The Biology of the HIV-1 Latent Reservoir and Implications for Cure Strategies

Lillian B Cohn, Nicolas Chomont, Steven G Deeks, Lillian B Cohn, Nicolas Chomont, Steven G Deeks

Abstract

Antiretroviral therapy (ART) inhibits HIV replication but is not curative. During ART, the integrated HIV genome persists indefinitely within CD4+ T cells and perhaps other cells. Here, we describe the mechanisms thought to contribute to its persistence during treatment and highlight findings from numerous recent studies describing the importance of cell proliferation in that process. Continued progress elucidating the biology will enhance our ability to develop effective curative interventions.

Conflict of interest statement

Declaration of Interests S.G.D. receives grant support from Gilead, Merck, and ViiV. He is a member of the scientific advisory boards for BryoLogyx and Enochian Biosciences and has consulted for AbbVie, Biotron, and Eli Lilly.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1.. HIV-1 persistence through clonal proliferation.
Figure 1.. HIV-1 persistence through clonal proliferation.
Three independent mechanisms are thought to drive proliferation of latently infected cells. First, the viral integration site may provide a survival advantage allowing preferential proliferation of the infected clone. Second, homeostatic cytokines, such as IL-7, may signal latently infected cells to divide. Finally, latently infected CD4+ T cells with antigen specific T cell receptors may divide in response to recurrent antigen exposure.
Figure 2.. Antigen driven viral persistence.
Figure 2.. Antigen driven viral persistence.
The presence of chronic viral infection (in blue) leads to specific activation of antigen responsive CD4+ T cells. These activated T cells are targets for primary HIV-1 infection. Upon initiation of antiretroviral therapy, the majority of productively infected cells die rapidly, leaving behind latently infected cells. During repeated exposure to chronic virus, the latently infected, antigen specific cells divide, and the clones wax and wane in response to antigen exposure. If therapy is ceased, chronic viral antigen can be presented to latently infected cells which may trigger HIV-1 transcription and virus production, resulting in viral rebound and latent reservoir reseeding.
Figure 3.. Clinical strategies for eradication.
Figure 3.. Clinical strategies for eradication.
Strategies are divided into those which aim to reduce the size of the reservoir, control viral rebound, or silence the reservoir.

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