HIV provirus is regulated at the level of transcription and involves changes in transcription initiation, chromatin organization and elongation. In particular, transcription elongation has been demonstrated to be a limiting step for HIV expression. We hypothesize that the coordinated control of RNA polymerase II processivity and premature transcription termination coupled with chromatin remodeling creates a key checkpoint that limits provirus transcription and directly impact HIV latency in different cellular and molecular contexts. We have shown that RNA polymerase II processivity is a check point for HIV transcription and that NELF, a factor that pauses RNA polymerase II, re-enforces repression of HIV proviruses by recruiting a termination factor Pcf11 and transcriptional corepressors to the HIV-1 long terminal repeat. Using a variety of biochemical approaches, including chromatin immunoprecipitation, RNAPII footprinting, in vitro transcription systems and mass spectrometry, we propose to determine the biochemical mechanisms and characterize the cellular factors that negatively regulate HIV transcription elongation. These studies will provide new insights into the establishment, maintenance and reversal of HIV latency. Understanding the regulation of HIV transcription elongation will provide novel cellular targets for controlling and purging HIV in different cellular reservoirs.

Public Health Relevance

A major barrier to eradicating HIV infection is cellular reservoirs that poorly express the virus. Goals of this proposal are to understand the biochemical mechanisms that establish and maintain HIV latency to gain insights into factors that may be targeted to purge repressed HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI097117-01A1
Application #
8468555
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2013-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$412,458
Indirect Cost
$169,836
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118