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.
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.
|Miller, Caitlin M; Akiyama, Hisashi; Agosto, Luis M et al. (2017) Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells. J Virol 91:|
|Agosto, Luis M; Hirnet, Juliane B; Michaels, Daniel H et al. (2016) Porphyromonas gingivalis-mediated signaling through TLR4 mediates persistent HIV infection of primary macrophages. Virology 499:72-81|
|Kaczmarek Michaels, Katarzyna; Natarajan, Malini; Euler, Zelda et al. (2015) Blimp-1, an intrinsic factor that represses HIV-1 proviral transcription in memory CD4+ T cells. J Immunol 194:3267-74|
|Kaczmarek Michaels, Katarzyna; Wolschendorf, Frank; Schiralli Lester, Gillian M et al. (2015) RNAP II processivity is a limiting step for HIV-1 transcription independent of orientation to and activity of endogenous neighboring promoters. Virology 486:7-14|
|Collins, Matthew H; Henderson, Andrew J (2014) Transcriptional regulation and T cell exhaustion. Curr Opin HIV AIDS 9:459-63|
|Kaczmarek, Katarzyna; Morales, Ayana; Henderson, Andrew J (2013) T Cell Transcription Factors and Their Impact on HIV Expression. Virology (Auckl) 2013:41-47|
|Natarajan, Malini; Schiralli Lester, Gillian M; Lee, Chanhyo et al. (2013) Negative elongation factor (NELF) coordinates RNA polymerase II pausing, premature termination, and chromatin remodeling to regulate HIV transcription. J Biol Chem 288:25995-6003|
|Cary, Daniele C; Clements, Janice E; Henderson, Andrew J (2013) RON receptor tyrosine kinase, a negative regulator of inflammation, is decreased during simian immunodeficiency virus-associated central nervous system disease. J Immunol 191:4280-7|