HIV latency: experimental systems and molecular models

Hakre, Shweta; Chávez, Leonard; Shirakawa, Kotaro; Verdin, Eric

doi:10.1111/j.1574-6976.2012.00335.x

Cited by 64 publications

(72 citation statements)

References 54 publications

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“…SWI/SNF complexes control the nucleosome landscape at active promoters and are required for HIV Tat transactivation [29]. Interestingly, we found that two core components of the SWI/SNF ATP-dependent BAF chromatin remodeling complex, SWI/SNF related, matrix associated, Actin dependent Regulator of Chromatin, subfamily D1 (SMARCD1), member 1 BAF60, and SMARCB1 (SNF5/INI1) were down-regulated two hours following vorinostat (red arrowhead Figure 6B ).…”

Section: Resultsmentioning

confidence: 92%

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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Section: Resultsmentioning

confidence: 92%

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

et al. 2014

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“…As such cells are not immortalized or clonal, primary cell models might offer a more physiologically relevant representation of latency than cell lines, and their responsiveness to stimuli might be more representative of in vivo biology. Several cell models are currently being used 81–88 (reviewed in REFS 89,90), and there are important differences in the cell subsets, viral strains and mechanisms that are used to establish latency 89,90 (TABLE 1). A careful comparison of latent HIV-1 reactivation by different stimuli across multiple primary cell models revealed diverse responses to the same stimuli.…”

Section: Model Systems Of Hiv-1 Latencymentioning

confidence: 99%

Eradicating HIV-1 infection: seeking to clear a persistent pathogen

et al. 2014

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Effective antiretroviral therapy (ART) blunts viraemia, which enables HIV-1-infected individuals to control infection and live long, productive lives. However, HIV-1 infection remains incurable owing to the persistence of a viral reservoir that harbours integrated provirus within host cellular DNA. This latent infection is unaffected by ART and hidden from the immune system. Recent studies have focused on the development of therapies to disrupt latency. These efforts unmasked residual viral genomes and highlighted the need to enable the clearance of latently infected cells, perhaps via old and new strategies that improve the HIV-1-specific immune response. In this Review, we explore new approaches to eradicate established HIV-1 infection and avoid the burden of lifelong ART.

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“…Despite these challenges, several in vitro latency models exist, which have led to important observations about how latently infected cells are maintained and reactivated (reviewed in references [16, 17]).…”

Section: Introductionmentioning

confidence: 99%

HIV Latency Is Established Directly and Early in Both Resting and Activated Primary CD4 T Cells

2015

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Highly active antiretroviral therapy (HAART) suppresses human immunodeficiency virus (HIV) replication to undetectable levels but cannot fully eradicate the virus because a small reservoir of CD4+ T cells remains latently infected. Since HIV efficiently infects only activated CD4+ T cells and since latent HIV primarily resides in resting CD4+ T cells, it is generally assumed that latency is established when a productively infected cell recycles to a resting state, trapping the virus in a latent state. In this study, we use a dual reporter virus—HIV Duo-Fluo I, which identifies latently infected cells immediately after infection—to investigate how T cell activation affects the estab-lishment of HIV latency. We show that HIV latency can arise from the direct infection of both resting and activated CD4+ T cells. Importantly, returning productively infected cells to a resting state is not associated with a significant silencing of the integrated HIV. We further show that resting CD4+ T cells from human lymphoid tissue (tonsil, spleen) show increased latency after infection when compared to peripheral blood. Our findings raise significant questions regarding the most commonly accepted model for the establishment of latent HIV and suggest that infection of both resting and activated primary CD4+ T cells produce latency.

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HIV latency: experimental systems and molecular models

Cited by 64 publications

References 54 publications

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

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

Eradicating HIV-1 infection: seeking to clear a persistent pathogen

HIV Latency Is Established Directly and Early in Both Resting and Activated Primary CD4 T Cells

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