Coaxing HIV-1 from resting CD4 T cells

Ylisastigui, Loyda; Archin, Nancie M.; Lehrman, Ginger; Bosch, Ronald J.

doi:10.1097/00002030-200405210-00003

Cited by 230 publications

(95 citation statements)

References 42 publications

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“…The primary latent cell models in this study were utilized instead of cells directly isolated from HIV-1 infected patients for a specific reason. Generally, when using patient samples for latency activation studies, the addition of allogeneic, MHC mismatched CD4 + T cells is required to allow viral outgrowth upon latent viral reactivation [4,61-64] . The addition of allogeneic cells themselves might contribute to the activation of latent virus in patient sample systems and therefore, the latently infected primary cell models, described in the results section, were chosen for testing the antagonist activity of PIs.…”

Section: Discussionmentioning

confidence: 99%

Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication

et al. 2013

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BackgroundExisting highly active antiretroviral therapy (HAART) effectively controls viral replication in human immunodeficiency virus type 1 (HIV-1) infected individuals but cannot completely eradicate the infection, at least in part due to the persistence of latently infected cells. One strategy that is being actively pursued to eliminate the latent aspect of HIV-1 infection involves therapies combining latency antagonists with HAART. However, discordant pharmacokinetics between these types of drugs can potentially create sites of active viral replication within certain tissues that might be impervious to HAART.ResultsA preliminary reverse genetic screen indicated that the proteasome might be involved in the maintenance of the latent state. This prompted testing to determine the effects of proteasome inhibitors (PIs) on latently infected cells. Experiments demonstrated that PIs effectively activated latent HIV-1 in several model systems, including primary T cell models, thereby defining PIs as a new class of HIV-1 latency antagonists. Expanding upon experiments from previous reports, it was also confirmed that PIs inhibit viral replication. Moreover, it was possible to show that PIs act as bifunctional antagonists of HIV-1. The data indicate that PIs activate latent provirus and subsequently decrease viral titers and promote the production of defective virions from activated cells.ConclusionsThese results represent a proof-of-concept that bifunctional antagonists of HIV-1 can be developed and have the capacity to ensure precise tissue overlap of anti-latency and anti-replication functions, which is of significant importance in the consideration of future drug therapies aimed at viral clearance.

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Section: Discussionmentioning

confidence: 99%

Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication

et al. 2013

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“…Histone deacetylase inhibitors (HDACi) can activate HIV production efficiently in nearly all latently infected cell lines [4]–[9] and in many but not all primary CD4 + T-cell models of latency [10]. Using resting CD4 + T-cells from HIV-infected patients on cART ex vivo , HDACi induce both virus transcription and production of free virus [11], although the amount of virus produced from resting CD4+ T-cells is significantly less than that induced by a T-cell mitogen [12].…”

Section: Introductionmentioning

confidence: 99%

Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

et al. 2014

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Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.Trial RegistrationClinicalTrials.gov NCT01365065

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“…In addition to the sequestration and nuclear exclusion of critical transcription factors, the recruitment of histone deacetylases (HDACs) to the viral long terminal repeat (LTR) region and the resulting reduced chromatin accessibility also represent a mechanism whereby viral expression is inhibited and latent infection is maintained (reviewed in reference 26). Indeed, ex vivo treatment of CD4 ϩ T cells from cART-suppressed patients with histone deacetylase inhibitors (HDACi) has resulted in increased levels of histone acetylation and associated expression of intracellular viral RNA (vRNA) and the production of virions (27)(28)(29)(30)(31)(32). These findings were the impetus for the recent clinical evaluations in cART-suppressed subjects of a single dose and multiple doses of suberoylanilide hydroxamic acid (SAHA; Vorinostat), an HDACi approved for the treatment of cutaneous T cell lymphoma (30,33).…”

mentioning

confidence: 99%

“…Treatment of latently infected cells with SAHA and other HDACi compounds has been shown to induce viral transcription and virus production in several in vitro models of HIV-1 latency (58-65) and in primary CD4 ϩ T cell from cART-suppressed patients (27)(28)(29)(30)(31)(32). Moreover, HIV-1 cellassociated viral RNA levels in resting CD4…”

mentioning

confidence: 99%

Effect of Suberoylanilide Hydroxamic Acid (SAHA) Administration on the Residual Virus Pool in a Model of Combination Antiretroviral Therapy-Mediated Suppression in SIVmac239-Infected Indian Rhesus Macaques

Prete

Shoemaker

Oswald

et al. 2014

Antimicrob Agents Chemother

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Nonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0-to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool. Ex vivo SAHA treatment of CD4 ؉ T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration. In vivo virologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHAtreated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression for in vivo assessments of AIDS virus functional cure/eradication approaches.

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Coaxing HIV-1 from resting CD4 T cells

Cited by 230 publications

References 42 publications

Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication

Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication

Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

Effect of Suberoylanilide Hydroxamic Acid (SAHA) Administration on the Residual Virus Pool in a Model of Combination Antiretroviral Therapy-Mediated Suppression in SIVmac239-Infected Indian Rhesus Macaques

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