Mechanisms of HIV Latency: an Emerging Picture of Complexity David M. Margolis Published online: 27 January 2010 # Springer Science+Business Media, LLC 2010 Abstract Rarely HIV type 1 establishes proviral latency within the host genome, maintained with little or no viral gene expression. This state has been quantitated in peripheral blood and lymphoid tissues of HIV-infected patients, appearing in the earliest days of infection. These rare cellular reservoirs are unaffected by current antiretro- viral therapy and unrecognized by the host immune response, and can regenerate disseminated viremia if therapy is interrupted. Proviral latency may be established when a newly HIV-infected cell exits the cell cycle and returns to the resting state. Rarely, direct infection of resting cells may also occur. Multiple molecular mechanisms appear to underlie the establishment and maintenance of persistent, latent HIV infection, most frequent in the resting central memory CD4+ T cell. Interrupting processes that maintain latency may allow therapeutic attack of this primary form of persistent HIV infection, but a better understanding of relevant mechanisms in vivo is needed. Keywords Latency . Resting CD4+ T cell . Chromatin . Histone . HDAC . Methylation . IL-7 Introduction Antiretroviral therapy (ART) has markedly decreased morbidity and mortality in HIV-1-infected individuals in the developed world. Successful therapy often results in stable plasma levels of HIV-1 RNA below the limits of detection of clinical assays. Nevertheless, HIV-1 infection has not been cured by ART. The causes of persistence of HIV infection in the face of current therapy appear to be multifactorial: latent but replication-competent provirus in resting CD4 + T lymphocytes, cryptic viral expression below the limits of detection of clinical assays, and viral sanctuary sites might all contribute to persistence. Evidence that cellular factors are required to maintain quiescence implies that proviral latency is an unstable state of HIV infection, amenable to therapeutic attack. An understanding of how latency is maintained may lead to novel therapies directed at the viral reservoir within resting cells. Other obstacles to the therapeutic clearance of established HIV infection exist—therapies to attack proviral genomes must be developed before eradication of HIV infection can be considered. Clearance of HIV infection will almost certainly require a multimodality approach that includes potent suppression of HIV replication, therapies that reach all compartments of residual HIV replication, and depletion of any reservoirs of persistent, quiescent proviral infection. Here we highlight the basic mechanisms for the establishment and maintenance of viral reservoirs, suggesting approaches toward their elimination. The persistence of virus in HIV-infected patients receiving potent ART was conclusively demonstrated when rare, integrated, replication-competent HIV was recovered from patients’ resting CD4 memory T cells [1–3]. To date, this reservoir remains the most widely studied and best understood cause of viral persistence. Evidence suggests that the resting T-cell reservoir is established early after infection and is extremely stable. Current estimates based on long-term clinical studies suggest that the half-life of these stably infected cells is approximately 44 months in successfully treated individuals [4], and that without ART D. M. Margolis (*) Departments of Medicine, Microbiology and Immunology, and Epidemiology, University of North Carolina at Chapel Hill, 3302 Michael Hooker Research Center, CB#7435, Chapel Hill, NC 27599-7435, USA e-mail: dmargo@med.unc.edu Curr HIV/AIDS Rep (2010) 7:37–43 DOI 10.1007/s11904-009-0033-9