Progress and challenges in the use of latent HIV-1 reactivating agents

Shang, Hongtao; Ding, Jiwei; Yu, Shufei; Wu, Tao; Zhang, Qiuli; Liang, Fujun

doi:10.1038/aps.2015.22

Cited by 40 publications

(26 citation statements)

References 80 publications

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“…After 400 days of viral suppression, defined as fewer than 30 SIV copies/ml in plasma measured by qPCR and confirmed by digital droplet PCR, one animal (Mn0) was maintained as procedural control and two macaques (Mn1 and Mn2) were treated with latency reversing agents. Because no Food and Drug Administration-approved compound has been successfully used to reactivate HIV-1 latent reservoirs in virally suppressed humans or nonhuman primates [28–31], we used the novel PKC activator ingenol-B, which had been previously evaluated in vitro and was efficient in activating HIV-1 long-term repeats in reporter cell lines [32–34]. Before testing the compound in our SIV-macaque model, however, we evaluated whether ingenol-B activates viral genomes in ex-vivo primary cells.…”

Section: Resultsmentioning

confidence: 99%

Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques

Gama

Abreu

Shirk

et al. 2017

Aids

130

120

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Objective:Resting CD4+ T cells have been recognized as the major cell reservoir of latent HIV-1 during antiretroviral therapy (ART). Using an simian immunodeficiency virus (SIV)/macaque model for AIDS and HIV-related neurocognitive disorders we assessed the contribution of the brain to viral latency and reactivation.Design:Pigtailed macaques were dual inoculated with SIVDeltaB670 and SIV17E-Fr and treated with an efficacious central nervous system-penetrant ART. After 500 days of viral suppression animals were treated with two cycles of latency reversing agents and increases in viral transcripts were examined.Methods:Longitudinal plasma and cerebrospinal fluid (CSF) viral loads were analyzed by quantitative and digital droplet PCR. After necropsy, viral transcripts in organs were analyzed by PCR, in-situ hybridization, and phylogenetic genotyping based on env V1 loop sequences. Markers for neuronal damage and CSF activation were measured by ELISA.Results:Increases in activation markers and plasma and CSF viral loads were observed in one animal treated with latency reversing agents, despite ongoing ART. SIV transcripts were identified in occipital cortex macrophages by in-situ hybridization and CD68+ staining. The most abundant SIV genotype in CSF was unique and expanded independent from viruses found in the periphery.Conclusion:The central nervous system harbors latent SIV genomes after long-term viral suppression by ART, indicating that the brain represents a potential viral reservoir and should be seriously considered during AIDS cure strategies.

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Section: Resultsmentioning

confidence: 99%

Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques

Gama

Abreu

Shirk

et al. 2017

Aids

130

120

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“…Although prolonged cART therapy suppresses HIV replication below the detectable level, HIV persists as a transcriptionally inactive provirus in resting memory CD4 ϩ T cells; this so-called latent reservoir has a long half-life and prevents HIV eradication by cART alone (8). HIV latency may be reversed by inducing resting CD4 ϩ T cell activation and subsequent release of infectious viruses capable of new infection (45,46). To determine whether a latent HIV reservoir exists in the resting CD4 ϩ T cells isolated from cART-treated aviremic hu-NSG mice, we conducted a viral outgrowth assay (VOA).…”

Section: Resultsmentioning

confidence: 99%

HIV Replication and Latency in a Humanized NSG Mouse Model during Suppressive Oral Combinational Antiretroviral Therapy

Satheesan

Burnett

et al. 2018

J Virol

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Although current combinatorial antiretroviral therapy (cART) is therapeutically effective in the majority of HIV patients, interruption of therapy can cause a rapid rebound in viremia, demonstrating the existence of a stable reservoir of latently infected cells. HIV latency is therefore considered a primary barrier to HIV eradication. Identifying, quantifying, and purging the HIV reservoir is crucial to effectively curing patients and relieving them from the lifelong requirement for therapy. Latently infected transformed cell models have been used to investigate HIV latency; however, these models cannot accurately represent the quiescent cellular environment of primary latently infected cells For this reason, humanized murine models have been developed for screening antiviral agents, identifying latently infected T cells, and establishing treatment approaches for HIV research. Such models include humanized bone marrow/liver/thymus mice and SCID-hu-thy/liv mice, which are repopulated with human immune cells and implanted human tissues through laborious surgical manipulation. However, no one has utilized the human hematopoietic stem cell-engrafted NOD/SCID/IL2rγ (NSG) model (hu-NSG) for this purpose. Therefore, in the present study, we used the HIV-infected hu-NSG mouse to recapitulate the key aspects of HIV infection and pathogenesis Moreover, we evaluated the ability of HIV-infected human cells isolated from HIV-infected hu-NSG mice on suppressive cART to act as a latent HIV reservoir. Our results demonstrate that the hu-NSG model is an effective surgery-free system in which to efficiently evaluate HIV replication, antiretroviral therapy, latency and persistence, and eradication interventions. HIV can establish a stably integrated, nonproductive state of infection at the level of individual cells, known as HIV latency, which is considered a primary barrier to curing HIV. A complete understanding of the establishment and role of HIV latency would greatly enhance attempts to develop novel HIV purging strategies. An ideal animal model for this purpose should be easy to work with, should have a shortened disease course so that efficacy testing can be completed in a reasonable time, and should have immune correlates that are easily translatable to humans. We therefore describe a novel application of the hematopoietic stem cell-transplanted humanized NSG model for dynamically testing antiretroviral treatment, supporting HIV infection, establishing HIV latency The hu-NSG model could be a facile alternative to humanized bone marrow/liver/thymus or SCID-hu-thy/liv mice in which laborious surgical manipulation and time-consuming human cell reconstitution is required.

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“…This reality has driven efforts to identify novel LRAs with more potent and globally encompassing effects. Results from preclinical and clinical analysis of FDA approved LRAs has revealed a need for optimization of compounds with this activity to produce sufficiently effective responses to enable elimination of the latently infected population . Importantly however, all of the clinical trials performed to date have involved drugs that had been repurposed from treatment of other conditions; and consequently, the full capability of LRAs with respect to the “shock and kill” strategy in general may not be realized until trials with compounds specifically designed and optimized for this purpose.…”

Section: Discussionmentioning

confidence: 99%

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

Hashemi

Sadowski

2019

Medicinal Research Reviews

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The latency phenomenon produced by human immunodeficiency virus (HIV-1) prevents viral clearance by current therapies, and consequently development of a cure for HIV-1 disease represents a formidable challenge. Research over the past decade has resulted in identification of small molecules that are capable of exposing HIV-1 latent reservoirs, by reactivation of viral transcription, which is intended to render these infected cells sensitive to elimination by immune defense recognition or apoptosis. Molecules with this capability, known as latency-reversing agents (LRAs) could lead to realization of proposed HIV-1 cure strategies collectively termed "shock and kill," which are intended to eliminate the latently infected population by forced reactivation of virus replication in combination with additional interventions that enhance killing by the immune system or virus-mediated apoptosis. Here, we review efforts to discover novel LRAs via low-and high-throughput small molecule screens, and summarize characteristics and biochemical properties of chemical structures with this activity.We expect this analysis will provide insight toward further research into optimized designs for new classes of more potent LRAs.---

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Progress and challenges in the use of latent HIV-1 reactivating agents

Cited by 40 publications

References 80 publications

Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques

Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques

HIV Replication and Latency in a Humanized NSG Mouse Model during Suppressive Oral Combinational Antiretroviral Therapy

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

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