Eliminating HIV reservoirs for a cure

Finding a cure for HIV is challenging because the virus is able to integrate itself into the host cell genome and establish a silent state, called latency, allowing it to evade antiviral drugs and the immune system. Various “shock and kill” strategies are being explored in attempts to eliminate latent HIV reservoirs. The goal of these approaches is to reactivate latent viruses (“shock”), thereby exposing them to clearance by viral cytopathic effects or immune-mediated responses (“kill”). To date, there has been limited clinical success using these methods. In this review, we highlight various functions of the HIV accessory protein Nef and discuss their double-edged effects that may contribute to the limited effectiveness of current “shock and kill” methods to eradicate latent HIV reservoirs in treated individuals.

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HIV Reservoirs in Lymph Nodes and Spleen

Encyclopedia of AIDS ◽

10.1007/978-1-4939-7101-5_431 ◽

2018 ◽

pp. 813-818

Author(s):

Sean G. Kelly ◽

Babafemi O. Taiwo

Keyword(s):

Lymph Nodes ◽

Hiv Reservoirs

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HIV INFECTION MANIFESTATIONS IN GASTROENTEROLOGY: EMERGING ISSUES IN PATHOGENESIS

Epidemiology and Infectious Diseases (Russian Journal) ◽

10.18821/1560-9529-2018-23-4-190-198 ◽

2018 ◽

Vol 23 (4) ◽

pp. 190-198

Author(s):

T. R. Khalilulin ◽

Timur P. Bessarab ◽

A. I. Mazus ◽

M. V. Nagibina

Keyword(s):

Hiv Infection ◽

Digestive System ◽

Current Data ◽

Hiv Reservoirs ◽

Gastrointestinal Manifestations ◽

Emerging Issues

The review provides current data on the pathogenesis of HIV infection, focusing on its gastrointestinal manifestations. The authors deal with specific characteristics of the digestive system, which play a key role in infecting, preserving HIV reservoirs, and HIV-caused disease progressing. The study addresses various aspects of the gastroenterological pathology combined with the HIV infection.

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HIV-1 Productively Infects and Integrates in Bronchial Epithelial Cells

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2020.612360 ◽

2021 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Dinesh Devadoss ◽

Shashi P. Singh ◽

Arpan Acharya ◽

Kieu Chinh Do ◽

Palsamy Periyasamy ◽

...

Keyword(s):

Epithelial Cells ◽

Bronchial Epithelial Cells ◽

Lung Epithelial Cells ◽

People Living With Hiv ◽

Sequencing Analysis ◽

Hiv Reservoirs ◽

Bronchial Epithelial ◽

Lung Epithelial ◽

Hiv 1

BackgroundThe role of lung epithelial cells in HIV-1-related lung comorbidities remains unclear, and the major hurdle in curing HIV is the persistence of latent HIV reservoirs in people living with HIV (PLWH). The advent of combined antiretroviral therapy has considerably increased the life span; however, the incidence of chronic lung diseases is significantly higher among PLWH. Lung epithelial cells orchestrate the respiratory immune responses and whether these cells are productively infected by HIV-1 is debatable.MethodsNormal human bronchial epithelial cells (NHBEs) grown on air–liquid interface were infected with X4-tropic HIV-1LAV and examined for latency using latency-reversing agents (LRAs). The role of CD4 and CXCR4 HIV coreceptors in NHBEs were tested, and DNA sequencing analysis was used to analyze the genomic integration of HIV proviral genes, Alu-HIVgag-pol, HIV-nef, and HIV-LTR. Lung epithelial sections from HIV-infected humans and SHIV-infected macaques were analyzed by FISH for HIV-gag-pol RNA and epithelial cell-specific immunostaining.Results and DiscussionNHBEs express CD4 and CXCR4 at higher levels than A549 cells. NHBEs are infected with HIV-1 basolaterally, but not apically, by X4-tropic HIV-1LAV in a CXCR4/CD4-dependent manner leading to HIV-p24 antigen production; however, NHBEs are induced to express CCR5 by IL-13 treatment. In the presence of cART, HIV-1 induces latency and integration of HIV provirus in the cellular DNA, which is rescued by the LRAs (endotoxin/vorinostat). Furthermore, lung epithelial cells from HIV-infected humans and SHIV-infected macaques contain HIV-specific RNA transcripts. Thus, lung epithelial cells are targeted by HIV-1 and could serve as potential HIV reservoirs that may contribute to the respiratory comorbidities in PLWH.

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Clinical Eradication of Latent HIV Reservoirs: Where are we Now?

10.2174/9789811464454121050003 ◽

2021 ◽

pp. 1-38

Author(s):

Lilly M. Wong ◽

Guochun Jiang

Keyword(s):

Hiv Reservoirs ◽

Latent Hiv

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Modeling HIV-1 Latency Using Primary CD4+ T Cells from Virally Suppressed HIV-1-Infected Individuals on Antiretroviral Therapy

Journal of Virology ◽

10.1128/jvi.02248-18 ◽

2019 ◽

Vol 93 (11) ◽

Cited By ~ 4

Author(s):

Hiroshi Takata ◽

Cari Kessing ◽

Aaron Sy ◽

Noemia Lima ◽

Julia Sciumbata ◽

...

Keyword(s):

T Cells ◽

Ex Vivo ◽

Viral Reactivation ◽

Hiv Latency ◽

Cell Models ◽

Hiv Cure ◽

Hiv Reservoirs ◽

Hiv 1

ABSTRACT The low frequency of latently HIV-infected cells in vivo limits the testing of potential HIV cure strategies using cells from successfully suppressed individuals. To date, primary cell models of latency use cells infected in vitro. Primary CD4+ T cell models carrying an individual’s endogenous HIV reservoir that recapitulate in vivo conditions of HIV latency are still outstanding. We developed a primary CD4+ T cell model of HIV latency derived from memory CD4+ T cells isolated from virally suppressed HIV-infected individuals that recapitulates HIV-1 latency and viral reactivation events. This model is based on the expansion of primary CD4+ T cells up to 300-fold in cell number. These cells reestablish a resting state without active virus production after extended culture and maintain a stable number of total HIV proviruses. The ability of these cells to respond to various classes of latency-reversing agents is similar to that of ex vivo CD4+ T cells directly isolated from blood. Importantly, viral outgrowth assays confirmed the ability of these expanded cells to produce replication-competent endogenous virus. In sum, this model recapitulates ex vivo viral reactivation conditions, captures the variability between individuals with different HIV reservoirs, and provides large numbers of cells for testing multiple agents from a single donor. The use of this novel model will allow accurate exploration of novel cure approaches aimed either at promoting viral reactivation or maintaining sustained latency. IMPORTANCE Primary cell models of HIV latency have been very useful to identify mechanisms contributing to HIV latency and to evaluate potential HIV cure strategies. However, the current models utilize in vitro infection with exogenous virus that does not fully recapitulate virus reactivation profiles of endogenous HIV in in vivo-infected CD4+ T cells. In contrast, obtaining sufficient amounts of CD4+ T cells from HIV-infected individuals to interrogate the HIV reservoir in vitro requires leukapheresis. In the model we propose here, in vitro expansion and extended culture of primary CD4+ T cells isolated from virally suppressed HIV-infected individuals enable obtaining large numbers of cells harboring endogenous latent HIV reservoirs without performing leukapheresis. This model captures the variability of HIV reservoirs seeded in different individuals and should be useful to evaluate future HIV cure strategies.

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