The development of combination antiretroviral therapy (ART) in the mid-1990s initially raised hopes that HIV was a curable disease; however, further studies revealed that the virus persists, even in patients with undetectable levels of HIV in their plasma. Resting CD4+ T cells harbor stably integrated viral genomes that can produce infectious virus following T cell activation. Importantly, treatment interruption leads to a rapid recrudescence of infection from this latent reservoir, usually within 2 to 3 weeks. Several distinct areas of HIV research are now focused on the development of strategies to prevent the latent reservoir from replicating or to eliminate it entirely. Reviews in this series detail progress in our understanding of the molecular and cellular mechanisms of viral latency, efforts to accurately assess the size and composition of the latent viral reservoir, the characterization and development of HIV-targeted broadly neutralizing antibodies and cytolytic T lymphocytes, as well as animal models for the study of HIV latency and therapeutic strategies.
Combination antiretroviral therapy (ART) can suppress plasma HIV to undetectable levels, allowing HIV-infected individuals who are treated early a nearly normal life span. Despite the clear ability of ART to prevent morbidity and mortality, it is not curative. Even in individuals who have full suppression of viral replication on ART, there are resting memory CD4+ T cells that harbor stably integrated HIV genomes, which are capable of producing infectious virus upon T cell activation. This latent viral reservoir is considered the primary obstacle to the development of an HIV cure, and recent efforts in multiple areas of HIV research have been brought to bear on the development of strategies to eradicate or develop a functional cure for HIV. Reviews in this series detail progress in our understanding of the molecular and cellular mechanisms of viral latency, efforts to accurately assess the size and composition of the latent reservoir, the characterization and development of HIV-targeted broadly neutralizing antibodies and cytolytic T lymphocytes, and animal models for the study HIV latency and therapeutic strategies.
Janet D. Siliciano, Robert F. Siliciano
Current antiretroviral drug therapies do not cure HIV-1 because they do not eliminate a pool of long-lived cells harboring immunologically silent but replication-competent proviruses — termed the latent reservoir. Eliminating this reservoir and stimulating the immune response to control infection in the absence of therapy remain important but unsolved goals of HIV-1 cure research. Recently discovered broadly neutralizing antibodies (bNAbs) exhibit remarkable breadth and potency in their ability to neutralize HIV-1 in vitro, and recent studies have demonstrated new therapeutic applications for passively administered bNAbs in vivo. This Review discusses the roles bNAbs might play in HIV-1 treatment regimens, including prevention, therapy, and cure.
Ariel Halper-Stromberg, Michel C. Nussenzweig
HIV persistence in patients undergoing antiretroviral therapy is a major impediment to the cure of HIV/AIDS. The molecular and cellular mechanisms underlying HIV persistence in vivo have not been fully elucidated. This lack of basic knowledge has hindered progress in this area. The in vivo analysis of HIV persistence and the implementation of curative strategies would benefit from animal models that accurately recapitulate key aspects of the human condition. This Review summarizes the contribution that humanized mouse models of HIV infection have made to the field of HIV cure research. Even though these models have been shown to be highly informative in many specific areas, their great potential to serve as excellent platforms for discovery in HIV pathogenesis and treatment has yet to be fully developed.
J. Victor Garcia
The apparent cure of an HIV-infected person following hematopoietic stem cell transplantation (HSCT) from an allogeneic donor homozygous for the
Daniel R. Kuritzkes
A substantial research effort has been directed to identifying strategies to eradicate or control HIV infection without a requirement for combination antiretroviral therapy (cART). A number of obstacles prevent HIV eradication, including low-level viral persistence during cART, long-term persistence of HIV-infected cells, and latent infection of resting CD4+ T cells. Mechanisms of persistence remain uncertain, but integration of the provirus into the host genome represents a central event in replication and pathogenesis of all retroviruses, including HIV. Analysis of HIV proviruses in CD4+ lymphocytes from individuals after prolonged cART revealed that a substantial proportion of the infected cells that persist have undergone clonal expansion and frequently have proviruses integrated in genes associated with regulation of cell growth. These data suggest that integration may influence persistence and clonal expansion of HIV-infected cells after cART is introduced, and these processes may represent key mechanisms for HIV persistence. Determining the diversity of host genes with integrants in HIV-infected cells that persist for prolonged periods may yield useful information regarding pathways by which infected cells persist for prolonged periods. Moreover, many integrants are defective, and new studies are required to characterize the role of clonal expansion in the persistence of replication-competent HIV.
HIV seeds reservoirs of latent proviruses in the earliest phases of infection. These reservoirs are found in many sites, including circulating cells, the lymphoid system, the brain, and other tissues. The “shock and kill” strategy, where HIV transcription is reactivated so that antiretroviral therapy and the immune system clear the infection, has been proposed as one approach to curing AIDS. In addition to many defective viruses, resting hematopoietic cells harbor transcriptionally latent HIV. Understanding basic mechanisms of HIV gene expression provides a road map for this strategy, allowing for manipulation of critical cellular and viral transcription factors in such a way as to maximize HIV gene expression while avoiding global T cell activation. These transcription factors include NF-κB and the HIV transactivator of transcription (Tat) as well as the cyclin-dependent kinases CDK13 and CDK11 and positive transcription elongation factor b (P-TEFb). Possible therapies involve agents that activate these proteins or release P-TEFb from the inactive 7SK small nuclear ribonucleoprotein (snRNP). These proposed therapies include PKC and MAPK agonists as well as histone deacetylase inhibitors (HDACis) and bromodomain and extraterminal (BET) bromodomain inhibitors (BETis), which act synergistically to reactivate HIV in latently infected cells.
Daniele C. Cary, Koh Fujinaga, B. Matija Peterlin
After the success of combination antiretroviral therapy (cART) to treat HIV infection, the next great frontier is to cure infected persons, a formidable challenge. HIV persists in a quiescent state in resting CD4+ T cells, where the replicative enzymes targeted by cART are not active. Although low levels of HIV transcripts are detectable in these resting cells, little to no viral protein is produced, rendering this reservoir difficult to detect by the host CD8+ T cell response. However, recent advances suggest that this state of latency might be pharmacologically reversed, resulting in viral protein expression without the adverse effects of massive cellular activation. Emerging data suggest that with this approach, infected cells will not die of viral cytopathic effects, but might be eliminated if HIV-specific CD8+ T cells can be effectively harnessed. Here, we address the antiviral properties of HIV-specific CD8+ T cells and how these cells might be harnessed to greater effect toward achieving viral eradication or a functional cure.
R. Brad Jones, Bruce D. Walker
Current efforts toward achieving a cure for HIV are focused on developing strategies to eliminate latently infected CD4+ T cells, which represent the major barrier to virus eradication. Sensitive, precise, and practical assays that can reliably characterize and measure this HIV reservoir and can reliably measure the impact of a candidate treatment strategy are essential. PCR-based procedures for detecting integrated HIV DNA will overestimate the size of the reservoir by detecting replication-incompetent proviruses; however, viral outgrowth assays underestimate the size of the reservoir. Here, we describe the attributes and limitations of current procedures for measuring the HIV reservoir. Characterizing their relative merits will require rigorous evaluation of their performance characteristics (sensitivity, specificity, reproducibility, etc.) and their relationship to the results of clinical studies.
Marta Massanella, Douglas D. Richman