From reactivation of latent HIV-1 to elimination of the latent reservoir: the presence of multiple barriers to viral eradication

Abstract

The discovery of a stable latent reservoir for HIV-1 in resting memory CD4(+) T cells provides a mechanism for lifelong persistence of HIV-1. The long-lived latently infected cells persist in spite of prolonged highly active antiretroviral therapy and present a major barrier to a cure of HIV-1 infection. In this review, we discuss the current understanding of HIV-1 persistence and latent viral infection in the context of effective antiretroviral therapy and the recent progress in purging latent viral reservoirs. Recent studies demonstrate that reactivation of latent HIV-1 is a promising strategy for the depletion of these viral reservoirs. A thorough evaluation of the anti-latency activity of drug candidates should include the measurement of changes in intracellular viral RNA, plasma virus levels, and the size of latent viral reservoirs, as well as potential adverse effects. Currently, there are several technical barriers to the evaluation of anti-latency drugs in vivo. We also discuss these challenging issues that remain unresolved.

Figure 1. HIV-1 latent infection

In productively infected cells, HIV-1 rapidly completes all the steps including entry, reverse transcription, integration, viral gene transcription and virus production. There are two forms of latent infection: post-integration latency and pre-integration latency. Post-integration latency can be generated when some activated CD4⁺ T cells survives and reverts back to a resting state. In these cells, HIV-1 completes integration but its gene transcription is silenced. Post-integration latency can also be generated when HIV-1 infects resting CD4⁺ T cells and completes all the steps in the life cycle through integration. However, infection of resting CD4⁺ T cells is less efficient because of the blocks at the steps of reverse transcription and integration. Latently infected resting CD4⁺ T cells with integrated provirus can produce viruses after encountering its cognate antigen. Pre-integration latency can be generated when HIV-1 completes reverse transcription in resting CD4⁺ T cells but fails to integrate into the host genome. Pre-integration latency is a labile form of latency that decays rapidly due to the short half life of HIV-1 double-stranded DNA.

Figure 2. (A) Establishment and maintenance of latent reservoir for HIV-1

Latently infected cells appear to arise when activated CD4⁺ T cells become infected and a small fraction of them survive and revert to a resting memory state. In patient under suppressive antiretroviral therapy, ongoing viral infection of activated and resting CD4⁺ T cells is inhibited by antiretroviral drugs. The viral latent reservoir is established prior to the initiation of HAART. Due to the lack of viral gene expression, latently infected resting CD4⁺ T cells avoid viral CPE or host immune response. When encountering their cognate antigen, resting CD4⁺ T cells harboring latent virus become activated and induce viral gene expression and virus production, which appears to be the major source of residual plasma viremia. Latently infected resting CD4⁺ T cells also undergo homeostatic proliferation driven by IL-7 or IL-15, thus replenish the latent reservoir. (B) Strategies for purging viral latent reservoir. Nonspecific reactivation of latent HIV-1 using interleukin-2 plus anti-CD3 antibodies did not deplete the viral reservoir for unknown reasons. Such strategy caused global T cell activation, massive cytokine release and severe adverse effects. Compounds that reactivate latent HIV-1 but avoid activating the host cells are identified using cell models of HIV-1 latency. However, virus reactivation does not cause the death of infected resting cells due to insufficient viral CPE and defective CTL responses. Priming CTL response prior to virus reactivation is a promising strategy to enhance killing of resting CD4⁺ T cells in which the latent infection is reversed.