Epigenetic Silencing of HIV Transcription Through Formation of Restrictive Chromatin Structures at the Viral LTR Drives the Progressive Entry of HIV into Latency
Year: 2009
Type: article
Abstract: The clinical relevance of HIV latency is now well understood but the molecular mechanisms that are utilized by HIV to enter into a latent state are yet to be determined.The development of a suitable experimental system for studying HIV latency, which permits detailed biochemical analysis and drug screening, is a critical step in the effort to develop therapeutic strategies that will lead to viral eradication.The work outlined in this thesis reports that, when Jurkat T-cells are infected with lentiviral vectors that express the transactivator protein (Tat) in cis, HIV gene expression is gradually silenced.Silencing is enhanced when the lentiviral vectors carry an attenuated Tat gene.Following these observations we were able to develop a Jurkat cell-based model system of HIV latency.Detailed analysis of transcription initiation and elongation using chromatin immunoprecipitation (ChIP) assays confirms that Tat levels are restricted in latently infected cells but rise during proviral reactivation.ChIP assays using clones of latently infected cells demonstrate that the latent proviruses carry markers of repressive chromatin structure that were lost after TNF-α activation and replaced with a more transcriptionally permissive state.The progressive shutdown of HIV transcription suggests that epigenetic mechanisms targeting chromatin structures selectively restrict the HIV LTR.
Author: Richard D. Pearson
Institution: Case Western Reserve University
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2497873575