Studies of the molecular events that establish and maintain latency have been hampered by the rarity and inaccessibility of latently infected cells. 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 and overcoming this block is the primary activity of the viral factor Tat. We hypothesize that cellular factors that regulate transcription elongation and premature transcription termination have a direct impact on HIV transcription, including extinguishing HIV transcription and establishing latency. Preliminary data show that Pol II processivity is a check point for HIV transcription in the absence of Tat and that two factors, NELF and Pcf11, negatively regulate HIV transcription elongation. Using a variety of biochemical approaches, including chromatin immunoprecipitation, Pol II foot printing and in vivo and in vitro transcription systems, we propose to determine the biochemical mechanisms and characterize the cellular factors that negatively regulate HIV transcription elongation. We expect that 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

Successfully eradicating HIV infection will require understanding how cellular reservoirs that poorly express virus are established and maintained as well as determining whether these populations can be purged of HIV. This proposal focuses on the biochemical mechanisms that repress HIV transcription, in order to gain insights into factors that regulate HIV latency with long term goals of identifying novel targets for controlling HIV expression in different cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI077463-01A2
Application #
7685816
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2009-06-19
Project End
2011-05-31
Budget Start
2009-06-19
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$416,152
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118