key: cord-0079175-bftxqfe6
authors: Sfera, Adonis; Thomas, Karina G.; Andronescu, Christina V.; Jafri, Nyla; Sfera, Dan O.; Sasannia, Sarvin; Zapata-Martín del Campo, Carlos M.; Maldonado, Jose C.
title: Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration
date: 2022-05-12
journal: Front Neurosci
DOI: 10.3389/fnins.2022.904816
sha: 0d9723903145b8aab748b41bff38d5c4ee177824
doc_id: 79175
cord_uid: bftxqfe6

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) comprise a group of illnesses marked by memory and behavioral dysfunction that can occur in up to 50% of HIV patients despite adequate treatment with combination antiretroviral drugs. Iron dyshomeostasis exacerbates HIV-1 infection and plays a major role in Alzheimer’s disease pathogenesis. In addition, persons living with HIV demonstrate a high prevalence of neurodegenerative disorders, indicating that HAND provides a unique opportunity to study ferroptosis in these conditions. Both HIV and combination antiretroviral drugs increase the risk of ferroptosis by augmenting ferritin autophagy at the lysosomal level. As many viruses and their proteins exit host cells through lysosomal exocytosis, ferroptosis-driving molecules, iron, cathepsin B and calcium may be released from these organelles. Neurons and glial cells are highly susceptible to ferroptosis and neurodegeneration that engenders white and gray matter damage. Moreover, iron-activated microglia can engage in the aberrant elimination of viable neurons and synapses, further contributing to ferroptosis-induced neurodegeneration. In this mini review, we take a closer look at the role of iron in the pathogenesis of HAND and neurodegenerative disorders. In addition, we describe an epigenetic compensatory system, comprised of bromodomain-containing protein 4 (BRD4) and microRNA-29, that may counteract ferroptosis by activating cystine/glutamate antiporter, while lowering ferritin autophagy and iron regulatory protein-2. We also discuss potential interventions for lysosomal fitness, including ferroptosis blockers, lysosomal acidification, and cathepsin B inhibitors to achieve desirable therapeutic effects of ferroptosis-induced neurodegeneration.

Neurodegeneration and Iron Dysmetyabolism, Likely Implicating Ferroptosis in this pathology. -Many viruses, including HIV-1, exploit the host endosomallysosomal system to acquire iron and egress host cells. -Both HIV-1 and cART can disrupt the lysosomes, promoting ferroptosis by releasing cathepsin B, iron, and Ca 2+ . -Dysfunctional lysosomes impair both ferritinophagy and myelin synthesis, increasing the risk of neuronal and glial ferroptosis. -An epigenetic BRD4/miR-29 system may oppose ferroptosis by boosting SLC7A11 and lowering ferritin autophagy.

HIV-associated neurocognitive disorder (HAND), encountered in up to 50% of HIV patients, is characterized by cognitive deficits that may occur despite adequate treatment with combination antiretroviral therapy (cART) (Ru and Tang, 2017) . Although the severity of HAND is lowered by cART, people living with HIV (PLWH), continue to display high rates of cognitive impairment and often develop Alzheimer's disease (AD) earlier in life compared to the general population (Calcagno et al., 2021; Sharma, 2021) . As high intracellular iron worsens HIV-1 prognosis and iron proteins are upregulated in HAND, ferroptosis-induced neurodegeneration (FIN) may contribute to this disorder (Patton et al., 2017; Milanini et al., 2019) . Viruses require iron for replication and often obtain this nutrient by targeting the iron-rich organelles, mitochondria, and lysosomes, disrupting their function, including ferritinophagy and myelination (Chang et al., 2015) .

Ferroptosis is a programmed cell death triggered by ironmediated lipid peroxidation in the absence of antioxidants glutathione (GSH) or glutathione peroxidase 4 (GPX4). Under normal circumstances, iron is stored in ferritin, a protein that undergoes lysosomal autophagy to release this biometal as needed. Dysfunctional ferritinophagy triggers toxic oxidative stress by upregulating intracellular iron, promoting pathology, including neurodegeneration. Aside from iron, ferroptosis can be triggered by low uptake of cysteine or glutamine via SLC7A11, an amino acid transporter specific for cysteine and glutamate, as well as the loss of GPX4 . Viral infections associated with increased iron absorption or upregulation of intracellular iron are likely to result in ferroptosis. Ferroptotic cell death is characterized by the release of damage-associated molecular patterns (DAMPs) that trigger immunogenicity and neuroinflammation, hallmarks of both HAND and AD (Smail and Brew, 2018; Sun et al., 2018) . Lysosomes, the master regulators of iron metabolism, control ferroptosis via ferritin autophagy (ferritinophagy), a process characterized by iron release (Rizzollo et al., 2021) . Many viruses hijack the endosomal-lysosomal system (ELS) to acquire iron, precipitating ferroptosis and FIN (Gao et al., 2017) .

Recent studies have found that both cART and the HIV-1 antigen, trans-activator of transcription (Tat), alter the host ELS, upregulating ferritinophagy and iron release (Fredericksen et al., 2002; Hui et al., 2012; Tripathi et al., 2019; Cao et al., 2021) (Graphical Abstract). In addition, virus or cART-induced lysosomal dysfunction can activate microglial cells that often eliminate healthy neurons and synapses, further contributing to neurodegeneration (Tripathi et al., 2019; Kapralov et al., 2020; Cao et al., 2021; Miyanishi et al., 2021) . Microglia are highly susceptible to ferroptosis and harbor latent HIV-1, therefore ferroptotic disintegration of these cells release DAMPs, triggering neuroinflammation (Lisi et al., 2016; Chivero et al., 2017; Shankaran et al., 2017; Wallet et al., 2019; Borrajo et al., 2021) . Indeed, iron-activated microglia and macrophages, documented in HIV-1 infection, are believed to drive HAND pathology (Boelaert et al., 1996; Kenkhuis et al., 2021) . In addition, microglia release cathepsin B (CatB), a protein associated with premature brain aging, neurotoxicity, and the accumulation of pathological, hyperphosphorylated Tau (pTau) (von Bernhardi et al., 2015; Nakanishi, 2020) . Interestingly, as CatB possesses endopeptidase activity, the SARS-CoV-2 virus hijacks this protein to activate the S (spike) antigen, increasing infectivity (Schornberg et al., 2006; Mitrović et al., 2016; Huang et al., 2020; Padmanabhan et al., 2020) . Moreover, individuals with HIV-1 infection on longterm cART present with higher brain deposition of pTau, linking this virus and its treatment to the risk of developing tauopathies (Anthony et al., 2006; Brown et al., 2014; Rao and Adlard, 2018; Mangan, 2021) . These findings indicate that HIV-1 and CART induce lysosomal damage and predispose to FIN as elevated intracellular iron increases the odds of lipid peroxidation and ferroptotic cell death .

Lysosomes are iron-rich subcellular organelles specialized in the degradation of proteins derived from autophagy, endocytosis, and phagocytosis (Platt et al., 2012 ; Figure 1 ). Aside from recycling endogenous biomolecule, autophagy also eliminates malignant and virus-infected cells, actively participating in host immunity (Choi et al., 2018) . Many viruses, including SARS-CoV-2 and HIV Tat protein exploit the ELS to enter and exit host cells, disrupting this pathway and predisposing to FIN (Fan and He, 2016; Khan et al., 2020; Chen D. et al., 2021) . Indeed, viruses that exploit the lysosome alter local pH and membrane permeability, facilitating the release of ferroptosis drivers iron, calcium (Ca 2+ ) and CatB (Hui et al., 2012; Gorshkov et al., 2021; Nagakannan et al., 2021; Pedrera et al., 2021) . For example, recent studies linked cytosolic Ca 2+ upregulation to both ferroptosis and excitotoxicity, connecting the two metals to cell death (Gleitze et al., 2021; Pedrera et al., 2021) . In addition, HIV has been reported to generate massive reactive oxygen and nitrogen species (RONS) associated with HAND, likely by aberrant microglial activation (Borrajo et al., 2021) .

Recent studies have reported that lysosomal exocytosis is required for oligodendrocytes (OLGc) and Schwan cells myelination, suggesting that dysfunctional ELS could lead to white matter damage in HAND and AD . FIGURE 1 | SARS-CoV-2 virus and HIV Tat antigen ingress host cells via ELS. The SARS-CoV-2 envelope (E) protein is a direct inhibitor of BRD4, increasing the risk of ferroptosis. Viruses that exploit ELS to egress host cells may disrupt lysosomal exocytosis of myelin and Tau protein (not shown). Late endosomes generate extracellular vesicles (EVs) that can spread viral proteins to the neighboring cells. Dysfunctional lysosomes may "leak" ferroptosis-driving molecules, including iron, Ca 2+ and CatB, contributing to ferroptosis-induced neurodegeneration (FIN).

Others have connected dysfunctional ELS with the dissemination and seeding of pTau, further implicating this system in tauopathies (Tanaka et al., 2019; Jiang and Bhaskar, 2020; Polanco et al., 2021; Sebastián-Serrano et al., 2022) .

In this mini review, we take a closer look at the virus induced ELS dysfunction in the pathogenesis of HAND and neurodegenerative disorders. In addition, we propose that FIN, triggered by HIV-1 infection and long-term cART use, may be counteracted by an epigenetic system comprised of bromodomain protein 4 (BRD4) and microRNA-29 (miR 29) that inhibits ferritinophagy by several mechanisms, including direct antiviral action, lysosomal suppression, SLC7A11 activation, and iron regulatory protein-2 (IRP-2) inhibition. We also discuss potential interventions for lysosomal fitness, including V-ATPase inhibitors, ferroptosis blockers, and CatB inhibitors.

The ELS is comprised of intracellular vesicular compartments, including early endosomes, recycling endosomes, and late endosomes [also called multivesicular bodies (MVBs)] that merge with lysosomes. Autophagosomes also join the lysosomes to recycle their cargoes (Figure 1 ). Many viruses, including HIV-1 and SARS-CoV-2, acquire iron by usurping the lysosome, a process that upregulates ferritinophagy, iron release and the risk of FIN (Hui et al., 2012; Chauhan and Khandkar, 2015; Hu et al., 2015; Yambire et al., 2019; Blaess et al., 2020 ; Figure 1 ).

As autophagy controls viral infections by catabolizing infected cells along with the virus, many viruses have developed the ability to evade immunity by manipulating autophagy. For example, HIV-1 hijacks the ELS by Tat, Nef, and ENV antigens interaction with the autophagy proteins or mammalian target of rapamycin (mTor) components (Nardacci et al., 2017) .

Lysosomal exocytosis, a mechanism of content secretion into the extracellular space, is mediated by lysosomal fusion with the cell plasma membrane that enables cargo release. HIV-1 and SARS-CoV-2 hijack the ELS to enter and egress host cells, disrupting vesicular homeostasis, including lysosomal exocytosis, and local pH (Hui et al., 2012; Nardacci et al., 2017; Blaess et al., 2020) . Recent studies have reported that myelin biosynthesis requires adequate lysosomal exocytosis, suggesting that dysfunctional ELS may lead to both gray and white matter pathology Kreher et al., 2021) . Indeed, viruses that exit host cells through the lysosomes may disrupt myelination, promoting HAND and neurodegenerative disorders (Jensen et al., 2015; Buratta et al., 2020) . Along these lines, novel neuroimaging studies have detected white matter changes in the prodromal phase of AD [prior to the development of pTau or beta-amyloid (Aβ)], indicating that myelin pathology is more common in his disorder than previously thought (Nasrabady et al., 2018; Pichet Binette et al., 2021) . Moreover, a growing body of evidence has demonstrated myelin breakdown and dysfunctional OLGc progenitor cells (OPCs) in HAND and AD, linking both conditions to white matter pathology (Kimura-Kuroda et al., 1994; Bernardo et al., 1997; Lackner et al., 2010; Jensen et al., 2019) . Furthermore, as OLGc are the predominant iron-containing cells in the brain and highly susceptible to ferroptosis, their demise may increase local iron, predisposing to FIN (Nobuta et al., 2019; Jhelum et al., 2020) . Also, the ELS-released pTau, iron, Ca 2+ , CatB, and myelin maintain the neurodegenerative and HAND pathology (Joy et al., 2010; Chen et al., 2012; .

Recent studies found that elevated intracellular iron increases pTau and its aggregation, linking tauopathies to dysfunctional ELS (Brown et al., 2014; Rao and Adlard, 2018) . In addition, iron dyshomeostasis and excessive pTau, documented in HAND, AD, and traumatic brain injury (TBI), implicate ELS in these pathologies (Canzoniero and Snider, 2005; Ravi et al., 2016; Cantres-Rosario et al., 2019; Hook et al., 2020; Nagakannan et al., 2021; Pedrera et al., 2021) . Furthermore, as pTau acts as a cell-penetrating peptide, it may trigger cell-cell fusion and senescence, probably accounting for the accelerated aging and early development of AD in PLWH on long term cART (Ferrell and Giunta, 2014; Veloria et al., 2017; Osorio et al., 2022) . Along these lines, HIV infected macrophages were shown to enter the brain and secrete neurotoxic CatB, triggering premature senescence, ferroptosis and FIN (Cantres-Rosario et al., 2019) . Excessive CatB was also associated with cancer, connecting ELS dysfunction to tumorigenesis and metastases (Gondi and Rao, 2013; Ruan et al., 2015) . On the other hand, CatB inhibitors may avert HAND, TBI, and cancer (Ha et al., 2012; Kos et al., 2014; Hook et al., 2015; Zenón-Meléndez et al., 2022) . Cathepsin B was also associated with autoimmune disorders and osteoporosis, suggesting that a better understanding of this protein and its inhibitors could improve the treatment of several disorders that lack specific therapies (Toomey et al., 2014; Li et al., 2017; Ansari et al., 2022) . In addition, several antipsychotic agents possess anticancer and antiviral properties, suggesting that these pathologies may intersect at the ELS level (Daniel et al., 2001; Kuzu et al., 2017; Girgis and Lieberman, 2021; Lu et al., 2021) (discussed in the section Psychotropic drugs). Other novel studies show that viral infections may precipitate ferroptosis by hijacking Ca 2+ channels and pumps, suggesting a role for calcium channel blockers in the treatment of viral infections Jayaseelan and Paramasivam, 2020; Straus et al., 2021) . Indeed, as HIV Tat antigen upregulates pTau, it likely promotes FIN (Tripathi et al., 2016; Majerníková et al., 2021; Wang et al., 2022) . Moreover, HIV infection was shown to increase apolipoprotein ε4 (ApoE4), an iron-upregulated biomolecule and AD risk factor, suggesting FIN involvement (Ayton et al., 2015; Diouf et al., 2019; Kagerer et al., 2020) . Furthermore, as viruses upregulate both ApoE4 and iron, they may be capable of triggering FIN directly (Corder et al., 1998; Burt et al., 2008; Kuo et al., 2020; Gkouskou et al., 2021; Yim et al., 2022) .

Taken together, ELS is situated at the crossroad of viral infections, cancer, and neuropsychiatric illness, probably explaining the beneficial effect of lysosomal therapeutics in these pathologies.

Bromodomains are chromatin-associated molecules that interact with acetylated lysine residues on histone proteins, regulating numerous cellular processes, including replication, genome repair and the autophagic lysosomal function (Mujtaba et al., 2007; Fujisawa and Filippakopoulos, 2017; Sakamaki et al., 2017; Li et al., 2018) . BRD4 is an epigenetic reader that regulates gene expression by forming a complex with the positive transcription elongation factor b (P-TEFb), promoting RNA polymerase II (Pol II), a mediator of DNA-dependent RNA synthesis (Jung et al., 2014) . Novel studies have implicated BRD4 in various pathologies, ranging from inflammation, to cancer, CNS, and viral diseases (Zhu et al., 2012; Korb et al., 2015; Hajmirza et al., 2018) . In preclinical studies, bromodomain and extraterminal motif (BET) inhibitors (BETis) were shown to limit the progression of several cancers, rendering this protein a pharmacological target.

Recently, however, pan-BRD4 blockers, such as JQ1, were found detrimental as they trigger ferroptosis, damaging the genome, immunity and white matter (Chiu et al., 2017; Donati et al., 2018; Mita and Mita, 2020) . On the other hand, domainspecific BETis appear to have fewer adverse effects and some have already been approved for clinical use (Pérez-Salvia and Esteller, 2017; Petretich et al., 2020) . BRD4 negatively regulates ferroptosis by activating xCT, repairing the DNA, and inducing senescence-associated secretory phenotype (SASP), a ferroptosis resistant cellular program (Tasdemir et al., 2016; Sui et al., 2019; Lam et al., 2020; Tang et al., 2022) . In addition, BRD4 promotes iron sequestration in ferritin to withhold it from pathogens, likely implicating this protein in nutritional immunity (Sui et al., 2019) . Moreover, BRD4 displays direct antiviral properties, including inhibition of HIV Tat antigen, hence viruses must neutralize this protein to thrive (Wang et al., 2020; Alamer et al., 2021; Xu X. et al., 2021 ; Table 1 ). Indeed, several viruses, including HIV and SARS-CoV-2 have developed the ability to usurp BRD4, overcoming nutritional immunity (Chen I. P. et al., 2021) . For example, the E (envelope) protein of SARS-CoV-2 virus inhibits BRD4, neutralizing the function of this epigenetic reader (Gordon et al., 2020) . As BRD4 represses lysosomal autophagy, including ferritinophagy, viral hijacking of this protein may directly induce ferroptosis (Sakamaki et al., 2017) . Moreover, BRD4 protects mitochondria by safeguarding the transcription of mitochondrial genes located in the nucleus . This is significant as earlier studies have implicated mitochondria and BRD4 in memory formation, suggesting a direct mechanism for virus-mediated neurodegeneration (Korb et al., 2015; Khacho et al., 2017; Zhang et al., 2022) .

MicroRNAs (miRs) are non-coding ribonucleic acids (RNAs) that regulate gene expression by interacting with the 3 untranslated region (3 UTR) of target mRNAs (O'Brien et al., 2018) . MiR-29 family, comprised of miR-29a, miR-29b, and miR-29c, displays antiviral properties, including inhibition of HIV-1 Nef protein (Ahluwalia et al., 2008; Adoro et al., 2015; Monteleone et al., 2015) . In addition, IL-21/miR-29 axis was associated with HIV-1 latency, suggesting that enhancing this pathway may eradicate the virus from reservoirs (Frattari et al., 2017) . Indeed, to counteract its antiviral action, HIV-1 has developed the ability to inhibit miR-29 via Tat antigen, promoting viral latency (Bennasser et al., 2005; Ruelas and Greene, 2013; Monteleone et al., 2015) . As there is an inverse relationship between miR-29 and BRD4, HIV-1-mediated miR-29 downregulation lowers ferritinophagy by increasing BRD4 (Kohnken et al., 2018; Huang et al., 2019) . Recently, miR-29 was found to lower intracellular iron by inhibiting iron regulatory protein 2 (IRP-2), lowering the risk of ferroptosis and FIN (Ripa et al., 2017) Frattari et al., 2017; Wang et al., 2020; Alamer et al., 2021; Xu X. et al., 2021 HIV Tat protein inhibition Zhu et al., 2012; Huang et al., 2017 Decrease ferritinophagy Shimizu et al., 2007; Sui et al., 2019 Improve mitochondrial function Kim et al., 2020 Decrease HIV latency Frattari et al., 2017 Upregulate xCT (SLC7A11) Tasdemir et al., 2016; Tang et al., 2022 Genome repair Lam et al., 2020 Promotes SASP Tasdemir et al., 2016 Promotes iron sequestration Sui et al., 2019 associated miR-29 family with gene expression in aging brain, showing that this miR lowers the expression of IRP-2 and the signaling with the iron responsive element (IRE), decreasing the intracellular iron load (Ripa et al., 2017) . Opposing this mir-29 action, the HIV-1 glycoprotein 120 (gp 120) activates IRP-2 via E2F transcription factor 1 (E2F1), precipitating ferrocytosis (Shimizu et al., 2007) . This is significant as several studies demonstrated low miR-29 expression in AD, linking this miR to the pathogenesis of neurodegenerative disorders and HAND (Lu et al., 2016; Müller et al., 2016; Pereira et al., 2016; Jahangard et al., 2020) . Moreover, BRD4 has inhibitory effects on HIV-1 Tat protein, blocking viral latency and indicating that BRD4/miR-29 manipulation could eradicate latent HIV-1 (Zhu et al., 2012; Huang et al., 2017 ; Table 1 ). Taken together, BRD4/miR-29 may comprise an epigenetic system that opposes FIN by several mechanisms, including direct antiviral action, iron sequestration in ferritin, IRP-2 downregulation, and suppression of lysosomal function, including ferritinophagy. As BRD4/miR-29 axis withholds iron from pathogens, we speculate that this system may drive nutritional immunity.

The role of ferroptosis in viral infections is closely connected to the concept of nutritional immunity, intracellular iron sequestration to withhold it from pathogens (Núñez et al., 2018) . Although protective against infections, iron sequestration may escalate the risk of ferroptosis as it places this biometal in the proximity of lipids, increasing the risk of peroxidation (Chao et al., 2020; Chen et al., 2020) . For this reason, lowering neuronal ferroptosis by upregulating BRD4 may decrease ferritinophagy and neuronal ferroptosis.

In this section, we focus on pharmacological agents that may lower the FIN risk at the ELS level.

Under normal circumstances, lysosomal pH must be highly acidic (4.5-5.5) for protein degradation to occur. This is accomplished via vacuolar (H + ) ATPase (or V-ATPase) that pumps protons into the organelle to lower its pH (Song et al., 2020) . Several viruses and their antigens, including HIV-1 Nef protein, usurp V-ATPase, increasing ferritin autophagy and intracellular iron, as well as the risk of ferroptosis and FIN (Lu et al., 1998; Castro-Gonzalez et al., 2021) .

Over the past two decades, several V-ATPase inhibitors have been developed, including concanamycin A, bafilomycin A1, saliphenylhalamide, and quinazolines (Garcia-Rodriguez et al., 2015) . Quinazolines were the newest addition to the armamentarium of V-ATPase inhibitors. They are small electrophilic molecules that comprise the common denominator of over 150 naturally occurring alkaloids with numerous biological properties . These agents possess anti-HIV, anticancer and anti-neurodegenerative properties, implicating ELS dysfunction in these pathologies (Colacurcio and Nixon, 2016; Hu et al., 2018; Whitton et al., 2018; Le-Nhat-Thuy et al., 2020) . Indeed, the quinazolinone compound, PBT434 possess iron chelating properties suggesting that lowering this biometal may benefit the patients with these conditions (Bailey et al., 2021) .

Recent studies have shown that N-acetylcysteine (NAC) can reverse cART-induced microglial activation and inhibit ferritinophagy (Tripathi et al., 2020) . NAC is a widely used drug, primarily as an antidote for acetaminophen overdose, but possesses many other beneficial effects, including correcting the oxidative stress-mediated ELS dysfunction, suggesting that it may reverse some neurological complications of HAND (Tripathi et al., 2020) . Interestingly, NAC has been evaluated for its senolytic properties against brain aging, indicating potential efficacy against HAND and AD (Tardiolo et al., 2018) . In addition, NAC possesses anticancer and anti-HIV, properties, further linking ELS to these pathologies (Roederer et al., 1992; Deng et al., 2019) . Moreover, as NAC supplementation increases GSH and GPX, it may also suppress ferroptosis and FIN (Karuppagounder et al., 2018; Hu et al., 2021) .

Aryl-thiazole compounds are novel agents that include N2-[2chloro-4(3,4,5-trimethoxy phenyl azetidin-1-yl]-N4-(substituted aryl)-1,3-thiazole-2,4-diamine (4a-g), a lipid peroxidation blocker, indicating potential beneficial effect against FIN (Djukic et al., 2018) . Aryl-thiazole compounds possess antiviral, anticancer and anti-neurodegenerative properties by modulating γ-secretase (Lu et al., 2009; Dawood et al., 2015; Bhattarai et al., 2021) . In addition, (3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-one presents with reverse transcriptase inhibiting properties, potentially lowering HIV-1 replication (Meleddu et al., 2015) .

Pyridine, acetamide, and benzohydrazine are CatB inhibitors with antiviral, anti-neurodegenerative and anticancer properties (Prachayasittikul et al., 2017; Alizadeh and Ebrahimzadeh, 2021; Chitranshi et al., 2021) . As CatB is a ferroptosis driver, the inhibitors of this cysteine protease may benefit the patients with AD and HAND. In addition, these molecules were shown to modulate the HIV-1 gene expression and inhibit Tat protein, suggesting antiviral properties (Balachandran et al., 2017) . Other recently developed CatB inhibitors are nitroxoline (8-hydroxy 5-nitroquinoline) derivatives, inhibitors of endopeptidase and exopeptidase activities of this enzyme. These drugs have established antibiotic, anticancer and anti-neurodegenerative properties (Knez et al., 2015) .

Ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) comprise a new generation of ferroptosis inhibitors that function as radical traps and scavengers of lipid hydroperoxyl groups (Miotto et al., 2020) . These agents are potential COVID-19 treatments, while their inhibitors have been studied as ferroptosis inducers in cancer cells (Subburayan et al., 2020; Yang and Lai, 2020) . Moreover, Fer-1 and Lip-1 have been evaluated for efficacy against viral infections and neurodegeneration Wang et al., 2021) .

Iron chelation was demonstrated to protect lysosomal membranes against peroxidative injury, lowering the risk of ferroptosis (Kurz et al., 2006) . Indeed, iron chelators are currently being assessed for efficacy against neurodegenerative disorders, including AD (Dusek et al., 2016 ) (NCT03234686). These agents have shown antiviral effects, especially against HIV-1 and SARS-CoV-2, suggesting that withholding iron from pathogens can be an efficient anti-infectious strategy (van Asbeck et al., 2001; Chhabra et al., 2020) . By protecting lysosomal membranes, chelation therapy lowers CatB cytosolic "escape" and subsequent neurotoxicity (Lin et al., 2010) . In addition, iron chelators have shown beneficial effects in cancer, probably by decreasing mitochondrial energy production and starving the tumors (Fryknäs et al., 2016) .

The anti-malaria drugs, chloroquine (CQ) and hydroxychloroquine (HCQ) are autophagy blockers that accumulate in the ELS, neutralizing luminal pH. These compounds possess antiviral and anticancer properties, probably by blocking lysosomal exocytosis (Neely et al., 2003; Halcrow et al., 2019) . Interestingly, recent studies in patients with rheumatoid arthritis (RA) showed that prolonged treatment with CQ and HCQ decreased the risk of Parkinson's disease (PD), indicating anti-neurodegenerative properties (Paakinaho et al., 2022) . Indeed, as CQ and HCQ inhibit CatB, a protein implicated in the pathogenesis of both RA and PD, it is likely that these drugs inhibit CatB (Hashimoto et al., 2001; Tsujimura et al., 2015; Mahoney-Sánchez et al., 2021; Zhao et al., 2022) .

Second generation antipsychotic drugs, and several antidepressants were shown to possess antioxidant properties by upregulating GSH, lowering the risk of ferroptosis (Quincozes-Santos et al., 2010; Caruso et al., 2020) . In addition, as GSH possesses antiviral properties, psychotropic drugs may enhance autophagy, facilitating the clearance of cancerous and pathogen-infected cells (Fraternale et al., 2006) . Indeed, as some psychotropics enter cells via ELS, they may eliminate the viruses they encounter throughout this pathway (Benton et al., 2010; Canfrán-Duque et al., 2016; Schneider et al., 2016; Vela, 2020; Fred et al., 2022) . Moreover, as several psychotropic drugs display anticancer properties, they likely inhibit CatB, lowering the cytotoxicity of this protein (Varalda et al., 2020) . Furthermore, newly synthesized ferroptosis inhibitors, the phenothiazine analogs, alter autophagy, probably explaining their efficacy against neurodegenerative disorders Posso et al., 2022) . Interestingly, the fast-acting antidepressant drug, ketamine, was found to upregulate miR-29, linking depression to ferroptosis, suggesting that the BRD4/miR-29 system may have antidepressant effects (Stolke et al., 1980; Paul et al., 2014; Wan et al., 2018) .

CatB dysfunction was associated with several pathologies, including autoimmune disorders, cancer, drug addiction, neurodegeneration, and viral infections (Toomey et al., 2014; Li et al., 2017; Ansari et al., 2022) . For example, the anthelminthic drug, niclosamide, demonstrates anticancer, antiviral, and neuroprotective properties, likely by inhibiting CatB and restoring ELS homeostasis (Circu et al., 2016; Goulding et al., 2021; Weiss et al., 2021) . Indeed, niclosamide was found to inhibit HIV-1 proliferation and activate PTEN-induced kinase 1 (PINK1), indicating potential benefit in neurodegenerative disorders and likely HAND (Niyomdecha et al., 2020; Jang et al., 2022) . Interestingly, sigma-1 (Sig1R) agonists, such as BD1047, were shown to downregulate CatB, ameliorating HAND, especially in cocaine users (López et al., 2019) . Along this line, fluvoxamine, a potent Sig1R agonist, with antiviral properties may be a yet unknown CatB inhibitor.

HIV-1 infection and long-term cART, enhance lysosomal ferritinophagy, releasing excessive amounts of iron, Ca 2+ and CatB that may trigger FIN. The host responds to this insult by activating an epigenetic system comprised of BRD4/miR-29 that blocks dysfunctional lysosomes and iron release via IRP-2 and SLC7A11. As BRD4 is upregulated by low miR-29 and HIV-1 inhibits miR-29, ferritinophagy is downregulated, lowering FIN. In addition, as BRD4 inhibits HIV-1 Tat protein, modulation of BRD4/miR-29 system may eradicate latent HIV-1 from reservoirs, such as microglia and macrophages.

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Identification of Novel Cathepsin B inhibitors with implications in Alzheimer's disease: computational refining and biochemical evaluation

Bromodomain proteins: repairing DNA damage within chromatin

HIV-1 Tat primes and activates microglial NLRP3 inflammasomemediated neuroinflammation

Autophagy during viral infection -a double-edged sword

A novel high content imaging-based screen identifies the Antihelminthic niclosamide as an inhibitor of lysosome anterograde trafficking and prostate cancer cell invasion

Disorders of lysosomal acidification-The emerging role of v-ATPase in aging and neurodegenerative disease

HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy

Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping

Synthesis and antiviral activity of some new bis-1,3-thiazole derivatives

N-acetylcysteine decreases malignant characteristics of glioblastoma cells by inhibiting Notch2 signaling

Cerebrospinal fluid ferritin levels predict brain hypometabolism in people with underlying β-amyloid pathology

In vitro antioxidant activity of thiazolidinone derivatives of 1,3-thiazole and 1,3,4-thiadiazole

BRD4 and Cancer: going beyond transcriptional regulation

Iron chelation in the treatment of neurodegenerative diseases

HIV-1 Tat promotes lysosomal exocytosis in astrocytes and contributes to astrocyte-mediated tat neurotoxicity

The impact of HIV-1 on neurogenesis: implications for HAND

Antiviral and immunomodulatory properties of new proglutathione (GSH) molecules

The role of miR-29a in HIV-1 replication and latency

Antidepressant and antipsychotic drugs reduce viral infection by SARS-CoV-2 and fluoxetine shows antiviral activity against the novel variants in vitro

Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus

Iron chelators target both proliferating and quiescent cancer cells

Functions of bromodomaincontaining proteins and their roles in homeostasis and cancer

Comprehensive proteome analysis of lysosomes reveals the diverse function of macrophages in immune responses

Synthesis and structure-activity studies of the V-ATPase inhibitor saliphenylhalamide (SaliPhe) and simplified analogs

Anti-viral properties of antipsychotic medications in the time of COVID-19

COVID-19 enters the expanding network of apolipoprotein E4-related pathologies

The calcium-iron connection in ferroptosis-mediated neuronal death

Cathepsin B as a cancer target

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The SARS-CoV-2 cytopathic effect is blocked by lysosome alkalizing small molecules

Quinacrine and niclosamide promote neurite growth in midbrain dopaminergic neurons through the canonical BMP-smad pathway and protect against neurotoxin and α-Synuclein-Induced neurodegeneration

Inhibition or deficiency of cathepsin B leads defects in HIV-1 Gag pseudoparticle release in macrophages and HEK293T cells

BET family protein BRD4: an emerging actor in NFκB signaling in inflammation and cancer

Role of endolysosomes and pH in the pathogenesis and treatment of glioblastoma

Significance of cathepsin B accumulation in synovial fluid of rheumatoid arthritis

Cathepsin B is a new drug target for traumatic brain injury therapeutics: evidence for E64d as a promising lead drug candidate

Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders

Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection

Suppression of uterine and placental ferroptosis by N-acetylcysteine in a rat model of polycystic ovary syndrome

The endosomallysosomal system: from acidification and cargo sorting to neurodegeneration

A novel bromodomain inhibitor reverses HIV-1 latency through specific binding with BRD4 to promote Tat and P-TEFb association

Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

MicroRNA-29a is a key regulon that regulates BRD4 and mitigates liver fibrosis in mice by inhibiting hepatic stellate cell activation

Role of endolysosomes in HIV-1 Tat-induced neurotoxicity

Therapeutic effects of transplanted exosomes containing miR-29b to a rat model of Alzheimer's disease

The PINK1 activator niclosamide mitigate mitochondrial dysfunction and thermal hypersensitivity in a paclitaxel-induced drosophila model of peripheral neuropathy

Repurposing calcium channel blockers as antiviral drugs

Altered oligodendrocyte maturation and myelin maintenance: the role of antiretrovirals in HIVassociated neurocognitive disorders

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

Ferroptosis mediates cuprizone-induced loss of oligodendrocytes and demyelination

Degradation and transmission of Tau by autophagic-endolysosomal networks and potential therapeutic targets for tauopathy

Ferroptosis: mechanisms, biology and role in disease

Lysosomal destabilization and cathepsin B contributes for cytochrome c release and caspase activation in embelin-induced apoptosis

Affinity map of bromodomain protein 4 (BRD4) interactions with the histone H4 tail and the small molecule inhibitor JQ1

APOE4 moderates effects of cortical iron on synchronized default mode network activity in cognitively healthy old-aged adults

Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death

N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E2 to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

Iron loading is a prominent feature of activated microglia in Alzheimer's disease patients

Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis

Role of endolysosomes in severe acute respiratory syndrome Coronavirus-2 infection and coronavirus disease 2019 pathogenesis: implications for potential treatments

Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) governs nucleus-encoded mitochondrial transcriptome to regulate cardiac function

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

Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents

Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma

BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice

The current stage of cathepsin B inhibitors as potential anticancer agents

Lysosomal functions in glia associated with neurodegeneration

APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort

Intralysosomal iron chelation protects against oxidative stress-induced cellular damage

Modulating cancer cell survival by targeting intracellular cholesterol transport

Antibodies to myelin oligodendrocyte glycoprotein in HIV-1 associated neurocognitive disorder: a cross-sectional cohort study

BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage

Synthesis and biological evaluation of novel quinazoline-triazole hybrid compounds with potential use in Alzheimer's disease

BRD4 promotes DNA repair and mediates the formation of TMPRSS2-ERG gene rearrangements in prostate cancer

Cathepsin B and L inhibitors: a patent review (2010 -present)

Intralysosomal iron induces lysosomal membrane permeabilization and cathepsin D-mediated cell death in trabecular meshwork cells exposed to oxidative stress

Antiretrovirals inhibit arginase in human microglia

Antiferroptotic activity of phenothiazine analogues: a novel therapeutic strategy for oxidative stress related disease

Sigma-1 receptor antagonist (BD1047) decreases Cathepsin B secretion in HIV-infected macrophages exposed to cocaine

Screened antipsychotic drugs inhibit SARS-CoV-2 binding with ACE2 in vitro

The BET inhibitor OTX015 reactivates latent HIV-1 through P-TEFb

Interactions between HIV1 Nef and vacuolar ATPase facilitate the internalization of CD4

Discovery of 4-substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: synthesis, biological evaluation, and structure-activity relationships

Ferroptosis and its potential role in the physiopathology of Parkinson's Disease

The potential of ferroptosis-targeting therapies for Alzheimer's disease: from mechanism to transcriptomic analysis

Iron: an underrated factor in aging

(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-one derivatives as dual inhibitors of HIV-1 reverse transcriptase

Longitudinal brain atrophy patterns and neuropsychological performance in older adults with HIV-associated neurocognitive disorder compared with early Alzheimer's disease

Insight into the mechanism of ferroptosis inhibition by ferrostatin-1

Bromodomain inhibitors a decade later: a promise unfulfilled?

Inhibition of endopeptidase and exopeptidase activity of cathepsin B impairs extracellular matrix degradation and tumour invasion

Synaptic elimination by microglia and disturbed higher brain functions

MicroRNA-29 family expression and its relation to antiviral immune response and viro-immunological markers in HIV-1-infected patients

Structure and acetyl-lysine recognition of the bromodomain

MicroRNA-29a is a candidate biomarker for Alzheimer's disease in cell-free cerebrospinal fluid

Cathepsin B is an executioner of ferroptosis

Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging

Role of autophagy in HIV infection and pathogenesis

White matter changes in Alzheimer's disease: a focus on myelin and oligodendrocytes

Effect of chloroquine on human immunodeficiency virus (HIV) vertical transmission

Inhibition of human immunodeficiency virus type 1 by niclosamide through mTORC1 inhibition

Oligodendrocyte death in Pelizaeus-Merzbacher disease is rescued by iron chelation

Innate nutritional immunity

Overview of MicroRNA biogenesis, mechanisms of actions, and circulation

Virus-Induced membrane fusion in neurodegenerative disorders

Disease-modifying antirheumatic drugs and risk of parkinson disease: nested case-control study of people with rheumatoid arthritis

Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function

Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics

Recombinant pre-miR-29b for Alzheimer's disease therapeutics

Bromodomain inhibitors and cancer therapy: from structures to applications

Domain-selective targeting of BET proteins in cancer and immunological diseases

Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer's disease

The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction

Exosomes induce endolysosomal permeabilization as a gateway by which exosomal tau seeds escape into the cytosol

Development of phenothiazine hybrids with potential medicinal interest: a review

Roles of pyridine and pyrimidine derivatives as privileged scaffolds in anticancer agents

Effects of atypical (risperidone) and typical (haloperidol) antipsychotic agents on astroglial functions

Untangling Tau and Iron: exploring the interaction between Iron and Tau in neurodegeneration

Biphasic regulation of lysosomal exocytosis by oxidative stress

MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging

The lysosome as a master regulator of iron metabolism

N-acetylcysteine: a new approach to anti-HIV therapy

HIV-associated synaptic degeneration

Targeting Cathepsin B for cancer therapies

An integrated overview of HIV-1 latency

Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function

Autophagy and schizophrenia: a closer look at how dysregulation of neuronal cell homeostasis influences the pathogenesis of schizophrenia

Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein

TNAP upregulation is a critical factor in Tauopathies and its blockade ameliorates neurotoxicity and increases lifeexpectancy

Effects of heme degradation products on reactivation of latent HIV-1

Interrogating the impact of combination antiretroviral therapies on HIV-associated neurocognitive disorders

Rab27b is involved in lysosomal exocytosis and proteolipid protein trafficking in oligodendrocytes

Role of the transcription factor E2F1 in CXCR4-mediated neurotoxicity and HIV neuropathology

HIV-associated neurocognitive disorder

The emerging roles of vacuolartype ATPase-dependent Lysosomal acidification in neurodegenerative diseases

Das Verhalten lysosomaler Enzyme des Hirngewebes auf die Narkose unter Ketamine

Inhibitors of L-Type calcium channels show therapeutic potential for treating SARS-CoV-2 infections by preventing virus entry and spread

Superoxide-mediated ferroptosis in human cancer cells induced by sodium selenite

Ferritinophagy is required for the induction of ferroptosis by the bromodomain protein BRD4 inhibitor (+)-JQ1 in cancer cells

Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells

Seeding activity-based detection uncovers the different release mechanisms of seed-competent tau versus inert tau via lysosomal exocytosis

Ferroptosis: molecular mechanisms and health implications

Research progress on SLC7A11 in the regulation of cystine/cysteine metabolism in tumors

Overview on the effects of N-Acetylcysteine in neurodegenerative diseases

BRD4 connects enhancer remodeling to senescence immune surveillance

Cathepsin B regulates the appearance and severity of mercury-induced inflammation and autoimmunity

N-Acetylcysteine reverses antiretroviral-mediated microglial activation by attenuating autophagy-lysosomal dysfunction

Antiretroviral-Mediated microglial activation involves dysregulated autophagy and lysosomal dysfunction

HIV encephalitis with subcortical tau deposition: imaging pathology in vivo using F-18 THK 5117

Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils

Anti-HIV effect of iron chelators: different mechanisms involved

Psychotropic drugs show anticancer activity by disrupting mitochondrial and lysosomal function

Repurposing Sigma-1 receptor ligands for COVID-19 therapy?

Novel cell model for tauopathy induced by a Cell-permeable Tau-related peptide

Microglial cell dysregulation in brain aging and neurodegeneration

Microglial cells: the main HIV-1 reservoir in the brain

Prefrontal cortex miR-29b-3p plays a key role in the antidepressant-like effect of ketamine in rats

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses

Ferroptosis in viral infection: the unexplored possibility

Ferroptosis promotes microtubule-associated protein tau aggregation via GSK-3β activation and proteasome inhibition

Niclosamide shows strong antiviral activity in a human airway model of SARS-CoV-2 infection and a conserved potency against the Alpha (B.1.1.7), Beta (B.1.351) and Delta variant (B.1.617.2)

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

Bromodomain containing protein 4 (BRD4) regulates expression of its interacting coactivators in the innate response to respiratory syncytial virus

TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading

Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo

SARS-CoV-2 infection: can ferroptosis be a potential treatment target for multiple organ involvement?

Magnetic susceptibility in the deep gray matter may be modulated by apolipoprotein E4 and age with regional predilections: a quantitative susceptibility mapping study

Inhibition of Cathepsin B and SAPC secreted by HIV-infected macrophages reverses common and unique apoptosis pathways

Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer's disease-related neuropathology in cell models

Ferroptosis in rheumatoid arthritis: a potential therapeutic strategy

Reactivation of latent HIV-1 by inhibition of BRD4

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.Copyright © 2022 Sfera, Thomas, Andronescu, Jafri, Sfera, Sasannia, Zapata-Martín del Campo and Maldonado. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.