the cytokine release collapses within 24 h seemingly because sustained opiate exposure inhibits the UPS thereby preventing degradation of the IκB subunit and nuclear translocation of NF-κB (Turchan-Cholewo et al. 2009 ). While neither astroglia nor microglia alone mimic the full inflammatory profile seen with opiates and HIV in the CNS; in combination, the neuroimmune signature more accurately mimics that seen in neuroHIV. Accordingly, we have proposed that opioids promote positive feedback through separate actions in astroglia and microglia in neuroHIVresulting in spiraling inflammation and cytotoxicity .

Besides accentuating HIV-induced neurotoxicity via glialmediated mechanisms, morphine appears to converge with HIV Tat to dysregulate ion homeostasis and dendritic injury through potential direct actions on neurons, even though some contributions of glia cannot be excluded in this study (Fitting et al. 2014a) . Combined morphine and Tat exposure accelerates the formation of Tat-induced focal dendritic varicosities/swelling via a MOR-related mechanism that was caused by focal increases in Na + influx and [Ca 2+ ] i , an overload of Na + /K + -ATPase, ATP depletion, and a collapse in mitochondrial inner membrane potential (Fitting et al. 2014a) . Importantly, morphine's additive effects were mediated via a MOR-related mechanism, as the exacerbating effects of morphine were absent in neurons from MOR knockout mice, thus excluding TLR4 involvement (Fitting et al. 2014a ). Further, morphine exacerbated Tat-dependent focal losses in ion homeostasis by mobilizing [Ca 2+ ] i through ryanodine-2 (RyR2)-sensitive sites (Fitting et al. 2014a ) (Fig. 2) . Although morphine typically acts via MOR in an inhibitory manner by activating G i/o -proteins (Sharma et al. 1977; Moises et al. 1994 ; Al-Hasani and Bruchas 2011), MOR-dependent stimulation of PI3-kinase and Ca 2+ mobilization (Leopoldt et al. 1998) (Sheng et al. 2003 )

Human, astrocytoma U87 cell line, primary astrocytes (Mahajan et al. 2002) • Tat Human, primary microglia (Chao et al. 1996b) • HIV JR-FL (R5)

• gp120

No

Human, fetal microglia (Sundar et al. 1995 • Nociceptin, no effect on p24

Human, fetal brain microglia and mixed neurons/glia (Chao et al. 1998b ) subunit (Mathews et al. 2008 ) is presumed operative here (Fig. 2) . Glial-derived neuronal injury is not unidirectional. Neuronal damage-associated molecular patterns (DAMPs) and dysfunction can trigger both infected and uninfected glia to become reactive, resulting in further neuronal damage and escalating pathology. Neuronal injury can reactivate HIV in latently infected microglia (Alvarez-Carbonell et al. 2019) . While the events underlying the disruption of neuronalmicroglial activation that trigger the emergence of latent HIV are unclear, the induction of HIV expression appears to involve the production of DAMPs by injured neurons and can be turned "on", e.g., by methamphetamine-induced sigma-1 (σ1) receptor activation, TNF-α and IL-1β, and TLR3 activation can be turned "off" by CX3CL1/fractalkine or glucocorticoid receptor activation (Alvarez-Carbonell et al. 2017 .

Despite growing evidence on how opiates and HIV interact to impact the neuropathology of HIV, little is known about their interactive effects on the blood-brain barrier (BBB). BBB integrity and function are critical for maintaining CNS homeostasis, and mediating neuroimmune interactions with the periphery and drug delivery into the CNS. HIV and many individual HIV proteins can breakdown the BBB disrupting tight junction proteins (Dallasta et al. 1999; Boven et al. 2000; Andras et al. 2003; Mahajan et al. 2008; Banerjee et al. 2010; Gandhi et al. 2010; Xu et al. 2012; Patel et al. 2017) and decreasing transendothelial electrical resistance (TEER) (an in vitro measure of barrier integrity) (Mahajan et al. 2008; Gandhi et al. 2010; Mishra and Singh 2014; Patel et al. 2017) , with resultant paracellular "leakage" of compounds/current between compromised barrier endothelial cells (Mahajan et al. 2008; Gandhi et al. 2010; Wen et al. 2011; McLane et al. 2014; Leibrand et al. 2017 Leibrand et al. , 2019 . Although opioids can also impair the BBB through alterations in tight junction proteins and/or increased paracellular flux (Baba et al. 1988; Mahajan et al. 2008; Wen et al. 2011; Leibrand et al. 2019) , others have found that it is morphine withdrawal, not the continued exposure to morphine, that most greatly disrupts BBB integrity (Sharma and Ali 2006) . In addition to perturbing paracellular dynamics, morphine may also alter the expression and/or function of drug efflux proteins, such as P-glycoprotein (P-gp). Sub-chronic and chronic morphine exposure is reported to increase P-gp expression and/or function (Aquilante et al. 2000; Mahajan et al. 2008; Yousif et al. 2008; Leibrand et al. 2019) . Alternatively, other investigators report no changes in P-gp with chronic exposure (Chaves et al. 2016 ), while some see increases upon morphine withdrawal (Yousif et al. 2012; Chaves et al. 2016) . Alterations in drug transport proteins would impact the central accumulation and efficacy of therapeutic drugs that are their substrates.

Using a primary human brain microvascular endothelial cell (BMEC) and astrocyte co-culture model, Mahajan et al. (2008) were among the first to demonstrate that co-exposure to morphine and HIV-1 Tat resulted in greater increases in TNF-α and IL-8 levels and decreases in barrier tightness (measured by TEER) than either morphine or Tat alone. Morphine and Tat co-exposure also additively increased JAM-2, while zonula occludens-1 (ZO-1) levels were decreased by morphine or by Tat individually, and occludin protein levels were decreased by morphine alone but not Tat (Mahajan et al. 2008 ). Using the inducible Tat transgenic mouse model, Leibrand et al. (2019) , also demonstrated that HIV-1 Tat and morphine act independently to disrupt BBB integrity. In these studies, morphine, and to a lesser extent Tat, exposure increased the leakage of fluorescently labeled dextrans from the circulation into the brain (Leibrand et al. , 2019 (Fig. 3) . Morphine exposure decreased the penetration of select ARVs in the brain, in a region-specific manner (Leibrand et al. 2019) (Fig. 3) . Morphine exposure also resulted in increased expression and function of the drug Fig. 1 Opioids exacerbate HIV-1-induced CNS inflammation, in part, by augmenting CCL5-dependent increases in CCL2-key sites of opioid-HIV convergent interactions in glial inflammatory signaling cascades. Subpopulations of striatal glial fibrillary acidic protein (GFAP)immunoreactive astrocytes in wildtype mice normally express CCR2 immunoreactivity (a-b; arrows), CCL2 (c; arrow), or μ-opioid receptor (MOR) (d; arrows) immunoreactivity (scale bars a-b = 25 μm; c-d = 15 μm). CCR2 deletion (−/−) significantly reduces HIV-1 Tat ± morphineinduced increases in GFAP+ astroglia (e) and F4/80+ macrophages/microglia (f) compared to wild type (+/+) mice at sites near (300 ± 100 μm) the site of Tat injection (*p < 0.05 vs. wild type mice) (see, El-Hage et al. 2006a ). In wild-type mice, Tat ± morphine administration markedly increases the proportion of CCL2 immunoreactive astrocytes (g) or macrophages/ microglia (h) [*p < 0.05 vs. other groups in wild-type or CCL5(−/−) mice; b p < 0.05 vs. vehicle-or Tat plus morphine-treated wild-type mice; # p < 0.05 vs. equivalent treatment in wild-type mice], while in CCL5 null mice, significant increases in CCL2 immunoreactivity were only seen in macrophages/microglia co-exposed to Tat and morphine ( § p < 0.05 vs. vehicle injected CCL5 knockout mice) (see, El-Hage et al. 2008a ). CCL5 expression in striatal GFAP-immunoreactive astrocytes (arrows) increases following Tat injections (i, j) compared to wild-type control mice (not shown) (El-Hage et al. 2008a ). Opioids exacerbate HIV-1-induced CNS inflammation, in part, by increasing CCL5 and augmenting CCR5dependent increases in CCL2 production by astrocytes resulting in the activation and recruitment of microglia/macrophages and spiraling inflammation (k). Additional factors likely mediate the proinflammatory cascade, but these are less well substantiated (?). Moreover, autocrine and reciprocal paracrine (astroglial ↔ macrophage/microglial) intercellular, feedback amplification mechanisms from macrophages/microglia are likely to be operative (dashed red arrow) (also see, Kang and Hebert 2011) and occur elsewhere within the cascade (not shown); effects of HIV-1 Tat/HIV, red arrows; sites of opioid convergence, blue arrows; pro-BDNF:mature BDNF (mBDNF) ratio (Kim et al. 2018) . (a-f) Modified and reprinted with b efflux transport protein, P-gp, suggesting a mechanism by which morphine decreased the ARV concentrations (Leibrand et al. 2019) . This finding suggests that morphine exposure could impact the efficient delivery of any therapeutic drug that is a substrate of P-gp into the CNS. Future research should also investigate morphine's impact on other drug transport proteins important for ARV delivery to the brain.

HIV, HIV-1 viral proteins, and opiate-induced barrier dysfunction is associated with increased infiltration of monocytederived macrophages (MDMs) into the brain. Enhanced influx of peripheral (infected) macrophages into the brain can serve to replenish viral reservoirs and further promote neuroinflammation. Several studies have examined the individual impact of HIV, Tat, or morphine on monocyte adhesion or migration into the CNS (Nottet et al. 1996; Wu et al. 2000; Fischer-Smith et al. 2001; Pello et al. 2006; Williams et al. 2013a Williams et al. , 2014 Strazza et al. 2016; Leibrand et al. 2017; Chilunda et al. 2019) . However, fewer studies have examined the combined effects of HIV/Tat and opiates. Co-exposure of HIV-1 Tat and morphine on astrocytes increases the production of chemoattractants, primarily CCL2 and CCL5, and increases microglial migration. These effects were inhibited by MOR blockade (El-Hage et al. 2006b ). Co-exposure of Tat and morphine or buprenorphine to a BBB model increases monocyte transmigration in response to CCL5 and other chemokines (Mahajan et al. 2008; Jaureguiberry-Bravo et. al. 2016) . In S. pneumoniae-infected mice, morphine and/or Tat exposure significantly enhances immune cell trafficking into the brain via actions at TLR2 and TLR4 (Dutta and Roy 2015) .

Taken together, BBB damage from HIV and/or opiates can disrupt the homeostasis within the brain. Breakdown of paracellular processes, through decreases in tight junction proteins and increased cellular adhesion proteins, increased leakage of circulating molecules into the brain and increased monocyte/MDM adhesion and transmigration into the brain, which if infected, can serve to replenish viral reservoirs within the CNS. Furthermore, alterations in drug transport proteins within the brain can decrease ARV efficacy by decreasing drug concentrations. Collectively, these changes serve to maintain HIV infection within the brain (see Fig. 4 ; Tables 1 and 2).

HIV can cause white matter damage (Gosztonyi et al. 1994; Langford et al. 2002; Xuan et al. 2013 ) even with less severe forms of HAND (Chen et al. 2009; Leite et al. 2013; Correa et al. 2015) . Diffusion tensor magnetic resonance imaging (DTI) demonstrates white matter damage early in HAND (Ragin et al. 2004; Stubbe-Drger et al. 2012; Leite et al. 2013; Correa et al. 2015) . White matter deficits are associated with cognitive impairment, including shortfalls in memory (Ragin et al. 2005) , executive function (Correa et al. 2015) , motor speed (Wu et al. 2006; Stubbe-Drger et al. 2012) , and perhaps depression (Schmaal and van Velzen 2019). Summary of HIV-1 Tat and morphine interactive neuronal injury in striatal medium spiny neurons. Combined Tat and morphine promotes structural and functional defects in dendrites via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), N-methyl-Daspartic acid receptors (NMDAR), and MOR, causing influxes of Na + and/or Ca 2+ , compensatory increases in Na + /K + -dependent ATPase activity, and a rapid loss in ATP mobilization with an inability to extrude excess Na + via Na + /K + -ATPase caused by mitochondrial hyperpolarization. Dysregulation of [Ca 2+ ] i homeostasis by combined Tat and morphine appears to be mediated downstream of [Na + ] i at the level of calcium mobilization, which in turn appears to be regulated via ryanodine (RyR)-sensitive sites, and enhanced by morphine exposure likely via MOR-dependent stimulation of PI3-kinase and Ca 2+ mobilization via the Gβγ protein subunit. (a-b) Modified and reprinted with permission from Fitting et al. (2014a) Preclinical studies in simian immunodeficiency virus-(SIV-) infected rhesus macaques (Marcario et al. 2008 ) and HIVinfected humanized mice (Boska et al. 2014 ) support the clinical findings. Injury to oligodendrocytes (OLs) can occur very early in the disease (see review, Liu et al. 2016b ). Viral proteins, including Tat, gp120, and Nef, have been implicated in OL injury in vitro (Kimura-Kuroda et al. 1994; Bernardo et al. 1997; Radja et al. 2003; Nukuzuma et al. 2012; Zou et al. 2015) , and in animal models in vivo (Radja et al. 2003; Hauser et al. 2009; Zou et al. 2015) . Importantly, Tat has been detected in OLs in the brains of AIDS patients (Del Valle et al. 2000) .

HIV likely damages OLs through both direct and indirect actions. OLs lack CD4, and reports of OL infection by HIV are variable (Esiri et al. 1991; Albright et al. 1996; Wohlschlaeger et al. 2009 ); thus, HIV infection of OLs is unlikely a major avenue of OL or white matter damage (discussed below). Alternatively, bystander damage to OLs through the production of "virotoxins" and "cellular toxins" (Nath 1999) HIV-1 Tat directly induces damage in isolated OLs through αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-D-aspartic acid (NMDA) receptor-dependent mechanisms (Zou et al. 2015) and is also associated with abnormal Kv1.3 activity (Liu et al. 2017) . Immature OLs are preferentially targeted by Tat compared to differentiated OLs (Khurdayan et al. 2004; Hahn et al. 2012; Zou et al. 2015 Zou et al. , 2019 . While the reasons why immature OLs are more susceptible to Tat are unclear, unlike mature OLs, Tat preferentially upregulates GSK-3β signaling in undifferentiated OLs by inhibiting Ca 2+ /calmodulin-dependent protein kinase II β (CaMKIIβ) (Zou et al. 2019) .

Opioid abuse by itself can result in demyelination, leukoencephalopathy, and lesions in white matter (Offiah and Hall 2008; Eran and Barak 2009; Morales Odia et al. 2010; Bora et al. 2012; Li et al. 2013) , and the degree of myelin disruption correlates with the duration of opiate dependence (Ivers et al. 2018) . Chronic oxycodone exposure in rats causes some axonopathies and reduces the size of axonal fascicles, decreases myelin basic protein levels, and causes the accumulation of amyloid-β precursor protein (APP) (Fan et al. 2018) . Most preclinical studies have examined the effects of opioids and opioid receptor blockade on OL maturation and/or the timing of myelination Knapp et al. 1998; Stiene-Martin et al. 2001; Sanchez et al. 2008; Knapp et al. 2009; Vestal-Laborde et al. 2014) . OLs can transiently express MORs and other opioid receptor types (Knapp et al. 1998; Tryoen-Toth et al. 2000; Knapp et al. 2001; Stiene-Martin et al. 2001) . Selective MOR and possibly KOR activation can directly modulate the growth of OLs in vitro (Knapp and Hauser 1996; Knapp et al. 1998 Knapp et al. , 2001 .

Despite long-standing evidence of white matter damage early during the infection even in asymptomatic PWH (Price et al. 1988; Gray et al. 1996; Chen et al. 2009; Stubbe-Drger et al. 2012; Jensen et al. 2019) , few studies have examined how opiate exposure affects OLs and myelin in neuroHIV (Tables 1 and 2 ). Increased demyelination is reported in SIV-infected rhesus macaques chronically treated with morphine (4× daily, up to 59 weeks) (Marcario et al. 2008 ). Specifically, morphine-treated SIV macaques developed more subtle, focal, dysmyelinating lesions, with accumulations of macrophages in areas of myelin loss (Marcario et al. 2008) , as well as accompanying gliosis (Marcario et al. 2008; Rivera-Amill et al. 2010a; Bokhari et al. 2011) . Morphine exposure increased degeneration of OLs in Tat+ mice, which was accompanied by elevations in caspase-3 activation and TUNEL reactivity in OLs and reversible by naloxone or naltrexone, respectively ). Although OLs can express MOR both in vivo (Stiene- ) and in vitro ), it remains unclear the extent to which MOR activation in OLs directly mediates HIV pathogenesis.

Even though neural progenitors (Krathwohl and Kaiser 2004; Lawrence et al. 2004; Rothenaigner et al. 2007; Schwartz et al. 2007; Balinang et al. 2017) , neuroblast cell lines (Ensoli et al. 1994; Rothenaigner et al. 2007) , and/or immature astroglia (Atwood et al. 1993; Tornatore et al. 1994; Barat et al. 2018) can harbor HIV infection (reviewed by Hauser and Knapp 2014; Putatunda et al. 2019) , the degree to which they are a source of active infection or serve as a latent viral reservoir (Blankson et al. 2002; Bruner et al. 2019 ) by retaining intact proviral DNA within incipient macroglial progeny is uncertain. In fact, spurious reports of HIV-infected adult Fig. 3 Effects of HIV-1 Tat and morphine on BBB leakiness and on antiretroviral brain concentrations. After 14 days of Tat induction, there was a significant increase in the 10 kDa (Cascade Blue®) tracer leakage into the brain in Tat + placebo as compared to Tat − placebo mice (*p < 0.05) and in Tat − mouse brains upon exposure to morphine as compared to Tat − placebo mice (*p < 0.05) (a). There was a significant main effect of morphine, resulting in reduced integrity of the BBB and increased leakage of the higher molecular weight (40 kDa and 70 kDa) tracers in morphine-exposed groups as compared to the those groups (Tat + and Tat − together) not exposed to morphine (placebo) ( # p < 0.05; significant main effect of morphine) (b, c). Data represent the fold change in mean fluorescence intensity ± SEM; n = 8 Tat−/placebo, n = 6 Tat+/placebo, n = 9 Tat−/morphine, and n = 7 Tat+/morphine mice. Additionally, morphine exposure increased horseradish peroxidase (HRP) extravasation from the vasculature into the perivascular space and/or parenchyma in the striatum (d, e). HRP antigenicity was detected by indirect immunofluorescence (red) in tissue sections counterstained with Hoechst 33342 (blue) to reveal cell nuclei and visualized by differential interference contrast (DIC)-enhanced confocal microscopy. HRP extravasation into the striatal perivascular space/ parenchyma was especially prevalent in morphine-exposed mice (arrowheads; left-hand panels in e versus d). The dotted lines (············) indicate the approximate edge of the capillaries/post-capillary venules; while intermittent dotted lines (· · · · · · ·) indicate the approximate edge of a partly sectioned blood vessel that appears partially outside the plane of section. The asterisks (*) indicate white matter tracts within the striatum. Representative samples from ≥ n = 4 mice per group. All images are the same magnification. Scale bar = 10 μm. Antiretroviral tissue-to-plasma ratios in striatum (f-g). Irrespective of Tat exposure, morphine significantly reduced the levels of dolutegravir (f) and abacavir (g), but not lamivudine (h), within the striatum, as compared to placebo. (* p < 0.05; main effect for morphine). Data represent the tissue-to-plasma ratios ± SEM sampled from n = 9 Tat−/placebo, n = 9 Tat+/placebo, n = 6 Tat−/morphine, and n = 8 Tat+/morphine mice. (a-h) Modified and reprinted with permission from Leibrand et al. (2019) neurons (Torres-Munoz et al. 2001; Canto-Nogues et al. 2005 ) may result from the retention of proviral genes that integrated into pluripotent neural progenitors or neuroblasts at earlier stages during maturation. Importantly, prolonged exposure to opioids can increase the production of HIV in human neural progenitor cells (hNPCs). Exposure of R5tropic HIV BaL -infected hNPCs to morphine continuously for 21 d increased viral production compared to HIV BaL infection alone in vitro (Balinang et al. 2017) .

Besides being able to infect hNPCs, HIV may also affect their maturation and the fate of neural stem cells. That HIV or gp120 can inhibit adult neurogenesis (Okamoto et al. 2007; Lee et al. 2013; Putatunda et al. 2018) has been the topic of past reviews (Schwartz and Major 2006; Venkatesan et al. 2007; Peng et al. 2008 Peng et al. , 2011 Ferrell and Giunta 2014; Hauser and Knapp 2014; Putatunda et al. 2019 ). How HIV inhibits the self-renewal, tripotential differentiation, and survival of neural progenitors/stem cells or the genesis of adult neurons in the subgranular zone (SGZ) of the dentate gyrus is uncertain. HIV and gp120 [via actions at the same chemokine receptor(s) (Tran and Miller 2005; Li and Ransohoff 2008) ] are proposed to modulate the adult neurogenesis via Notch (Fan et al. 2016) , by obstructing a cell cycle checkpoint via the activation MAPK-activated protein kinase 2 and Cdc25B/ C (Okamoto et al. 2007 ), or through signaling by plateletderived growth factor BB (Chao et al. 2014) or BDNF (Lee et al. 2013) . The extent that HIV regulates the genesis of neural progenitors within the subventricular zone of the developing CNS through similar mechanisms as in the adult SGZ of the dentate gyrus is uncertain-even though HIV disrupts the generation of neurons and glia during maturation or in adults. For example, MAPK/ERK1/2 enhances p53-and p21-dependent downregulation of cyclin D1 hindering progression through the G 1 phase of the cell cycle in hNPCs (Mishra et al. 2010; Malik et al. 2014) . Importantly, opioids too can affect the genesis of neurons and glia during maturation or in the adult directly via convergent pathways Kibaly et al. 2018 ) suggesting yet another site of opioid and HIV interactions in dysregulating the creation and fate of new neurons and glia.

Few studies have examined the interplay between opioids, neural progenitors and HIV/HIV proteins. Sustained exposure (4 d) to morphine (500 nM) and Tat 1-72 (100 nM) decreased the viability of MOR-expressing striatal glial precursors, and to a lesser extent astrocytes, and this coincided with caspase-3 activation (Khurdayan et al. 2004) . By contrast, comparably administered morphine or Tat alone was sufficient to decrease the viability of immature glia/glial progenitors in spinal cord cultures, while Tat and morphine failed to interact ). Collectively, these findings were the first to indicate that opioid and/or Tat could enhance programmed cell death in subpopulations of glial precursors in a developmentally regulated and region-dependent manner (Khurdayan et al. 2004; Buch et al. 2007 ). In human glial progenitors, co- Fig. 4 Schematic representation of the blood-brain barrier and other components of the neurovascular unit. Under normal conditions (represented above the dotted line), tight junctions are intact which restricts the leakage of paracellular, typically small hydrophilic, compounds, across the barrier and into the brain. Additionally, there is a basal expression of efflux transporters, such as P-glycoprotein (P-gp), which effluxes substrates out of the brain, serving to restrict overall accumulation within the brain. In the setting of HIV and opiate exposure (represented below the dotted line), there is a breakdown of the tight junction proteins and increased leakage of paracellular compounds into the brain. Additionally, opiate exposure increases efflux transporter expression, including P-gp and potentially breast cancer resistance protein (Bcrp), thereby restricting overall brain penetration of drugs (like many antiretroviral drugs) which are substrates for these transporters and in response to HIV and/or opioid exposure.

administering morphine (500 nM) increased the antiproliferative effects of Tat (12-48 h) or conditioned medium from HIV-1 SF162 -infected MDMs (12 h), while paradoxically reversing the antiproliferative effects from HIV-1 IIIB conditioned medium (12 h) (Hahn et al. 2012) . In these studies, Tat or HIV exposure reduced the proliferation of Sox2+ and Olig2+ undifferentiated glial and oligodendroglial progenitors, respectively, while progenitor viability was unchanged (Hahn et al. 2012) . In human neural progenitor cells (hNPCs), sustained infection with R5-tropic HIV BaL increased the proliferation and premature differentiation of hNPCs into both neurons and astrocytes, and both measures were significantly enhanced by morphine co-exposure (Balinang et al. 2017) . Importantly, immunoneutralizing antibodies (Hahn et al. 2012) or the selective antagonist, maraviroc (Balinang et al. 2017) , were able to significantly attenuate the consequences of R5-tropic HIV infection on hNPC differentiation and fate confirming a direct role of CCR5 in these processes. Lastly, decreases in the proliferation of hNPCs seen with morphine and Tat are, in part, regulated by ERK1/2-dependent increases in p53 and p21 expression (Malik et al. 2014 ) and can be modulated by PDGF BB suggesting a possible therapeutic target (Malik et al. 2011) . Thus, morphine can exaggerate R5-tropic HIV-induced alterations in the maturation and fate of human and rodent NPCs, thereby further disrupting the balance of neural cell types and CNS function.

The interplay of complex host and viral genetic differences is likely to play a huge role in determining pathologic outcomes in PWH. For example, differences in HIV strains/variants (Rao et al. 2013 ) and human/host genetic variability (Proudnikov et al. 2012) , pharmacokinetics (Kuhlman et al. 1996; Eap et al. 2002; Elkader and Sproule 2005; Kharasch 2017; Kringen et al. 2017) , and sex (Zubieta et al. 2002; Taylor and Davies 2010; Venuto et al. 2014; Marinho et al. 2019 ) all contribute to variability in responsiveness. The following subsections will focus on key factors affecting opioid and HIV comorbidity.

Genetic differences among HIV-1 variants have a significant impact on HIV transmission, disease progression, as well as the response to ARV therapy (see reviews, Geretti 2006; Taylor et al. 2008; Tyor et al. 2013 ; Tables 1 and 2). Pre-cART studies provide substantial evidence that HIV clade differences can influence HAND (Gupta et al. 2007; Sacktor et al. 2009; Boivin et al. 2010; McArthur et al. 2010; Rao et al. 2013) , with HAND severity being highest for clade D and B strains, followed by C and A clades . These findings are supported by preclinical studies in which clade B or clade C HIV-infected macrophages were intracranially injected into severe combined immunodeficient mice (SCID) mice. Exposure to clade B isolates induced more severe memory deficits, as well as greater astrogliosis and neuronal damage (Rao et al. 2008 (Rao et al. , 2013 . In another example, the Tat dicysteine motif (CC) at positions 30 and 31, which is commonly found in clade B isolates, appears to worsen HAND (Mishra et al. 2008; Rao et al. 2013) and has been studied extensively in vitro (Ranga et al. 2004; Rao et al. 2008; Zou et al. 2011; Krishnan and Chatterjee 2015) . Clade B Tat is more intrinsically cytotoxic to primary neurons in vitro than clade C Tat Campbell et al. 2011; Zou et al. 2011) , resulting in increased proinflammatory cytokine production (e.g., IL-6 and TNF-α) (Gandhi et al. 2009 ) and monocyte recruitment/migration into the brain (Ranga et al. 2004; Rao et al. 2008) , and increased disruption of the BBB (Gandhi et al. 2010) . Similarly, the production of the inflammatory mediators prostaglandin E 2 and the thromboxane A 2 receptor by astrocytes is more significantly increased by clade B than clade C gp120 (Samikkannu et al. 2011) . Sequence and structural alterations in gp120 have been demonstrated between clades B and C (Gnanakaran et al. 2007 ) and potentially contribute to these observed differences.

When considering effects of HIV clade variants in the presence of opioids, the overall toxicity in MSNs seen with clade C Tat (30% neuronal losses) was considerably less than with clade B (70% losses) . Although clade B HIV predominates in Western countries, future clinical longitudinal studies are necessary that employ HIV clade testing in HIV-1 infected opioid users to confirm the hypothesis that opioid interactive effects on HAND pathogenesis depend on the HIV clade assessed.

Besides HIV genetic diversity, differences in HIV tropism add another level of complexity. Morphine interactions can differ significantly between X4 and R5tropic gp120 variants depending on the outcome measure (El-Hage et al. 2011b; Podhaizer et al. 2012; Balinang et al. 2017; Kim et al. 2018) . Increased infectivity in the presence of morphine was noted for the R5-tropic HIV-1 SF162 strain in a human hepatoma Huh7.5.1 cell line model, whereas the infectivity rate with the X4-tropic HIV-1 LAI/IIIB strain was unaffected by morphine (El-Hage et al. 2011b) .

To date, no clinical studies have assessed whether opioid interactions with R5-or R4-preferring HIV strains differentially impact the severity of HAND. However, the findings from preclinical studies indicate that HIV-1 strain-specific differences are critical determinants in shaping both the timing and pattern of neurotoxic interactions with opioid drugs.

Host genetic variability can be a major determinant in individual susceptibility to HIV infectivity and may influence neuroHIV progression in the context of opiate co-exposure. The importance of CCR5 for HIV infectivity and polymorphisms in this gene are well established. Individuals who are homozygous in the CCR5 gene (CCR5Δ32) are highly resistant to infection by CCR5-(R5-) tropic HIV as demonstrated by individuals heterozygous for CCR5Δ32 who display partial resistance to infection and slower disease progression (Huang et al. 1996; Liu et al. 1996; van Rij et al. 1999) . Besides CCR5, polymorphisms of other chemokine coreceptors and/or their cognate ligands have been implicated in HIV infectivity, including CCR2 (Smith et al. 1997; Kostrikis et al. 1998 ), CCL5 (Liu et al. 1999; McDermott et al. 2000) , and CXCL12 (Winkler et al. 1998 ). Authoritative reviews on other gene polymorphisms that modify HIV infectivity and disease progression have been published (Lama and Planelles 2007; Singh and Spector 2009; Chatterjee 2010; Aouizerat et al. 2011) .

Gene polymorphisms of opioid (OPRM1 and OPRK1) and non-opioid (e.g., DRD1 and DRD2) drug/neurotransmitter receptor genes are associated with altered HIV infectivity, viral loads and CD4+ cell counts (Proudnikov et al. 2012; Regan et al. 2012; Jacobs et al. 2013; Proudnikov et al. 2013; Dever et al. 2014) . Not only do MORs mediate the behavioral consequences of opiate abuse (Bond et al. 1998; Szeto et al. 2001; Ikeda et al. 2005; Kreek et al. 2005; Xu et al. 2014b ), but the ability of MOR to modulate HIV chemokine co-receptor signaling through cross desensitization or through direct molecular interactions suggest MOR may influence HIV infectivity at multiple levels. The unique ability of MOR to modulate HIV co-receptor function, prompted inquiry regarding whether variants of the OPRM1 gene (polymorphisms or splicing variants) might differentially effect HIV infectivity and/or opiate addictive behaviors. In a sample of 1031 HIV-1-infected women, 18 OPRM1 polymorphisms were significantly associated with decreases or increases in HIV infectivity and responsiveness to cART (Proudnikov et al. 2012) . Other gene polymorphisms, such as enzymes affecting drug metabolism (Meyer and Zanger 1997; Benowitz et al. 2006 ) and other neurochemical systems (Herman and Balogh 2012; Koob and Volkow 2016) can also affect drug dependence. The A118G variant of OPRM1 alters the regulation of proinflammatory cytokine secretion (i.e., TNF-α, IL-10, IFN-γ) from peripheral immune cells (Matsunaga et al. 2009 ). Overall, these findings suggest that polymorphisms in MOR ligands/ genes (OPRM1) can influence the pathophysiology of HIV-1.

Nineteen different OPRM1 spliced variants have been described in humans (Pasternak 2004 (Pasternak , 2014 Xu et al. 2014a; Lu et al. 2015) . OPRM1 alternative splicing may also influence susceptibility to HIV-1 infection . Although many variants are thought to be non-functional and fail to traffic from the endoplasmic reticulum, increasing evidence suggests they may oligomerize other G Proteincoupled receptors or bind chaperones to assist in trafficking to the plasma membrane (Samoshkin et al. 2015; Zhu et al. 2019) . Quantitative and qualitative differences in human MOR splice variant expression levels have been noted across different CNS cell types following exposure to HIV . Interestingly, an excitatory, MOR-1 K splice variant, that couples to Gα S (Gris et al. 2010 ) is preferentially expressed in human astroglia ) and has been shown to correlate with HIVE and cognitive impairment .

The ability of opiates to modulate HIV infection and HIV neuropathogenesis/disease progression may be partly due to the interactive effects seen between the opioid and chemokine receptors, specifically MOR and CCR5 or CXCR4 (Rogers and Peterson 2003; Steele et al. 2003; Szabo et al. 2003; Festa and Meucci 2012) . The potential mechanisms for this interaction can include heterologous cross-desensitization via downstream signaling (Rogers et al. 2000; Steele et al. 2002; Song et al. 2011 ) and/or potentially via direct opioid-chemokine receptor dimeric or heteromeric interactions (Suzuki et al. 2002; Chen et al. 2004; Nash and Meucci 2014) . MOR and DOR activation can heterologously desensitize CCR5 responsiveness to CCL3, CCL4, and CCL5 in monocytes (Grimm et al. 1998; Szabo et al. 2003; Chen et al. 2004) . The crossdesensitization appears to be regulated by MOR-dependent PKCζ activation and CCR5 phosphorylation and downregulation (Song et al. 2011) . Alternatively, MOR-induced downregulation of CCL2 and CCL4 mRNA reciprocally upregulates the expression of their associated receptors, CCR2b, CCR3, and CCR5 (Mahajan et al. 2005) . A previous study reported significant upregulation of CCR5 and CXCR4 expression in CD14 monocytes with [D-Ala 2 , N-MePhe 4 , Gly-ol]-enkephalin (DAMGO), a MOR ligand, exposure with enhanced replication of both X4-and R5-tropic viral strains of HIV . For CXCR4, bidirectional heterologous desensitization is less evident with MOR but has been reported for KOR, with Ca 2+ signaling experiments suggesting that cross-desensitization occurs within seconds of KOR or CXCR4 activation in a concentration-dependent manner (Finley et al. 2008) . Thus, opiates acting at different opioid receptors in the presence of HIV appear to activate chemokine receptor signaling and can contribute to the synergistic effects of HIV and opioid drug co-exposure seen in neuroHIV progression.

The ability of opiates to modulate CCR5 expression in the CNS has been demonstrated to occur in various cell types, including microglia (Bokhari et al. 2009 ), and astrocytes (Mahajan et al. 2002) . Specifically, in astrocytes MOR activation enhanced CCR5 and additional HIV-1 entry coreceptor (CCR3 and CXCR2) expression, whereas local production of HIV-1 protective chemokines (IL-8, CCL4) was inhibited (Mahajan et al. 2002) . Deletion of CCR5 significantly attenuates morphine-induced increases in astrocyte CCL2 immunoreactivity in Tat transgenic mice (El-Hage et al. 2008a) (Fig. 1) . Interestingly, the proportion of CCL2 immunoreactive macrophages/microglia in CCL5(−/−) mice after Tat and morphine co-administration still showed a significant upregulation, suggesting CCL5 regulates Tat and morphine-induced increases in CCL2 in astrocytes, but not in microglia (El-Hage et al. 2008a) (Fig. 1) .

The cell type specific interactions between CCR5 and MOR were noted when using a bivalent ligand derivative of maraviroc linked to an opioid antagonist, naltrexone, with HIV-1 entry being significantly blocked in astrocytes but not microglia (El-Hage et al. 2013) (Fig. 5) . Interestingly, maraviroc's antiviral effects are completely negated in both astrocytes and microglia when morphine is present suggesting that maraviroc , and aqueous surrounds (red) system. The green protein represents MOR and the blue protein represents CCR5, while the bivalent ligand is colored in yellow. (b) Different binding pocket (green) for the triazole moiety of the bivalent ligand yellow) at 0 ns and 6.0 ns. (c) Construction of a chemical probe that interacts with both the MOR and CCR5 receptors simultaneously. To monitor HIV-1 infection (d) astrocytes and (e) microglia were transfected with a pBlue3′LTR-luc reporter sensitive to Tat expression and luciferase activity was measured. Data indicate that maraviroc's antiviral effects are completely negated in both astrocytes and microglia when morphine is present (red bars). Interestingly, unlike maraviroc, the bivalent compound blocked HIV entry in astrocytes irrespective of morphine treatment. By contrast, the bivalent antagonist exacerbated HIV infectivity in microglia in the presence of morphine (red bars). The findings reveal fundamental differences in co-regulation of MOR and CCR5 expression in astroglia and microglia upon HIV and/or morphine exposure (see El-Hage et al. 2013) . Values are luminescence intensity ± SEM from 3 to 5 independent experiments at 18 h post-infection (*p < 0.005 vs. un-infected cells; $ p < 0.05 vs. R5 HIV-1; # p < 0.05 vs. R5 + morphine (M); ¶ p < 0.05 vs. R5 + maraviroc (MVC); § p < 0.05 vs. R5 + M + MVC; ¥ p < 0.05 vs. R5 + M + MVC + naltrexone). (a-b) Modified and reprinted with permission from Arnatt et al. (2016) . (c-e) Modified and reprinted with permission from El-Hage et al. (2013) therapy may not be effective with opiate co-exposure. Importantly, unlike maraviroc, the bivalent compound blocked HIV entry in astrocytes irrespective of morphine treatment, while exacerbating HIV infectivity in morphine co-exposed microglia and revealing fundamental differences in the regulation of MOR and CCR5 expression in these glial types. Whereas, MOR and CCR5 expression appear to be similarly regulated in astrocytes, their expression patterns in microglia appear to be inversely correlated upon HIV and/or morphine exposure, with CCR5 being expressed at much higher levels than MOR (see El-Hage et al. 2013) . The differential effects of the bivalent ligand in astrocytes compared to microglia might be due to the fact that the expression levels of MOR and CCR5 are differentially regulated by HIV in each of the cell types Yuan et al. 2013; Arnatt et al. 2016) .

The importance of CCR5 activation in glia, but not neurons, in mediating the neurotoxic effects of morphine-dependent MOR activation is further supported in a recent study demonstrating that the loss of CCR5 from glia (but not neurons) eliminated neurotoxicity due to Tat and morphine interactions (Kim et al. 2018) . Similarly, short-duration (5 d) maraviroc pretreatment also eliminated neurotoxicity and attenuated neuronal increases in [Ca 2+ ] i caused by Tat ± morphine (Kim et al. 2018) . Selectively deleting either CCR5 (Kim et al. 2018) or MOR ) from glia completely protects MSNs from morphine's ability to exacerbate Tat neurotoxicity. However, deleting CCR5 from glia only revealed a paradoxical neuroprotective effect of morphine on Tat toxicity that is mediated by opioid receptors and appears to involve alterations in BDNF processing and signaling (Kim et al. 2018) .

Enhanced Mature BDNF (mBDNF) Produced by CCR5 Deficient Glia is Neuroprotective Mature BDNF (mBDNF) activates tyrosine receptor kinase B (TrkB) and is neuroprotective, while the precursor to BDNF, pro-BDNF, binds p75 NTR and can activate cell death pathways. Based on findings of significant, reversible reductions in glially produced BDNF after exposure to HIV-infected cell supernatant ± morphine (Masvekar et al. 2014) , altered BDNF processing in lymphocytes from PWH (Avdoshina et al. 2011) , and following exposure to HIV-1 gp120 (Bachis et al. 2012) , the pro-BDNF:mBDNF ratio was analyzed in supernatants from wild-type vs. CCR5-null striatal glial cultures exposed to Tat ± morphine for 6 or 24 h (Kim et al. 2018) (Fig. 6) . CCR5-deficiency reduced this ratio by over 2-fold in cells treated with Tat and morphine after 6 h (Fig. 6) , indicating a relative increase in mBDNF that may partially protect neurons in the CCR5-deficient glial environment.

Exogenous mBDNF treatment has been found to mimic the pro-survival effect of glial CCR5 deficiency against Tat ± morphine, and its neuroprotective effects have been supported in other neurodegenerative disease models (Cai et al. 2014; Xu et al. 2018) . Collectively, the findings suggest that the loss of CCR5 may fundamentally change MOR signaling in HIVexposed glia in a BDNF-dependent manner. Thus, overall the interaction of opioid and chemokine receptors, specifically Fig. 6 Role of CCR5 and BDNF in mediating HIV-1 Tat and morphineinduced interactive cytotoxicity in striatal medium spiny neurons (MSNs). A proportion of glial fibrillary acidic protein (GFAP)immunolabeled striatal astrocytes display punctate patterns of μ-opioid receptor (MOR) (a) and CCR5 (b) (43.8 ± 2.4%) immunofluorescencewith some faint immunoreactivity extending into the cell processes; scale bars = 10 μm (a-b). HIV-1 Tat and morphine are no longer toxic to MSNs when CCR5 is deleted from glia (c-f). In C57BL/J wild-type mixed glia-MSN co-cultures, Tat is neurotoxic (*p = 0.001 vs. controls), and coexposure to morphine enhanced Tat-induced toxicity over a 72-h period (**p < 0.001 vs. controls, p < 0.05 vs. Tat) and antagonized by naloxone (c). Naloxone or morphine by themselves had no effect on neuronal survival (c). In co-cultures with CCR5-deficit glia and wild-type neurons, exposure to Tat by itself is significantly toxic (*p < 0.001 vs. controls); however, the enhanced toxicity seen with combined morphine exposure was eliminated (d). Unexpectedly, morphine co-treatment entirely abolished the toxic effects of Tat, restoring MSN survival to control levels. Pre-treatment with naloxone re-established Tat toxicity, suggesting that the paradoxical protective effects of morphine are mediated by MOR (or perhaps another opioid receptor type) (d) (see Kim et al. 2018) . The neurotoxic patterns seen in CCR5-deficient MSNs and wild-type glial co-cultures are similar to wild-type cocultures (e). Co-cultures in which MSNs and glia are both deficient in CCR5 are similar to those in which CCR5 is only deficient in glia (f). CCR5 deletion alters the expression and processing of BDNF precursor (pro-BDNF) to mature (mBDNF) by mixed-glial cultures (g). BDNF is expressed by both astroglia and microglia; mBDNF is neuroprotective, while pro-BDNF can promote programmed cell death. mBDNF and pro-BDNF levels were analyzed in conditioned media from wild-type or CCR5-deficient mixed glia treated with Tat ± morphine after 6 h or 24 h to assess pro-BDNF and mBDNF levels. The proportion of pro-BDNF/mBDNF levels was significantly higher in wild-type compared to CCR5-null glia at 24 h (lower row; g), suggesting reduced neuronal support. Although morphine significantly decreased pro-BDNF in CCR5-deficient glia at both 6 h and 24 h compared to control levels (not shown), the pro-BDNF/mBDNF ratios were unaltered (upper and lower rows; g). By contrast, combined Tat and morphine significantly decreased the pro-BDNF/mBDNF ratio at 6 h, suggesting transient protection with CCR5 deficiency that was not fully sustained at 24 h (p = 0.17) (*p < 0.05, wild-type vs. CCR5-null) (g). Exogenous mBDNF is neuroprotective against combined Tat and morphine treatment (h). Wild-type, mixed glial-MSN co-cultures were treated with mBDNF and Tat, or combined Tat and morphine (represented by dotted survival curves). Tat alone was neurotoxic (*p < 0.05), and Tat was significantly worsened by co-exposing MSNs to morphine (**p < 0.0001). The addition of mBDNF (50 ng/ml; 72 h) fully protected MSNs against combined Tat and morphine toxicity, but only tended to protect (albeit not significantly) MSNs treated with Tat alone ( # )(h). Overall, the results in c-h suggest (1) an important role for glial CCR5 in mediating HIV-1 and opiate neurotoxic interactions, (2) that CCR5 deficiency influences signaling through MOR, and (3) that CCR5 (and perhaps MOR) act via a BDNF intermediary to promote or obstruct neuronal survival (Kim et al. 2018) . (a-b) Modified and reprinted with permission from Podhaizer et al. (2012) . (c-h) Modified and reprinted from Kim et al. (2018) , which is an open access article distributed under the terms of the Creative Commons CC BY license MOR and CCR5, may alter the neuropathogenesis of HIV in a qualitatively unique manner not seen with either disorder alone.

Little is known about the effects of HIV on the endogenous opioid system and the extent to which HIV might disrupt the expression and function of opioid peptides and receptors, and vice versa. Because opiate drugs act exclusively by mimicking endogenous peptides and engaging opioid receptors, it is likely that endogenous opioids also interact with HIV to some extent to affect the pathogenesis of neuroHIV. The endogenous opioid system comprises three originally described opioid receptors, MOR, KOR, and DOR and endogenous opioid peptide-expressing genes proopiomelanocortin (POMC), prodynorphin (PDYN), and proenkephalin (PENK) (Brownstein 1993; Trescot et al. 2008; Bodnar 2010; Pasternak and Pan 2013) , as well as a fourth receptor (OPRN1) and peptide (nociceptin/orphanin FQ) family member. The endogenous opioid system has a fundamental role in pain regulation and has been implicated in the pathophysiology of various neurologic diseases (Nandhu et al. 2010; Sauriyal et al. 2011; Benarroch 2012) and in pain management (Bruehl et al. 2013) .

Postmortem clinical studies indicate the endogenous opioid system is disrupted in neuroHIV (Gelman et al. 2012; Yuferov et al. 2014) . Specifically, OPRK1 mRNA is significantly upregulated in PWH (Yuferov et al. 2014 ) and in transgenic neuroHIV rodent models (Chang et al. 2007; Fitting et al. 2010b ) potentially as a compensatory neuroprotective function in response to inflammatory processes in the presence of HIV infection (Yuferov et al. 2014) . The upregulation of mRNA coding OPRK1 is triggered by factors released by activated macrophages and glia and is supported by mechanistic studies in dorsal root ganglia (Puehler et al. 2006; Gabrilovac et al. 2012) . Since leukocytes, including macrophages, can express β-endorphin and enkephalins, it is important to consider the potential influence of leukocyte-derived endogenous opioid peptides in neuroinflammation (Rittner et al. 2001) . Granulocytes express about 10-fold higher levels of β-endorphin, a preferential MOR and lower affinity KOR endogenous ligand, than lymphocytes (Pallinger and Csaba 2008) . Increases in β-endorphin expression by peripheral blood mononuclear cells (PBMCs) (Gironi et al. 2000; Gironi et al. 2003) , coincide with inflammation and relapse in multiple sclerosis. Moreover, increases in inflammatory cytokines, such as interleukin-1β (IL-1β), have been demonstrated to differentially increase the expression of proenkephalin transcripts in primary astrocytes cultured from different brain regions (Ruzicka and Akil 1997) and increase IL-10-stimulated β-endorphin expression in cultured primary microglia (Wu et al. 2017) . Interestingly, OPRM1 mRNA levels do not differ between HIV+ and HIV− subjects (Yuferov et al. 2014) .

PENK was downregulated in brain samples from 446 PWH compared to 67 HIV negative patients (Gelman et al. 2012 ). The subjects with HIV also expressed higher levels of interferon regulatory factor 1 (IRF1) transcripts. The idea that higher opioid peptide expression levels are neuroprotective has been supported in human studies and experimental animal models (Solbrig and Koob 2004; Sarkisyan et al. 2015; Nam et al. 2019) suggesting the reductions in PENK expression are deleterious.

The effects of HIV Tat on expression levels of opioid peptide and receptor levels depend on the individual CNS region involved as well as levels of tat transgene expression (Fitting et al. 2010b) . For example, while PDYN mRNA levels were significantly reduced in the hippocampus and striatum of Tatexpressing mice, POMC was only significantly reduced by Tat induction in the striatum and PENK mRNA levels in the hippocampus were affected by chronic (but not acute) Tat exposure (Fitting et al. 2010b ). Thus, HIV may alter the endogenous opioid system by modifying the expression of opioid peptides and their receptors in a brain-and cell-type specific manner. The consequences of HIV-1-dependent alterations in the endogenous opioid system to HAND are uncertain.

Modeling the Pharmacology of Opioid Self-Administration Opiate self-administration as seen with addiction can have different CNS consequences than "steady-state" (e.g., continuous via a pump or time-release drug implant) exposure to the same drug (Kreek 1987 (Kreek , 2001 Kreek et al. 2002) , and we predict the pharmacokinetic differences in opiate exposure will markedly impact neuroHIV progression. Differential effects based on "on-off" and "steady-state" drug administration schedules have been reported for the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, the endogenous opioid system, and the dopamine system (Kreek 1973; Kreek et al. 2002; George et al. 2012) . Acute opiate exposure typically activates the HPA axis, corticotropin releasing factor, and peripheral steroidogenesis in a species-dependent manner (Koob and Kreek 2007; Cleck and Blendy 2008) . Alternatively, chronic self-administration of short-acting opiates suppresses diurnal cortisol rhythmicity (Facchinetti et al. 1984; Vuong et al. 2010) , while opiate withdrawal typically evokes HPA activation (Culpepper- Morgan and Kreek 1997; Kreek 2007; Paris et al. 2020) . The daily, repeated bouts of relative withdrawal seen with opiate addiction cause sustained HPA activation, stress (Koob and Kreek 2007; Koob 2020) , and immune suppression (Eisenstein 2019) . Importantly, maintenance therapy with the long-acting drug methadone achieves steady-dose opiate levels and normalization of the HPA axis (Kreek 1973) . Further, it is known that HIV infection significantly alters the HPA axis, due to CNS toxicity and cytokine production (Costa et al. 2000; George and Bhangoo 2013; Chrousos and Zapanti 2014) .

Additionally, the nature of opiate exposure in the context of neuroHIV needs to be considered as it may induce different outcomes on neurotransmitter metabolism and gene expression. Specifically, the NAc shell demonstrates molecular and structural changes associated with intravenous heroin self-administration (Jacobs et al. 2005) . Moreover, earlier studies have reported differential alterations in the turnover rates of various neurotransmitters for active versus passive morphine administration, including dopamine, serotonin, γ-aminobutyric acid (GABA), acetylcholine, aspartate, and glutamate during exposure to morphine (Smith et al. 1982 (Smith et al. , 1984 . The disruptions were noticed specifically in brain regions involved in reinforcement processes, including the NAc, frontal cortex, and striatum, and encompassed increased dopamine and norepinephrine levels and turnover, which are central in opiate reward processes (Smith et al. 1982) . Heroin abuse is known to downregulate dopaminergic activity in the NAc and may reflect a compensatory reduction in of dopamine biosynthesis in response to excessive dopaminergic stimulation resulting from chronic opiate exposure (Kish et al. 2001) . Additionally, HIV is known to interfere with dopamine neurotransmission (Nath et al. 2000b; Gaskill et al. 2017) causing reductions in presynaptic dopamine terminals and dopamine transport in the striatum (Wang et al. 2004; Chang et al. 2008; Midde et al. 2012 Midde et al. , 2015 . The decline in dopamine function may exacerbate opioid abuse tendencies and drug-seeking behaviors as the rewarding effects of opioids are discounted by neuroHIV.

Although morphine, methadone, and buprenorphine all activate MOR, each can impart different signals through MOR, related to the nature and timing of their coupling to Gα, Gβγ, β-arrestin and/or regulators of G protein signaling (RGS), since each downstream effector couples into unique cell functions. Functional selectivity occurs at each opioid receptor type, and for most endogenous opioid peptides at all three receptor types (Gomes et al. 2020) . Moreover, opioid receptors can be expressed on a subset of virtually every cell type in the CNS-with second messenger coupling to each opioid receptor type potentially being unique, cell-type specific, and context dependent. Thus, the "pluridimensional" (Galandrin and Bouvier 2006; Kenakin 2011; Costa-Neto et al. 2016 ) actions of any opiate at MOR are sufficiently complicated that it is not possible to predict whether, e.g., morphine, methadone or buprenorphine, would similarly effect any aspect of neuroHIV pathology without empirical testing. Despite their significant use as medication-assisted therapies for treating opioid addiction, few studies have directly compared commonly used opiate substitution therapies (Bell and Strang 2020) , especially in relation to HIV (Khalsa et al. 2006; Choi et al. 2020) .

Opioid substitution therapies significantly reduce the frequency of injection drug use (Kwiatkowski and Booth 2001; Pettes et al. 2010) , decrease HIV transmission risk (MacArthur et al. 2012; Platt et al. 2016) , and reduce drug-related mortality (Mathers et al. 2013 ) and the risk of opioid overdose (Volkow et al. 2014 ). Further, improved ARV outcomes among PWH have been reported with opioid substitution therapies, including the uptake and retention on ARV, medication adherence rates, and viral suppression (Low et al. 2016; Mukandavire et al. 2017 ). The two main medications used for opioid substitution therapy include methadone, a MOR full agonist, and buprenorphine, a MOR partial agonist and partial antagonist of KOR (Noble and Marie 2018) . In comparison to methadone, buprenorphine has been shown to have fewer pharmacodynamic interactions with ARVs and causes less opioid withdrawal symptoms potentially due to its partial agonism on MOR, but also due to its high affinity and long duration of MOR binding (Walsh et al. 1994; McCance-Katz 2005; Whelan and Remski 2012) . Further, differential proinflammatory and neurotoxic effects have been noted for various opioid treatments (Boland et al. 2014; Fitting et al. 2014b; Carvallo et al. 2015; Dutta and Roy 2015) . In primary astrocytes, agonist-selective actions at MOR and KOR can be clearly demonstrated (Bohn et al. 2000; Belcheva et al. 2003; McLennan et al. 2008; Hahn et al. 2010) , and we found that morphine, methadone, and buprenorphine differentially increase ROS and [Ca 2+ ] i alone or following Tat co-exposure (Fitting et al. 2014b) . Morphine can enhance HIV-1-induced production of cytokines and specifically chemokines (El-Hage et al. 2008a; Dave 2012; El-Hage et al. 2014) , while other opioids including methadone, oxycodone, buprenorphine, and DAMGO can decrease inflammatory function and decrease monocyte migration (Boland et al. 2014; Carvallo et al. 2015; Jaureguiberry-Bravo et al. 2016; Chilunda et al. 2019) .

As most opiate drugs preferentially act via MOR, a potential explanation for differential interactive effects of opioids in the context of neuroHIV is the phenomenon of selective or "biased agonism", such that different agonists can trigger distinct signaling events at the same receptor . For example, coupling of MOR to Gα, Gβγ, and/or β-arrestin have been noted to differ depending on the MOR agonists involved (McPherson et al. 2010; Thompson et al. 2015; Burgueno et al. 2017) . Physiologic outcomes of MOR activation in any cell type are determined by a bias for specific signaling pathways, the initial step of which is activation of G proteins and/or βarrestin (Williams et al. 2013b; Violin et al. 2014; Suomivuori et al. 2020) . The subcellular organization of GPCR signaling transduced by heterotrimeric G proteins and β-arrestin has been recently reviewed in detail (Eichel and von Zastrow 2018) .

In the context of HIV, it has been shown that selective MOR agonists such as endomorphin-1, but not DAMGO or morphine, significantly increase HIV-1 replication in infected microglia (Peterson et al. 1999 ). This effect might be due to an apparent bias of endomorphin-1 towards arrestin recruitment and receptor phosphorylation, which was significantly correlated with agonist-induced internalization of MOR (McPherson et al. 2010) . It is suggested that ligands that display bias towards G protein-mediated pathways and away from β-arrestin 2 recruitment may have improved therapeutic profiles against the development of tolerance and dependence/addiction (McPherson et al. 2010 ).

Opioid misuse has been linked to poor adherence to cART (Jeevanjee et al. 2014 ). However, adherence to ARV therapy improves after initiation of opioid substitution therapy (Nosyk et al. 2015; Low et al. 2016; Adams et al. 2020) . Although better adherence can improve therapeutic outcomes in PWH, little information is currently available on the interaction between opioids or opioid substitution therapies and cART specifically within the CNS.

There are several known drug-drug interactions between opioids and ARVs that affect systemic concentrations. The partial opioid agonist, buprenorphine, is metabolized primarily by cytochrome P450 (CYP) 3A4 and 2C8. Both buprenorphine and its active metabolite, norbuprenorphine, are glucuronidated by UDP-glucuronosyltransferase (UGT) 1A1 and then excreted in bile. Several ARVs inhibit or induce these metabolic pathways. However, not all interactions are clinically relevant. The boosted protease inhibitor combination, atazanavir/ritonavir, inhibits CYP 3A4 and UGT 1A1, leading to increases in overall systemic exposure of buprenorphine and norbuprenorphine and also results in symptoms of opioid excess, such as increased sedation and impaired cognition (McCance-Katz et al. 2007 ). Dose adjustments of buprenorphine are recommended when initiating therapy with atazanavir to avoid symptoms of opioid excess. Methadone is a full opioid substrate with multiple metabolic pathways, including CYP 3A4, 2B6, 2C19, 2C9, and 2D6. Several pharmacokinetic interactions are reported between methadone and protease inhibitors. However, withdrawal symptoms are rare, and therefore, dose adjustments are not recommended (Bruce et al. 2006; Meemken et al. 2015) . In contrast, efavirenz and nevirapine induce CYP 3A4, resulting in decreased systemic concentrations of methadone and the development of opioid withdrawal symptoms. To avoid opioid withdrawal, increased methadone dosing is recommended when either efavirenz or nevirapine therapy is initiated (Marzolini et al. 2000; Clarke et al. 2001; Meemken et al. 2015) . Oxycodone metabolism is inhibited by lopinavir/ritonavir, increasing oxycodone concentrations as well as the self-reported drug effects (Nieminen et al. 2010; Feng et al. 2017 ).

The pharmacokinetic studies above focused on overall systemic exposure of drugs. Plasma concentrations, however, are not always accurate indicators of tissue exposure. Similarly, CNS drug exposure is often estimated based on drug concentrations within the CSF. However, CSF drug levels may not accurately predict brain concentrations. For many drugs with high efflux activities (e.g., substrates of P-gp), CSF tends to overpredict brain tissue concentrations Friden et al. 2009; Kodaira et al. 2011 Kodaira et al. , 2014 . This could be due, in part, to differential expression of transporters at the blood-CSF barrier vs. BBB. In a study of the ARV drug amprenavir, concentrations of [ 14 C]-amprenavir in CSF versus brain were 23.3 ± 11.2 and 3.33 ± 0.6 nCi/g, respectively, demonstrating overprediction of brain concentrations by CSF (Polli et al. 1999) . These studies illustrate the high likelihood of misinterpreting drug brain penetration when using CSF as the surrogate marker. Therefore, direct measurement of brain tissue concentrations in animal models are likely to be more predictive of the interactive effects of ARVs and opioids on ARV and/or opioid brain exposure.

A few studies have investigated the impact of opioids and ARV administration on drug concentrations within the brain. One study investigated the impact of 5 d continuous exposure to morphine on ARV brain concentrations (dolutegravir, lamivudine and abacavir) and demonstrated that morphine exposure resulted in regionally specific decreases in the concentrations of select ARV drugs (Leibrand et al. 2019 ) and, furthermore, that the decreases in ARV concentrations (dolutegravir and abacavir) were likely due to increased efflux by the drug efflux transport protein, P-gp (Leibrand et al. 2019) . Morphine alterations in P-gp within the brain could have wide reaching impact on other CNS active drugs.

HIV preferentially infects microglia and perivascular macrophages within the brain, although BMECs, astrocytes, and pericytes can also be infected (Kramer-Hammerle et al. 2005) . Achieving optimal intracellular ARV concentrations are essential to suppress the infection. Few studies have examined whether ARV drugs differentially accumulate within different neural cell types and especially within cells of the neurovascular unit. Although nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are efficacious in inhibiting viral replication within monocyte-derived macrophages, only a few drugs within each ARV class can effectively inhibit viral replication within astrocytes (Gray et al. 2013) , which could be a result of poor intracellular accumulation within astrocytes. In vitro studies have demonstrated darunavir and raltegravir intracellular concentrations to be approximately 100-fold lower (with higher EC 50 values) in microglia than in PBMCs (Asahchop et al. 2017) .

Another study measured intracellular concentrations of dolutegravir, tenofovir and emtricitabine in primary human astrocytes, microglia, pericytes and BMECs (Patel et al. 2019) . Intracellular ARV concentrations were typically significantly higher in BMECs than in the other brain cell types.

Dolutegravir achieved the highest relative concentrations within each cell type, whereas tenofovir accumulated the least (Patel et al. 2019) . Furthermore, 24 h treatment with morphine significantly decreased intracellular accumulation of composite ARV concentrations, but only in astrocytes. In contrast, morphine exposure significantly increased the net accumulation of drugs within BMECs compared to controls. BMECs may sequester ARV drugs as a protective mechanism (Patel et al. 2019) .

Using experimental data from SIV-infected, morphineaddicted macaques, mathematical modeling suggests that morphine exposure increases the proportion of cells with high susceptibility to SIV infection, at least in part, because of increased co-receptor expression (Vaidya et al. 2016 ). In addition to promoting a higher steady state viral loads and larger CD4 count declines, the model also predicts that morphine exposure results in the need for more efficacious ARV treatment than would be necessary for animals not exposed to morphine (Vaidya et al. 2016) . Although the direct impact of morphine on ARV concentrations was not investigated, the study provides evidence supporting morphine's negative impact on ARV efficacy. 

Conflict of Interest The authors declare that they have no conflict of interest.

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Association between diagnoses of chronic noncancer pain, substance use disorder, and HIV-related outcomes in people living with HIV

Differential expression and HIV-1 regulation of μ-opioid receptor splice variants across human central nervous system cell types

Differential expression of the alternatively spliced OPRM1 isoform μ-opioid receptor-1K in HIV-infected individuals

Three-dimensional imaging of HIV-1 virological synapses reveals membrane architectures involved in virus transmission

Neuroimmunomodulation by opiates and other drugs of abuse: relationship to HIV infection and AIDS

Opiates as potential cofactors in progression of HIV-1 infections to AIDS

Effects of cocaine and other drugs of abuse on immune function

CD4 cell recovery during successful antiretroviral therapy in naive HIV-infected patients: the role of intravenous drug use

Prescription opioids and risk of dementia or cognitive decline: a prospective cohort study

Effects of chronic expression of the HIVinduced protein, transactivator of transcription, on circadian activity rhythms in mice, with or without morphine

Mechanism(s) involved in opioid drug abuse modulation of HAND

Chronic morphine and HIV-1 Tat promote differential central nervous system trafficking of CD3+ and Ly6C+ immune cells in a murine Streptococcus pneumoniae infection model

Morphine modulation of toll-like receptors in microglial cells potentiates neuropathogenesis in a HIV-1 model of coinfection with pneumococcal pneumoniae

Histo-and immunocytochemical detection of inducible NOS and TNF-α in the locus coeruleus of human opiate addicts

Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence

Subcellular organization of GPCR signaling

The role of opioid receptors in immune system function

Synergistic increases in intracellular Ca 2+ , and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1

CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines

CCL5/ RANTES gene deletion attenuates opioid-induced increases in glial CCL2/MCP-1 immunoreactivity and activation in HIV-1 Tat-exposed mice

Morphine exacerbates HIV-1 Tat-induced cytokine production in astrocytes through convergent effects on [Ca 2+ ] , NF-κB trafficking and transcription

Toll-like receptor expression and activation in astroglia: differential regulation by HIV-1 Tat, gp120, and morphine

HIV-1 coinfection and morphine coexposure severely dysregulate hepatitis C virus-induced hepatic proinflammatory cytokine release and free radical production: increased pathogenesis coincides with uncoordinated host defenses

A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-μ-opioid receptor interactions between human astroglia and microglia

Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine

Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence

HIV-1 gene expression and replication in neuronal and glial cell lines with immature phenotype: effects of nerve growth factor

Posterior reversible encephalopathy syndrome after combined general and spinal anesthesia with intrathecal morphine

Delta and kappa opiate receptors in primary astroglial cultures. Part II: receptor sets in cultures from various brain regions and interactions with beta-receptor activated cyclic AMP

Profile of executive and memory function associated with amphetamine and opiate dependence

The cognitive effects of opioids

Fate of oligodendrocytes in HIV-1 infection

Human immunodeficiency virus infection of human astrocytes disrupts bloodbrain barrier integrity by a gap junction-dependent mechanism

Evaluation -Institute for Health Metrics and Evaluation (2017) Global burden of disease study. Global Health Data Exchange

Impaired circadian rhythmicity of beta-lipotrophin, betaendorphin and ACTH in heroin addicts

Opiates as immunosuppressive and genotoxic agents

HIV tat impairs neurogenesis through functioning as a notch ligand and activation of notch signaling pathway

Chronic oxycodone induces axonal degeneration in rat brain

Ending the HIV epidemic: a plan for the United States

Opioid analgesics-related pharmacokinetic drug interactions: from the perspectives of evidence based on randomized controlled trials and clinical risk management

The impact of HIV-1 on neurogenesis: implications for HAND. Cellular and molecular life sciences

Effects of opiates and HIV proteins on neurons: the role of ferritin heavy chain and a potential for synergism

Protease inhibitors, saquinavir and darunavir, inhibit oligodendrocyte maturation: Implications for Lysosomal Stress

Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the κ-opioid receptor

CNS invasion by CD14+/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection

Regional heterogeneity and diversity in cytokine and chemokine production by astroglia: differential responses to HIV-1 Tat, gp120, and morphine revealed by multiplex analysis

Interactive comorbidity between opioid drug abuse and HIV-1 Tat: chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons

Morphine efficacy is altered in conditional HIV-1 Tat transgenic mice

Interactive HIV-1 Tat and morphine-induced synaptodendritic injury is triggered through focal disruptions in Na + influx, mitochondrial instability, and Ca 2+ overload

Opiate addiction therapies and HIV-1 Tat: interactive effects on glial [Ca 2+ ] i oxyradical and neuroinflammatory chemokine production and correlative neurotoxicity

Morphine tolerance and physical dependence are altered in conditional HIV-1 Tat transgenic mice

Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids

Microglial activation involved in morphine tolerance is not mediated by tolllike receptor 4

IFN-γ up-regulates κ opioid receptors (KOR) on murine macrophage cell line J774

Distinct signaling profiles of β1 and β2 adrenergic receptor ligands toward adenylyl cyclase and mitogenactivated protein kinase reveals the pluridimensionality of efficacy

HIV, opiates, and enteric neuron dysfunction. Neurogastroenterology and motility : the official journal of the

Differential effects of HIV type 1 clade B and clade C Tat protein on expression of proinflammatory and antiinflammatory cytokines by primary monocytes

HIV, Tat and dopamine transmission

Interactive role of human immunodeficiency virus type 1 (HIV-1) clade-specific Tat protein and cocaine in blood-brain barrier dysfunction: Implications for HIV-1-associated neurocognitive disorder

Kappa-opioid receptor ligands inhibit cocaine-induced HIV-1 expression in microglial cells

Prefrontal dopaminergic and enkephalinergic synaptic accommodation in HIV-associated neurocognitive disorders and encephalitis

Human immune deficiency virus (HIV) infection and the hypothalamic pituitary adrenal axis

Allostasis and addiction: role of the dopamine and corticotropin-releasing factor systems

HIV-1 subtypes: epidemiology and significance for HIV management

Hypoxicischemic leukoencephalopathy in man

) β-endorphin concentrations in peripheral blood mononuclear cells of patients with multiple sclerosis: effects of treatment with interferon beta

) β endorphin concentrations in PBMC of patients with different clinical phenotypes of multiple sclerosis

Clade-specific differences between human immunodeficiency virus type 1 clades B and C: diversity and correlations in C3-V4 regions of gp120

Biased signaling by endogenous opioid peptides

CCR5 mediates HIV-1 Tatinduced neuroinflammation and influences morphine tolerance, dependence, and reward

Astrocyte infection by HIV-1: mechanisms of restricted virus replication, and role in the pathogenesis of HIV-1-associated dementia

Neuropathologic analysis of postmortal brain samples of HIV-seropositive and -seronegative i.v. drug addicts

Human immunodeficiency virus (HIV) distribution in HIV encephalitis: study of 19 cases with combined use of in situ hybridization and immunocytochemistry

Neuropathology of early HIV-1 infection

The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes

Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization

A novel alternatively spliced isoform of the mu-opioid receptor: functional antagonism

Neuropsychological consequences of opiate use

Morphine enhances HIV infection of human blood mononuclear phagocytes through modulation of β-chemokines and CCR5 receptor

Effects of vitamin a deficiency and opioids on parvalbumin + interneurons in the hippocampus of the HIV-1 transgenic rat

Neuropsychological deficits in human immunodeficiency virus type 1 clade C-seropositive adults from South India

HIV-Tat elicits microglial glutamate release: role of NAPDH oxidase and the cystine-glutamate antiporter

) κ-opioid receptor expression defines a phenotypically distinct subpopulation of astroglia: relationship to Ca 2+ mobilization, development, and the antiproliferative effect of opioids

Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro

Mu and kappa opioids modulate mouse embryonic stem cell-derived neural progenitor differentiation via MAP kinases

HIV-1 alters neural and glial progenitor cell dynamics in the central nervous system: coordinated response to opiates during maturation

Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered μopioid receptor-mediated G-protein activation and β-arrestin 2 activity in the forebrain

Interactions of HIV and drugs of abuse: the importance of glia, neural progenitors, and host genetic factors

Opiate drugs with abuse liability hijack the endogenous opioid system to disrupt neuronal and glial maturation in the central nervous system

Cellular localization of proenkephalin mRNA and enkephalin peptide products in cultured astrocytes

Endogenous opioid systems and the growth of oligodendrocyte progenitors: paradoxical increases in oligodendrogenesis as an indirect mechanism of opioid action

Godleske CC (1996) μ-Opioid receptor-induced Ca 2+ mobilization and astroglial development: morphine inhibits DNA synthesis and stimulates cellular hypertrophy through a Ca 2+ -dependent mechanism

Molecular targets of opiate drug abuse in neuroAIDS

HIV-1 neuropathogenesis: glial mechanisms revealed through substance abuse

HIV-1 tat and morphine have interactive effects on oligodendrocyte survival and morphology

Opiate drug use and the pathophysiology of neuroAIDS

Polymorphisms of the serotonin transporter and receptor genes: susceptibility to substance abuse

Methylnaltrexone antagonizes opioid-mediated enhancement of HIV infection of human blood mononuclear phagocytes

Immunomodulatory properties of kappa opioids and synthetic cannabinoids in HIV-1 neuropathogenesis

Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction

The role of a mutant CCR5 allele in HIV-1 transmission and disease progression

Minocycline suppresses morphineinduced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia

Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast)

Evidence that opioids may have toll-like receptor 4 and MD-2 effects

Opioid activation of toll-like receptor 4 contributes to drug reinforcement

How individual sensitivity to opiates can be predicted by gene analyses

Opioid rotation in the management of refractory cancer pain

Progressive white matter impairment as a predictor of outcome in a cohort of opioiddependent patient's post-detoxification

Long-term gene expression in the nucleus accumbens following heroin administration is subregion-specific and depends on the nature of drug administration

HIVrelated cognitive impairment shows bi-directional association with dopamine receptor DRD1 and DRD2 polymorphisms in substancedependent and substance-independent populations

Brain-associated autoimmune features in heroin addicts: correlation to HIV infection and dementia

Opioids and opioid maintenance therapies: their impact on monocyte-mediated HIV Neuropathogenesis

Opioid analgesic misuse is associated with incomplete antiretroviral adherence in a cohort of HIV-infected indigent adults in San Francisco

Altered oligodendrocyte maturation and myelin maintenance: the role of Antiretrovirals in HIV-associated neurocognitive disorders

White matter loss and oligodendrocyte dysfunction in HIV: a consequence of the infection, the antiretroviral therapy or both

Signaling pathways in reactive astrocytes, a genetic perspective

Functional selectivity and biased receptor signaling

Buprenorphine and HIV primary care: new opportunities for integrated treatment

Current concepts in methadone metabolism and transport

Opioid use disorder and COVID-19: crashing of the crises

Preferential vulnerability of astroglia and glial precursors to combined opioid and HIV-1 Tat exposure in vitro

Non-nociceptive roles of opioids in the CNS: opioids' effects on neurogenesis, learning, memory and affect

Exploring the opioid system by gene knockout

A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates

Inhibition of myelin formation by HIV-1 gp120 in rat cerebral cortex culture

Striatal dopaminergic and serotonergic markers in human heroin users

) μ-Opioid receptor activation enhances DNA synthesis in immature oligodendrocytes

Endogenous opioid system in developing normal and jimpy oligodendrocytes: μ and κ opioid receptors mediate differential mitogenic and growth responses

Endogenous opioids and oligodendroglial function: possible autocrine/paracrine effects on cell survival and development

Cell-specific loss of κ-opioid receptors in oligodendrocytes of the dysmyelinating jimpy mouse

Macrophages but not Astrocytes Harbor HIV DNA in the brains of HIV-1-infected Aviremic individuals on suppressive antiretroviral therapy

Quantitative evaluation of the impact of active efflux by P-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate

Quantitative investigation of the brain-to-cerebrospinal fluid unbound drug concentration ratio under steady-state conditions in rats using a pharmacokinetic model and scaling factors for active efflux transporters

The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction

Neurobiology of opioid addiction: opponent process, Hyperkatifeia, and negative reinforcement

Stress, dysregulation of drug reward pathways, and the transition to drug dependence

Neurobiology of addiction: a neurocircuitry analysis

A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation

Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions

Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus

HIV-1 promotes quiescence in human neural progenitor cells

Medical safety and side effects of methadone in tolerant individuals

Tolerance and dependence: implications for the pharmacological treatment of addiction

Drug addictions. Molecular and cellular endpoints

Opioids, dopamine, stress, and the addictions

Pharmacotherapy of addictions

Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments

Combined effect of CYP2B6 genotype and other candidate genes on a steady-state serum concentration of methadone in opioid maintenance treatment

Differential immune mechanism to HIV-1 Tat variants and its regulation by AEA

Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine

Chronic morphine exposure causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques

Methadone maintenance as HIV risk reduction with street-recruited injecting drug users

Glial and neuroimmune mechanisms as critical modulators of drug use and abuse

Host factors influencing susceptibility to HIV infection and AIDS progression

Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy

Critical role of Beclin1 in HIV Tat and morphine-induced inflammation and calcium release in glial cells from autophagy deficient mouse

The panorama of opioid-related cognitive dysfunction in patients with cancer: a critical literature appraisal

Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells

Impaired neurogenesis and neurite outgrowth in an HIV-gp120 transgenic model is reversed by exercise via BDNF production and Cdk5 regulation

HIV-1 tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice

HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood-brain barrier integrity

Diffusion tensor MRI evaluation of the corona radiata, cingulate gyri, and corpus callosum in HIV patients

Opioid misuse among HIV-positive adults in medical care: results from the medical monitoring project

Gβγ stimulates phosphoinositide 3-kinase-γ by direct interaction with two domains of the catalytic p110 subunit

Optimizing medication treatment of opioid use disorder during COVID-19 (SARS-CoV-2)

Opioid injection in rural areas of the United States: a potential obstacle to ending the HIV epidemic

HIV prevention with drug using populations. Current status and future prospects

Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology

NMDA receptor activation by HIV-Tat protein is clade dependent

White matter impairment in chronic heroin dependence: a quantitative DTI study

Cell-tocell contact facilitates HIV transmission from lymphocytes to astrocytes via CXCR4

Methadone-induced damage to white matter integrity in methadone maintenance patients: a longitudinal self-control DTI study

Productive HIV infection in astrocytes can be established via a non-classical mechanism

Modulation of the NO/CO-cGMP signaling cascade during chronic morphine exposure in mice

Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection

Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression

CD4-independent infection of astrocytes by human immunodeficiency virus type 1: requirement for the human mannose receptor

Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration

Spinal matrix metalloproteinase-9 contributes to physical dependence on morphine in mice

Interactions of opioids and HIV infection in the pathogenesis of chronic pain

Oligodendrocyte injury and pathogenesis of HIV-1-associated neurocognitive disorders

Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K + current conducted by K V 1.3

Differential regulation of proenkephalin expression in astrocytes by cytokines

Impact of opioid substitution therapy on antiretroviral therapy outcomes: a systematic review and meta-analysis

Mediation of opioid analgesia by a truncated 6-transmembrane GPCR

Opiate substitution treatment and HIV transmission in people who inject drugs: systematic review and meta-analysis

Microglia express mu opioid receptor: insights from transcriptomics and fluorescent reporter mice

Morphine regulates gene expression of α-and β-chemokines and their receptors on astroglial cells via the opioid μ receptor

Morphine modulates chemokine gene regulation in normal human astrocytes

Tight junction regulation by morphine and HIV-1 Tat modulates blood-brain barrier permeability

A growth factor attenuates HIV-1 Tat and morphine induced damage to human neurons: implication in HIV/AIDSdrug abuse cases

Involvement of extracellular signalregulated kinase (ERK1/2)-p53-p21 axis in mediating neural stem/progenitor cell cycle arrest in co-morbid HIV-drug abuse exposure

Effect of morphine on the neuropathogenesis of SIVmac infection in Indian rhesus macaques

Effects of morphine on behavioral task performance in SIV-infected rhesus macaques

Singularities of nevirapine metabolism: from sex-dependent differences to idiosyncratic toxicity

Verbal and spatial working memory among drug-using HIVinfected men and women

Double dissociation of HIV and substance use disorder effects on neurocognitive tasks dependent on striatal integrity

Drug abuse and hepatitis C infection as comorbid features of HIV associated neurocognitive disorder: neurocognitive and neuroimaging features

Efavirenz decreases methadone blood concentrations

Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART)

Roles of the ubiquitin proteasome system in the effects of drugs of abuse

Morphine enhances HIV-1 SF162 -mediated neuron death and delays recovery of injured neurites

Mortality among people who inject drugs: a systematic review and meta-analysis

A novel Gβγ-subunit inhibitor selectively modulates μ-opioid-dependent antinociception and attenuates acute morphine-induced antinociceptive tolerance and dependence

Association of polymorphism in the human muopioid receptor OPRM1 gene with proinflammatory cytokine levels and health perception

Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence

Opioid agonist treatment and improved outcomes at each stage of the HIV treatment cascade in people who inject drugs in Ukraine

Human immunodeficiency virus-associated neurocognitive disorders: mind the gap

Treatment of opioid dependence and coinfection with HIV and hepatitis C virus in opioid-dependent patients: the importance of drug interactions between opioids and antiretroviral agents

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the multicenter

Alteration of T and null lymphocyte frequencies in the peripheral blood of human opiate addicts: in vivo evidence for opiate receptor sites on T lymphocytes

Opiate inhibition of sheep erythrocyte binding to T lymphocytes: reversal by naloxone and cyclic nucleotides

Morphine increases hippocampal viral load and suppresses frontal lobe CCL5 expression in the LP-BM5 AIDS model

Morphine-potentiated cognitive deficits correlate to suppressed hippocampal iNOS RNA expression and an absent type 1 interferon response in LP-BM5 murine AIDS

Kappa opioids promote the proliferation of astrocytes via Gβγ and β-arrestin 2-dependent MAPK-mediated pathways

Mu-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization

Drug-drug interactions with antiviral agents in people who inject drugs requiring substitution therapy

Injecting drug use is associated with a more rapid CD4 cell decline among treatment naive HIVpositive patients in Indonesia

Heroin use in Indonesia is associated with higher expression of CCR5 on CD4+ cells and lower ex-vivo production of CCR5 ligands

Disruption of gut homeostasis by opioids accelerates HIV disease progression

Molecular mechanisms of genetic polymorphisms of drug metabolism

HIV and recent illicit drug use interact to affect verbal memory in women

HIV-1 Tat protein decreases dopamine transporter cell surface expression and vesicular monoamine transporter-2 function in rat striatal synaptosomes

Mutations at tyrosine 88, lysine 92 and tyrosine 470 of human dopamine transporter result in an attenuation of HIV-1 Tatinduced inhibition of dopamine transport

Primary headaches with HIV infection

HIV-1 tat C phosphorylates VE-cadherin complex and increases human brain microvascular endothelial cell permeability

Cladespecific differences in neurotoxicity of human immunodeficiency virus-1 B and C tat of human neurons: significance of dicysteine C30C31 motif

Human immunodeficiency virus type 1 Tat modulates proliferation and differentiation of human neural precursor cells: implication in NeuroAIDS

Mu-and kappa-opioid receptors selectively reduce the same transient components of high-threshold calcium current in rat dorsal root ganglion sensory neurons

Opioids, sleep, and cancer-related fatigue

Severe leukoencephalopathy following acute oxycodone intoxication

Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human

Impact of opioid substitution therapy on the HIV prevention benefit of antiretroviral therapy for people who inject drugs

Postmortem volumetric analysis of the nucleus accumbens in male heroin addicts: implications for deep brain stimulation

Total hypothalamic volume is reduced in postmortem brains of male heroin addicts

Reduced volumes of the external and internal globus pallidus in male heroin addicts: a postmortem study

The effects of opioids on HIV Neuropathogenesis

Reduced nucleus accumbens enkephalins underlie vulnerability to social defeat stress

Opioid system functional regulation in neurological disease management

Epigenetic regulation of HIV-1 latency in astrocytes

Direct evidence of astrocytic modulation in the development of rewarding effects induced by drugs of abuse

Functions of the chemokine receptor CXCR in the central nervous system and its regulation by μ-opioid receptors

Pathobiology of human immunodeficiency virus dementia

Eradication of human immunodeficiency virus from brain reservoirs

Critical questions for neuroscientists in interactions of drugs of abuse and HIV infection

Neurotoxicity and dysfunction of dopamine systems associated with AIDS dementia

Neurotoxicity and dysfunction of dopaminergic systems associated with AIDS dementia

Molecular basis for interactions of HIV and drugs of abuse

NIDA (2020) COVID-19: Potential implications for individuals with substance use disorders. In: (Volkow ND, ed) Nora's Blog

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Management of opioid addiction with opioid substitution treatments: beyond methadone and buprenorphine

Virus replication and disease progression inversely correlate with SIV Tat evolution in morphine-dependent and SIV/SHIV-infected Indian rhesus macaques

SIV Vpr evolution is inversely related to disease progression in a morphine-dependent rhesus macaque model of AIDS

Lack of correlation between SIV-Nef evolution and rapid disease progression in morphine-dependent nonhuman primate model of AIDS

Correlation between SIV tat evolution and AIDS progression in cerebrospinal fluid of morphine-dependent and control macaques infected with SIV and SHIV

The causal effect of opioid substitution treatment on HAART medication refill adherence

Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain

In vivo and in vitro studies of opiates and cellular immunity in narcotic addicts

Exogenous human immunodeficiency virus-1 protein, Tat, enhances replication of JC virus efficiently in neuroblastoma cell lines

Neuropathology in non-human immunodeficiency virus-infected drug addicts: hypoxic brain damage after chronic intravenous drug abuse

Heroin-induced leukoencephalopathy: characterization using MRI, diffusion-weighted imaging, and MR spectroscopy

HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cell-cycle withdrawal and G1 arrest

A hormone map of human immune cells showing the presence of adrenocorticotropic hormone, triiodothyronine and endorphin in immunophenotyped white blood cells

Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: physiological allopregnanolone is protective against neurotoxic and psychomotor effects

Multiple opiate receptors: deja vu all over again

Opioids and their receptors: are we there yet?

Mu opioids and their receptors: evolution of a concept

Perspectives on the N-methyl-D-aspartate/nitric oxide cascade and opioid tolerance

Effects of HIV-1 Tat and methamphetamine on blood-brain barrier integrity and function in vitro

Cell-type specific differences in antiretroviral penetration and the effects of HIV-1 Tat and morphine among primary human brain endothelial cells, astrocytes, pericytes, and microglia

Opioids trigger α 5 β 2 integrin-mediated monocyte adhesion

Chronic SIV and morphine treatment increases heat shock protein 5 expression at the synapse

HIV-1-infected and/or immune-activated macrophage-secreted TNF-α affects human fetal cortical neural progenitor cell proliferation and differentiation

HIV-1-infected and immune-activated macrophages induce astrocytic differentiation of human cortical neural progenitor cells via the STAT3 pathway

Morphine-mediated deterioration of oxidative stress leads to rapid disease progression in SIV/SHIV-infected macaques

Interaction of SIV/SHIV infection and morphine on plasma oxidant/antioxidant balance in macaque

HIV infection linked to injection use of oxymorphone in Indiana

Morphine promotes the growth of HIV-1 in human peripheral blood mononuclear cell cocultures

Microglial cell upregulation of HIV-1 expression in the chronically infected promonocytic cell line U1: the role of tumor necrosis factor-alpha

Enhancement of HIV-1 replication by opiates and cocaine: the cytokine connection

The opioid-cytokine connection

Endomorphin-1 potentiates HIV-1 expression in human brain cell cultures: implication of an atypical mu-opioid receptor

Methadone use among HIV-positive injection drug users in a Canadian setting

Cerebral CT findings in male opioid-dependent patients: stereological, planimetric and linear measurements

Neuronal ferritin heavy chain and drug abuse affect HIVassociated cognitive dysfunction

Effectiveness of needle/syringe programmes and opiate substitution therapy in preventing HCV transmission among people who inject drugs

Opioids: immunomodulators. A proposed role in cancer and aging

Morphine and gp120 toxic interactions in striatal neurons are dependent on HIV-1 strain

Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor

The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex

Delayed postanoxic encephalopathy after heroin use

Association of polymorphisms of the mu opioid receptor gene with the severity of HIV infection and response to HIV treatment

Polymorphisms of the kappa opioid receptor and prodynorphin genes: HIV risk and HIV natural history

Interleukin-1 beta contributes to the upregulation of kappa opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation

Do opioids activate latent HIV-1 by down-regulating anti-HIV microRNAs?

Adult neurogenic deficits in HIV-1 Tg26 transgenic mice

HIV-1 and compromised adult neurogenesis: emerging evidence for a new paradigm of HAND persistence

Progressive white matter microstructure damage in male chronic heroin dependent individuals: a DTI and TBSS study

Medications and their effects on sleep

Oligodendrocytespecific expression of human immunodeficiency virus type 1 Nef in transgenic mice leads to vacuolar myelopathy and alters oligodendrocyte phenotype in vitro

Whole brain diffusion tensor imaging in HIV-associated cognitive impairment

Diffusion tensor imaging of subcortical brain injury in patients infected with human immunodeficiency virus

Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers

Tat protein of human immunodeficiency virus type 1 subtype C strains is a defective chemokine

HIV-1 cladespecific differences in the induction of neuropathogenesis

Clade C HIV-1 isolates circulating in southern Africa exhibit a greater frequency of dicysteine motif-containing tat variants than those in Southeast Asia and cause increased neurovirulence

Role of the macrophage in HIV-associated neurocognitive disorders and other comorbidities in patients on effective antiretroviral treatment

Interactive effects of morphine on HIV infection: role in HIVassociated neurocognitive disorder

Epigenetics of µ-opioid receptors: intersection with HIV-1 infection of the central nervous system

Opioid peptide-expressing leukocytes: identification, recruitment, and simultaneously increasing inhibition of inflammatory pain

Pain and the immune system

Identification and molecular characterization of SIV Vpr R50G mutation associated with long term survival in SIV-infected morphine dependent and control macaques

Variable region 4 of SIV envelope correlates with rapid disease progression in morphine-exposed macaques infected with SIV/SHIV

Morphine and rapid disease progression in nonhuman primate model of AIDS: inverse correlation between disease progression and virus evolution

Accelerated evolution of SIV env within the cerebral compartment in the setting of morphine-dependent rapid disease progression

Frontal cortex dysfunction as a target for remediation in opiate use disorder: role in cognitive dysfunction and disordered reward systems

Association of self-reported painful symptoms with clinical and neurophysiologic signs in HIV-associated sensory neuropathy

Neuropsychological impairment among asymptomatic HIVpositive former intravenous drug users

Importance of autophagy in mediating human immunodeficiency virus (HIV) and morphine-induced metabolic dysfunction and inflammation in human astrocytes

Opioid G protein-coupled receptors: signals at the crossroads of inflammation

Bidirectional heterologous desensitization of opioid and chemokine receptors

Long-term HIV-1 infection of neural progenitor populations

Consequences on infectious diseases with special reference to AIDS

Modulation of immune function by morphine: implications for susceptibility to infection

HIV-1 infection and nervous system abnormalities among a cohort of intravenous drug users

Cognitive burden of common non-antiretroviral medications in HIV-infected women

Astrocytes resist HIV-1 fusion but engulf infected macrophage material

The interleukin-1β-mediated regulation of proenkephalin and opioid receptor messenger RNA in primary astrocyte-enriched cultures

Primary astroglial cultures derived from several rat brain regions differentially express μ, δ, and κ opioid receptor mRNA

Upregulation of soluble tumor necrosis factor receptor two in plasma of HIV-seropositive individuals who use opiates

HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala

Combined HIV-1 Tat and oxycodone activate the hypothalamic-pituitary-adrenal and -gonadal axes and promote psychomotor, affective, and cognitive dysfunction in female mice

Peroxynitrite and opiate antinociceptive tolerance: a painful reality

Human immunodeficiency virus type 1 clade B and C gp120 differentially induce neurotoxin arachidonic acid in human astrocytes: implications for neuroAIDS

Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling

Innovation during COVID-19: improving addiction treatment access

Opioid addiction and pregnancy: perinatal exposure to buprenorphine affects myelination in the developing brain

Downregulation of the endogenous opioid peptides in the dorsal striatum of human alcoholics

Extending pharmacological spectrum of opioids beyond analgesia: multifunctional aspects in different pathophysiological states

HIVassociated neurocognitive disorder-pathogenesis and prospects for treatment

Deficits in white matter microstructure in Major depressive disorder: cause, consequence, or correlate?

Drug and opioid-involved overdose deaths -United States

Neural progenitors and HIV-1-associated central nervous system disease in adults and children

Evidence of human immunodeficiency virus type 1 infection of nestinpositive neural progenitors in archival pediatric brain tissue

The mesolimbic dopamine system in chronic pain and associated affective comorbidities

Alterations in blood-brain barrier function by morphine and methamphetamine

Opiate-dependent modulation of adenylate cyclase

Immunomodulatory role of opioids in the central nervous system

inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes

Brain region and gene specificity of neuropeptide gene expression in cultured astrocytes

Acute brain injury following illicit drug abuse in adolescent and young adult patients: spectrum of neuroimaging findings

A prospective four-year follow-up of neuropsychological function in HIV seropositive and seronegative methadone-maintained patients

Diverse characteristics of addiction necessitate multiple preclinical models

Host genetic determinants of human immunodeficiency virus infection and disease progression in children

Impaired neuropsychological performance in chronic nonmalignant pain patients receiving longterm oral opioid therapy

Brain neurotransmitter turnover correlated with morphine-seeking behavior of rats

Limbic acetylcholine turnover rates correlated with rat morphine-seeking behaviors

Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia growth and development study (HGDS), multicenter AIDS cohort study (MACS), multicenter hemophilia cohort study (MHCS)

Brain viral burden, neuroinflammation and neurodegeneration in HAART-treated HIV positive injecting drug users

Epilepsy, CNS viral injury and dynorphin

Protein kinase Cζ mediates µopioid receptor-induced cross-desensitization of chemokine receptor CCR5

Ligand-gated purinergic receptors regulate HIV-1 tat and morphine related neurotoxicity in primary mouse striatal neuron-glia co-cultures

A neuropeptide precursor in cerebellum: proenkephalin exists in subpopulations of both neurons and astrocytes

Morphine-induced transactivation of HIV-1 LTR in human neuroblastoma cells

Interactions between opioid and chemokine receptors: heterologous desensitization

Mu-opioid modulation of HIV-1 coreceptor expression and HIV-1 replication

Attacking pain at its source: new perspectives on opioids

Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4

Glial growth is regulated by agonists selective for multiple opioid receptor types in vitro

Opiates selectively increase intracellular calcium in developing type-1 astrocytes: role of calcium in morphine-induced morphologic differentiation

Regional, developmental, and cell cycle-dependent differences in μ, δ, and κ-opioid receptor expression among cultured mouse astrocytes

Opioid system diversity in developing neurons, astroglia, and oligodendroglia in the subventricular zone and striatum: impact on gliogenesis in vivo

Threading the needle-how to stop the HIV outbreak in rural Indiana

Effect of mu-opioid agonist DAMGO on surface CXCR4 and HIV-1 replication in TF-1 human bone marrow progenitor cells

Prolonged morphine exposure induces increased firm adhesion in an in vitro model of the blood-brain barrier

Early microstructural white matter changes in patients with HIV: a diffusion tensor imaging study

Compartmentalized replication of R5 T cell-tropic HIV-1 in the central nervous system early in the course of infection

) β-Endorphin enhances the replication of neurotropic human immunodeficiency virus in fetal perivascular microglia

Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor

Interactions of opioid and chemokine receptors: oligomerization of mu, kappa, and delta with CCR5 on immune cells

Fractalkine/CX3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic losses and death

CDC report highlights link between drug abuse and spread of HIV

Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization

Association between mu opioid receptor gene polymorphisms and Chinese heroin addicts

Spinal bromodomain-containing protein 4 contributes to neuropathic pain induced by HIV glycoprotein 120 with morphine in rats

Antiretroviral drug concentrations in the male and female genital tract: implications for the sexual transmission of HIV

The challenge of HIV-1 subtype diversity

+)-morphine attenuates the (−)-morphine-produced conditioned place preference and the mu-opioid receptor-mediated dopamine increase in the posterior nucleus accumbens of the rat

Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving

Opioids and their proper use as analgesics in the management of head and neck cancer patients

Novel GPCR paradigms at the mu-opioid receptor

Upregulation of microglia in drug users with and without presymptomatic HIV infection

Temporal patterns of human immunodeficiency virus type 1 transcripts in human fetal astrocytes

Detection of HIV-1 gene sequences in hippocampal neurons isolated from postmortem AIDS brains by laser capture microdissection

HIV-1, chemokines and neurogenesis

Downregulation of mu-opioid receptor expression in rat oligodendrocytes during their development in vitro

Increased vulnerability of ApoE4 neurons to HIV proteins and opiates: protection by diosgenin and L-deprenyl

Cell-specific actions of HIV-Tat and morphine on opioid receptor expression in glia

Morphine and HIV-Tat increase microglial-free radical production and oxidative stress: possible role in cytokine regulation

Effect of HIV clade differences on the onset and severity of HIV-associated neurocognitive disorders

Global overview of drug demand and supply

Alterations in brain structure and functional connectivity in prescription opioiddependent patients

Modeling the effects of morphine on simian immunodeficiency virus dynamics

Reduced prevalence of the CCR5 Δ32 heterozygous genotype in human immunodeficiency virus-infected individuals with AIDS dementia complex

HIV eradication strategies: implications for the central nervous system

Adult hippocampal neurogenesis: regulation by HIV and drugs of abuse

Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group study A5202

The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination

Expression of preproenkephalin mRNA by cultured astrocytes and neurons

Biased ligands at G-protein-coupled receptors: promise and progress

The brain on drugs: from reward to addiction

Medication-assisted therapies-tackling the opioid-overdose epidemic

The effects of opioids and opioid analogs on animal and human endocrine systems

An overdose surge will compound the COVID-19 pandemic if urgent action is not taken

Delta opioid agonists attenuate TAT(1-72)-induced oxidative stress in SK-N-SH cells

Clinical pharmacology of buprenorphine: ceiling effects at high doses

Decreased brain dopaminergic transporters in HIVassociated dementia patients

Morphine activates neuroinflammation in a manner parallel to endotoxin

Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: implication for vascular permeability

Buprenorphine vs methadone treatment: a review of evidence in both developed and developing worlds

Mechanisms of HIV entry into the CNS: increased sensitivity of HIV infected CD14+CD16+ monocytes to CCL2 and key roles of CCR2, JAM-A, and ALCAM in diapedesis

Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance

Monocytes mediate HIV neuropathogenesis: mechanisms that contribute to HIV associated neurocognitive disorders

Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE study, hemophilia growth and development study (HGDS), multicenter AIDS cohort study (MACS), multicenter hemophilia cohort study (MHCS)

White matter changes in HIV-1 infected brains: a combined gross anatomical and ultrastructural morphometric investigation of the corpus callosum

Neuropsychological functioning in opioid use disorder: a research synthesis and meta-analysis

Mechanisms of leukocyte trafficking into the CNS

Diffusion alterations in corpus callosum of patients with HIV

Autocrine Interleukin-10 mediates glucagon-like Peptide-1 receptor-induced spinal microglial β-endorphin expression

Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T lymphocytes

Inhibition of GABAergic neurotransmission by HIV-1 Tat and opioid treatment in the striatum involves μ-opioid receptors

HIV-1 tat protein increases the permeability of brain endothelial cells by both inhibiting occludin expression and cleaving occludin via matrix metalloproteinase-9

Isolating and characterizing three alternatively spliced mu opioid receptor variants: mMOR-1A, mMOR-1O, and mMOR-1P

A heroin addiction severity-associated intronic single nucleotide polymorphism modulates alternative pre-mRNA splicing of the mu opioid receptor gene OPRM1 via hnRNPH interactions

Exogenous brain-derived neurotrophic factor attenuates cognitive impairment induced by okadaic acid in a rat model of Alzheimer's disease

Initial study of magnetic resonance diffusion tensor imaging in brain white matter of early AIDS patients

Effect of chronic exposure to morphine on the rat blood-brain barrier: focus on the P-glycoprotein

Induction of P-glycoprotein and Bcrp at the rat blood-brain barrier following a subchronic morphine treatment is mediated through NMDA/COX-2 activation

A bivalent ligand targeting the putative μ opioid receptor and chemokine receptor CCR5 heterodimers : bi nd i ng af fin it y ve rs us fu n cti on al ac ti vi ti es

Neurocognitive and neuroinflammatory correlates of PDYN and OPRK1 mRNA expression in the anterior cingulate in postmortem brain of HIV-infected subjects

Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling

Morphine potentiates neurodegenerative effects of HIV-1

Tat through actions at μ-opioid receptor-expressing glia

Oligodendrocytes are targets of HIV-1 Tat: NMDA and AMPA receptor-mediated effects on survival and development

Effects of HIV-1 Tat on oligodendrocyte viability are mediated by CaMKIIβ-GSK3β interactions

Mu-opioid receptormediated antinociceptive responses differ in men and women

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Acknowledgements Portions of this review were initially presented at the Satellite Symposium of the 25th SNIP Scientific Conference entitled, "Unraveling NeuroAIDS in the Presence of Substance Use Disorder" that was sponsored and organized by NIH/NIDA. Co-Chairs: Yu (Woody) Lin and Roger Sorensen (April 10, 2019)