New Concepts in Therapeutic Manipulation of HIV-1 Transcription and Latency: Latency Reversal versus Latency Prevention

Abstract

Antiretroviral therapy (ART) has dramatically improved the prognosis for people living with HIV-1, but a cure remains elusive. The largest barrier to a cure is the presence of a long-lived latent reservoir that persists within a heterogenous mix of cell types and anatomical compartments. Efforts to eradicate the latent reservoir have primarily focused on latency reversal strategies. However, new work has demonstrated that the majority of the long-lived latent reservoir is established near the time of ART initiation, suggesting that it may be possible to pair an intervention with ART initiation to prevent the formation of a sizable fraction of the latent reservoir. Subsequent treatment with latency reversal agents, in combination with immune clearance agents, may then be a more tractable strategy for fully clearing the latent reservoir in people newly initiating ART. Here, we summarize molecular mechanisms of latency establishment and maintenance, ongoing efforts to develop effective latency reversal agents, and newer efforts to design latency prevention agents. An improved understanding of the molecular mechanisms involved in both the establishment and maintenance of latency will aid in the development of new latency prevention and reversal approaches to ultimately eradicate the latent reservoir.

Keywords: HIV-1 eradication and cure; HIV-1 latency and reactivation; HIV-1 latent reservoir; chromatin and epigenetics; mechanisms and therapeutic opportunities; viral and host transcriptional regulators.

Figure 1

During ongoing viremia or early ART, cells are infected with circulating viral species (purple). Some of these infected cells may survive to enter gradually deeper states of proviral quiescence and latency (red arrow). Recent and older clones (illustrated by progressively darker colors) may proliferate and may enter deeper states of latency, or may progressively leave quiescence (green arrow) due to the effects of host cell or viral activation. Infected cells may also die due to immune clearance, viral cytopathic effects, or simply host cell senescence. The frequency of cells harboring the virus in “deep latency” (darker-colored circles) is therefore limited. Once ART is initiated, new infections are prevented. With the resolution of viremia, immune activation wanes, and the forces that enforce latency (red line) may strengthen, while those that induce viral expression and the exit from latency (green line) wane. Over time the frequency of latent infection reaches a balance, where the proliferation rate of latent clones is roughly matched by clonal clearance or cell death.

Figure 2

Prior to ART initiation, very little virus is in deep latency because of immune activation, host cell turnover, and higher rates of viral reactivation. Administration of a latency prevention agent (LPA) near the time of ART initiation may therefore prevent the host changes that establish and enforce latency. After ART is initiated, the latent reservoir is stabilized and subject to multiple molecular mechanisms of latency. Virus in deep latency, in particular, is suppressed by layers of host-driven mechanisms, including epigenetic modifications. A single LRA may therefore move the virus “uphill” into a shallower state of latency (red arrows) without restoring viral gene expression. A combination of distinct LRAs may be required to allow broad and clinically effective reversal of latency, making the proviral reservoir vulnerable to immune mechanisms and therapeutics to eradicate persistent HIV infection.