Control of HIV latency by epigenetic and non-epigenetic mechanisms.
Intensive antiretroviral therapy successfully suppresses viral replication but is unable to eradicate the virus. HIV persists in a small number of resting memory T cells where 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. There are no specific repressors of HIV transcription encoded by the virus, instead latency arises when the regulatory feedback mechanism driven by HIV Tat expression is disrupted. Small changes in transcriptional initiation, induced by epigenetic silencing, lead to profound restrictions in Tat levels and force the entry of proviruses into latency. In resting memory T cells, which carry the bulk of the latent viral pool, additional restrictions, especially the limiting cellular levels of the essential Tat cofactor P-TEFb and the transcription initiation factors NF-κB and NFAT ensure that the provirus remains silenced unless the host cell is activated. The detailed understanding of HIV transcription is providing a framework for devising new therapeutic strategies designed to purge the latent viral pool. Importantly, the recognition that there are multiple restrictions imposed on latent proviruses suggest that proviral reactivation will not be achieved when only a single reactivation step is targeted and that any optimal activation strategy will require both removal of epigenetic blocks and the activation of P-TEFb.
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Uri
U
Mbonye
Jonathan
J
Karn
D023241:Antiretroviral Therapy, Highly Active; D004197:Disease Reservoirs / Q000821:virology; D044127:Epigenesis, Genetic / Q000502:physiology*; D006678:HIV / Q000235:genetics / Q000502:physiology*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D013601:T-Lymphocytes / Q000821:virology; D014158:Transcription, Genetic; D017735:Virus Latency / Q000235:genetics / Q000502:physiology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors / Q000378:metabolism
D054322:tat Gene Products, Human Immunodeficiency Virus