Latency reversal and viral clearance to cure HIV-1

Next steps toward curing HIV-1 Since the discovery of HIV-1 more than 30 years ago, prevention and treatment strategies have dominated the research agenda. More recently, however, scientists are also focusing their efforts toward finding a cure. Margolis et al. review an approach that involves HIV-1 latency reversal and viral clearance. The idea is to reactivate any dormant virus and coax it to produce viral proteins that the immune system can recognize. By combining a latency reversal strategy with immunotherapies, the body might be able to rid itself of all infected cells. Science, this issue p. 362 BACKGROUND A central challenge to emerging efforts to cure HIV infection is the persistence of quiescent but replication-competent proviral genomes in resting CD4+ T lymphocytes and, to an unknown extent, in other cell populations. Targeted approaches are sought to reverse latency, induce viral antigen expression within formerly latently infected cells, and use immune clearance mechanisms to eradicate persistent infection. Small-molecule HIV latency-reversing agents (LRAs) capable of modulating pathways that control HIV-1 latency are the first tools to be studied in this effort. However, despite the successful reversal of latency, the only clinical interventions to date producing a significant decrease in the viral reservoir involved bone marrow transplantation. Moreover, whether the HIV-1 RNA expression induced by LRAs leads to durable viral protein presentation on the surface of infected cells sufficient to allow immune mediated clearance is unknown. Because multiple mechanisms are involved in maintaining the transcriptional silence of HIV-1, a combination of LRAs may be necessary to effectively perturb persistent HIV-1 infection. Defining the cells that harbor persistent HIV-1 is technically challenging, burdening the development of antilatency therapy. Last, immune interventions designed to clear persistently infected cells have yet to be combined with LRAs in a successful, coordinated therapeutic strategy. ADVANCES Histone deacetylase (HDAC) inhibitors have been the most widely investigated LRAs, inducing cell-associated HIV-1 RNA in four clinical studies. The complex nature of the mechanisms that restrict HIV-1 expression of the population of latent integrated proviruses suggests the hypothesis that combinations of agents could more effectively disrupt latency. Numerous in vitro studies support this hypothesis, but thus far, only one animal model study used several LRAs; although results appeared promising, the effect of this combination was not directly assessed. A study of latently infected cells obtained from HIV-1+ donors on antiretroviral therapy revealed that instantaneous reversal of latency across all cells harboring integrated proviruses may be challenging and suggests that effective LRA strategies will likely need to be delivered serially over time. This study also illustrates the limitations of assessing the persistence of latent infection via HIV-1 RNA expression because a majority of such RNA transcripts are defective and therefore irrelevant. New approaches,such as novel techniques that can quantitate the frequency of rare cells in a large population that are capable of expressing viral antigen, may surmount this challenge. Other recent efforts have examined the obstacles to clearance of persistent, latent infection. For example, the latent reservoir harbors viral mutant subspecies that have previously escaped the extant antiviral immune response. Tissue sanctuaries that may be poorly accessed by the cytotoxic T lymphocyte (CTL) response have been described, as has the potential for some LRAs to interfere with CTL activity. Whether the extent of antigen presentation induced by the current generation of LRAs is sufficient to allow targeting and clearance of infected cells remains unknown. OUTLOOK Although the challenges of latent HIV-1 infection are daunting, the stability of the latent pool over years of antiviral therapy gives hope that an effective perturbation of the homeostasis that maintains the latent pool may allow substantial depletion, and eventually eradication, of persistent infection. The steady advances in animal models of HIV-1 latency, tools for the assessment of persistent infection, LRAs to disrupt latency, and emerging immunotherapeutics to clear persistently infected cells suggest that the first effective combination studies may be close at hand. Such studies will likely represent progress toward the goal of HIV-1 cure while also revealing new challenges to be overcome. HIV latency. Potential obstacles to HIV eradication. (A) True virological and transcriptional latency, with little HIV RNA expression, and no detectable HIV antigen presentation. (B) So-called “active latency” with ongoing production of HIV RNA and antigen. (C) Proliferation of latently infected cells, driven by homeostatic forces, or by dysregulation of the host gene program by a viral integrant, without viral production. (D) The possibility that de novo infection occurs despite effective ART. (E) Failure of immune clearance owing to viral epitope escape or host immune exhaustion. Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication—a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society.