key: cord-0801720-moxcnhzu
authors: Huerta, Leonor
title: Editorial: Anti-infective 2020: HIV—From pathogenesis to treatment
date: 2021-01-11
journal: Curr Opin Pharmacol
DOI: 10.1016/j.coph.2020.12.001
sha: 3f6afa114ff0f847fc563686d4a8b584c6e09987
doc_id: 801720
cord_uid: moxcnhzu

nan

Editorial: Anti-infective 2020: HIV-From pathogenesis to treatment Leonor Huerta In spite of the success of a number of vaccines in controlling or eradicating infectious diseases, global social conditions remain as effective breeding grounds for the emergence of new pathogens, as has been shown by the epidemics of HIV and SARS-Cov-2, the virus causing the coronavirus disease 2019 (COVID- 19) , to cite those viral infections that have affected a significant number of people [1, 2] . Although strategies for effective, organized surveillance, and prevention measures should be routinely implemented, there is a constant need for new forms of treatment.

HIV is an enveloped virus that has a special tropism by cells of the immune system, in which it replicates. The virus produces an acute infection that subsequently persists as a mostly asymptomatic disease in the majority of HIV þ individuals, while causing cumulative deleterious effects on immune function. Key findings that relate to the mechanism of AIDS pathogenesis frame the search for new therapeutic approaches and include the following list. i) Gut mucosal immunity is seriously damaged early in the infection by HIV replication and direct viral cytopathic effects, resulting in the loss of the gut barrier integrity and leading to permeability to microbial products and dysbiosis. The appearance in the circulation of translocated bacterial products is closely linked to the systemic chronic immune activation that drives disease pathogenesis and chronic inflammation, even in patients under antiretroviral therapy (ART) [3, 4] ii) HIV viral particle retention in lymphoid tissues induces local innate and adaptive immune responses to HIV. The sustained activation causes damage to the lymphoid tissue architecture by scarring [5, 6] , limiting the access of these cells to essential homeostatic factors. This process contributes to immune cell loss and is related to the failure of antiretroviral therapy (ART) to meaningfully increase CD4(þ) T-cell populations [7] . iii) The HIV genome is established as a latent virion in different cell types and tissues early in infection. The persistence of latent virus in these reservoirs is perhaps the major barrier to virus eradication [8] . The 2020 Anti-Infective Section of Current Opinion in Pharmacology covers established and new approaches to HIV treatment, factors associated with therapeutic efficacy, and the processes favoring replication and persistence of the virus in the organism despite the ART approach. It also includes clinical and preclinical aspects associated with improving treatment. After almost four decades of development, ARTs have proven effective in inducing the long-term suppression of HIV plasma viremia and in increasing patient life expectancy when combined with improvements in health care [9, 10] . A treatment regimen against HIV is composed of three or four drugs, commonly referred to as ART or combined antiretroviral therapy (cART). To date, 10 of 23 Food and Drug Administrationeapproved anti-HIV medicines target the HIV reverse transcriptase (RT) [11] . These are divided into two categories, nucleoside RT inhibitors (NRTIs) and non-NRTIs(NNRTIs). The genetic diversity of HIV in a single individual is reflected in the integrated proviral reservoir. The review by Wilson and Lynch [17] from the Lynch laboratory in the Department of Microbiology, Immunology and Tropical Medicine at George Washington University, Washington DC, USA, summarizes current understanding of the diversity and complexity of the viral reservoir in ART-treated patients and its manifestations after analytical treatment interruption studies, which demonstrated that viremia re-emerges quickly after ART cessation [18, 19] . In principle, broadly neutralizing antibodies, which target conserved epitopes of the virus and are highly effective against most circulating strains in vitro, represent an alternative to confront the rebound. This promising strategy includes antibody combinations, prescreening individuals for bNAb sensitivity, focusing on low-diversity individuals, and targeting of host proteins.

The equilibrium between the gut microbiota, the intestinal barrier and the mucosal immune system is altered by HIV early in the infection. Local and systemic inflammatory events are key features of untreated HIV infection and are only partially reversed by ART. Modest results have been obtained when aiming at restoring the mucosal immune system. The review by Rosel-Pech et al. [20] from the Cardoso group at the Instituto Nacional de Enfermedades Respiratorias, Mexico City, México, discusses the current evidence supporting a role for microbial dysbiosis in HIV pathogenesis. The authors show that after controlling for sexual preference [21] and gender, gut microbiota alterations present in HIV infection are linked to metabolic syndromes. Therapeutic approaches using fecal microbiota transplantation to restore the mucosal immune system and the gut barrier by increasing the abundance of bacteria with immunomodulatory properties, however, remain at an early stage of investigation.

The topic of HIV is an outstanding example of cooperative efforts to contain a chronic disease with drug combinations and approaches targeted to the pathogenic mechanisms. It is hoped that this collation of reviews on key milestones in the search for AIDS therapies may guide researchers in other chronic disease areas.

WHO: Coronavirus disease (COVID-19) dashboard. 2020. https:// covid19.who.int/?gclid=Cj0KCQjw8r T8BRCbARIsALWiOvR0EkrY4m-FfTaVmJq37nPdJep wGSdT9NLFcmOxmMQRpGLhSFJWhLcaAsHeEALw_wcB

Markowitz Martin: Mechanisms of gastrointestinal CD4 + T-cell Depletion during acute and early human immunodeficiency virus type 1 infection

Microbial translocation is a cause of systemic immune activation in chronic HIV infection

Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection

CD8+ T cells with high TGF-b1 expression cause lymph node fibrosis following HIV infection

Persistent HIV-1 replication maintains the tissue reservoir during therapy

Barriers and strategies to achieve a cure for HIV

Antiretroviral Therapy Cohort Collaboration: Survival of HIVpositive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies

Improved life expectancy of people living with HIV: who is left behind? Lancet HIV 2017

Non-nucleoside reverse transcriptase inhibitors (NNRTIs): a brief overview of clinically approved drugs and combination regimens

Recent discoveries in HIV-1 reverse transcriptase inhibitors

Pharmacologic approaches to HIV-associated neurocognitive disorders

Design strategies for long-acting anti-HIV pharmaceuticals

RNAi therapeutics: an antiviral strategy for human infections

Embracing diversity: how can broadly neutralizing antibodies effectively target adverse HIV-1 reservoir?

Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption

Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection

Therapeutic avenues for restoring the gut microbiome in HIV infection

Gut microbiota linked to sexual preference and HIV infection