The molecular biology of HIV latency: breaking and restoring the Tat-dependent transcriptional circuitKarn, JonathanCurrent Opinion in HIV and AIDS: January 2011 - Volume 6 - Issue 1 - p 4–11 doi: 10.1097/COH.0b013e328340ffbb HIV reservoirs: from pathogenesis to drug development: Edited by Robert F. Siliciano and Janet D. Siliciano Abstract Author Information Purpose of review Despite the remarkable success of intensive antiretroviral drug therapy in blocking the HIV replication, the virus persists in a small number of cells in which HIV has been transcriptionally silenced. This review will focus on recent insights into the HIV transcriptional control mechanisms that provide the biochemical basis for understanding latency. Recent findings Latency arises when the regulatory feedback mechanism driven by HIV Tat expression is disrupted. Small changes in transcriptional initiation, induced by epigenetic silencing, can lead to restrictions in Tat levels and entry of proviruses into latency. In resting memory T-cells, which carry the bulk of the latent viral pool, additional restrictions limiting cellular levels of the essential Tat cofactor P-TEFb and the transcription initiation factors nuclear factor kappa B and nuclear factor of activated T cells ensure that the provirus remains silenced unless the host cell is activated. Summary Strategies to purge the latent proviral pool require nontoxic activator molecules. The multiple restrictions imposed on latent proviruses that need to be overcome suggest that proviral reactivation will not be achieved when only a single reactivation step is targeted but will require both removal of epigenetic blocks and the activation of P-TEFb. Alternatively, new inhibitors that block proviral reactivation could be developed. Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA Correspondence to Jonathan Karn, PhD, Reinberger Professor and Chair, Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Room W200, Cleveland, OH 44106-4960, USA Tel: +1 216 368 3915; fax: +1 216 368 3055; e-mail: firstname.lastname@example.org © 2011 Lippincott Williams & Wilkins, Inc.