Regulation of HIV-1 latency by T-cell activation

Abstract

HIV-infected patients harbor approximately 10(5)-10(6) memory CD4 T-cells that contain fully integrated but transcriptionally silent HIV proviruses. While small in number, these latently infected cells form a drug-insensitive reservoir that importantly contributes to the life-long persistence of HIV despite highly effective antiviral therapy. In tissue culture, latent HIV proviruses can be activated when their cellular hosts are exposed to select proinflammatory cytokines or their T-cell receptors are ligated. However, due to a lack of potency and/or dose-limiting toxicity, attempts to purge virus from this latent reservoir in vivo with immune-activating agents, such as anti-CD3 antibodies and IL-2, have failed. A deeper understanding of the molecular underpinnings of HIV latency is clearly required, including determining whether viral latency is actively reinforced by transcriptional repressors, defining which inducible host transcription factors most effectively antagonize latency, and elucidating the role of chromatin in viral latency. Only through such an improved understanding will it be possible to identify combination therapies that might allow complete purging of the latent reservoir and to realize the difficult and elusive goal of complete eradication of HIV in infected patients.

Figure 1

T-cell activation status influences establishment of active, preintegration- or postintegration latency. (A) HIV infection of unactivated, resting T-cells results in labile preintegration latency with unintegrated, cytoplasmasmic provirus. (B) Infection of activated T-cells results in integrated provirus and active infection with efficient production of progeny virions. (C) Infection of cells in the process of resolving T-cell activation permits completion of reverse transcription and integration, but fails to support active expression of viral genes, i.e. postintegration latency.

Figure 2

Signaling networks linking T-cell activating stimuli to HIV-inducing transcription factors. NF-κB, NFAT, and AP-1 mediate activation of latent HIV in response to cytokines, TCR ligation, and mitogens.

Figure 3

Molecular mechanisms of postintegration HIV-1 latency. Multiple mechanisms underlying HIV-1 latency have been observed in various models, including transcriptional interference by proximal promoters of host genes (A), exclusion of basal transcription factors from the HIV promoter by heterochromatin (B), or HDAC-mediated chromatin condensation (C), insufficiency of transcriptional coactivators (D), or basal nuclear export factors (E).