Understanding HIV Latency: The Road to an HIV Cure

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Abstract

Treatment with antiretroviral therapy dramatically increases the survival of HIV-infected individuals. However, treatment has to be continued for life because it does not lead to the full eradication of infection. HIV persists in resting CD4+ T cells, and possibly other cell types, and can reemerge from these cells when therapy is interrupted. Here, we review molecular mechanisms that have been proposed to contribute to HIV latency, as well as the relative roles of cis- and trans-acting mechanisms. We also discuss existing and future therapeutic opportunities regarding HIV latency that might lead to a future cure for HIV infection.

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Most cited references 65

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Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells

Alex Shalek, Rahul Satija, Xian Adiconis … (2013)

Recent molecular studies have revealed that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels, and phenotypic output 1–5 , with important functional consequences 4,5 . Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs 1,2 or proteins 5,6 simultaneously because genomic profiling methods 3 could not be applied to single cells until very recently 7–10 . Here, we use single-cell RNA-Seq to investigate heterogeneity in the response of bone marrow derived dendritic cells (BMDCs) to lipopolysaccharide (LPS). We find extensive, and previously unobserved, bimodal variation in mRNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization (RNA-FISH) for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits.

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HIV reproducibly establishes a latent infection after acute infection of T cells in vitro.

Albert Jordan, Dwayne Bisgrove, Eric Verdin (2003)

The presence of latent reservoirs has prevented the eradication of human immunodeficiency virus (HIV) from infected patients successfully treated with anti-retroviral therapy. The mechanism of postintegration latency is poorly understood, partly because of the lack of an in vitro model. We have used an HIV retroviral vector or a full-length HIV genome expressing green fluorescent protein to infect a T lymphocyte cell line in vitro and highly enrich for latently infected cells. HIV latency occurred reproducibly, albeit with low frequency, during an acute infection. Clonal cell lines derived from latent populations showed no detectable basal expression, but could be transcriptionally activated after treatment with phorbol esters or tumor necrosis factor alpha. Direct sequencing of integration sites demonstrated that latent clones frequently contain HIV integrated in or close to alphoid repeat elements in heterochromatin. This is in contrast to a productive infection where integration in or near heterochromatin is disfavored. These observations demonstrate that HIV can reproducibly establish a latent infection as a consequence of integration in or near heterochromatin.

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Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation.

Liang Shan, Kai Deng, Neeta S Shroff … (2012)

Highly active antiretroviral therapy (HAART) suppresses HIV-1 replication but cannot eliminate the virus because HIV-1 establishes latent infection. Interruption of HAART leads to a rapid rebound of viremia, so life-long treatment is required. Efforts to purge the latent reservoir have focused on reactivating latent proviruses without inducing global T cell activation. However, the killing of the infected cells after virus reactivation, which is essential for elimination of the reservoir, has not been assessed. Here we show that after reversal of latency in an in vitro model, infected resting CD4(+) T cells survived despite viral cytopathic effects, even in the presence of autologous cytolytic T lymphocytes (CTLs) from most patients on HAART. Antigen-specific stimulation of patient CTLs led to efficient killing of infected cells. These results demonstrate that stimulating HIV-1-specific CTLs prior to reactivating latent HIV-1 may be essential for successful eradication efforts and should be considered in future clinical trials. Copyright Â© 2012 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Title: Annual Review of Medicine

Abbreviated Title: Annu. Rev. Med.

Publisher: Annual Reviews

ISSN (Print): 0066-4219

ISSN (Electronic): 1545-326X

Publication date Created: January 14 2015

Publication date (Print): January 14 2015

Volume: 66

Issue: 1

Pages: 407-421

Affiliations

[1 ]Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94941; email:

Article

DOI: 10.1146/annurev-med-092112-152941

PMC ID: 4381961

PubMed ID: 25587657

SO-VID: 29d69d1b-5f8e-44f9-8955-da3483384d8d

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ScienceOpen disciplines: Medicine,Cell biology,Immunology,Human biology,Microbiology & Virology,Life sciences

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ScienceOpen disciplines: Medicine, Cell biology, Immunology, Human biology, Microbiology & Virology, Life sciences

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Understanding HIV Latency: The Road to an HIV Cure

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Annual Reviews HIV/AIDS: Public Health and Society

Most cited references 65

Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells

HIV reproducibly establishes a latent infection after acute infection of T cells in vitro.

Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation.

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