My research focuses on cellular mechanisms that regulate HIV replication and transcription. Active projects in the lab include elucidating T cell costimulatory signal transduction cascades that positively and negatively regulate HIV transcription, determining mechanisms by which HIV circumvents anti-inflammatory signals to promote HIV replication and AIDS-associated inflammatory diseases and characterizing the transcriptional status of HIV provirus in T cell and macrophage subsets. Although, HIV is our primary experimental system, our research provides general insights into signal transduction, tissue-specific gene expression, immune cell function and mechanisms that contribute to inflammatory disorders and autoimmunity. Below highlights some of the current on-going projects in the lab:
T cell signals regulate HIV replication. T cell activation through the T cell receptor and costimulatory molecules, including CD28, influences susceptibility of T cells to HIV infection as well as proviral transcription. Incomplete T cell receptor signaling has been proposed to be a mechanism that contributes to proviral latency. We hypothesize that CD28 engagement results in distinct signaling cascades that have very different consequences for HIV transcription. We are actively characterizing signaling events emanating from critical tyrosine residues within the cytoplasmic tail of CD28 that either inhibit or induce HIV transcription to fully appreciate how costimulatory signals impact HIV transcription. In addition, we are characterizing the transcriptional machinery that regulates HIV expression in response to T cell signals. Understanding mechanisms by which CD28 regulates HIV transcription will further define pathways associated with this receptor as well as identify putative upstream signal transduction events critical for controlling HIV expression.
Related projects have suggested that non-receptor tyrosine kinases necessary for T cell activation and function, such as the Src kinase Lck and the Tec kinase Itk mediate efficient release of HIV. The mechanisms by which these kinases influence these late steps of HIV virus replication are actively being studied.
Regulation of HIV transcription elongation. 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, which through the recruitment of P-TEFb to the LTR, post-translationally modifies RNA polymerase II and associated factors to increase processive transcription. Whether this initial lack of RNA polymerase II processivity represents proximal paused RNA polymerase II, premature termination, or both has not been resolved. Recent work from our lab shows that negative elongation factor NELF and the transcription termination factor Pcf11 repress HIV transcription. We hypothesize that the coordinate control of RNA Polymerase II activity and premature transcription termination coupled with chromatin changes create key check-points for HIV transcription that directly contributes to proviral transcriptional latency. In addition, we posit that there are cellular signals that extinguish HIV expression by inducing promoter proximal pausing and premature termination. Using a receptor tyrosine kinase that represses HIV expression, we are mapping signaling pathways that are upstream of transcription initiation, elongation and termination. Understanding the regulation of HIV transcription elongation will provide novel cellular targets for controlling and purging HIV in different cellular reservoirs.
- Assistant Dean, Boston University School of Medicine, Graduate Medical Sciences
- Associate Professor, Microbiology, Boston University School of Medicine
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Graduate Medical Sciences
- Boston Medical Center
- University of California, Riverside, PhD
- University of California, Riverside, MS
- University of California, Riverside, BS
- Published on 3/21/2019
Pedro KD, Henderson AJ, Agosto LM. Mechanisms of HIV-1 cell-to-cell transmission and the establishment of the latent reservoir. Virus Res. 2019 May; 265:115-121. PMID: 30905686.
- Published on 8/21/2018
Agosto LM, Herring MB, Mothes W, Henderson AJ. HIV-1-Infected CD4+ T Cells Facilitate Latent Infection of Resting CD4+ T Cells through Cell-Cell Contact. Cell Rep. 2018 Aug 21; 24(8):2088-2100. PMID: 30134170.
- Published on 7/9/2018
Pena-Cruz V, Agosto LM, Akiyama H, Olson A, Moreau Y, Larrieux JR, Henderson A, Gummuluru S, Sagar M. HIV-1 replicates and persists in vaginal epithelial dendritic cells. J Clin Invest. 2018 Aug 01; 128(8):3439-3444. PMID: 29723162.
- Published on 7/9/2018
Agosto LM, Henderson AJ. CD4+ T Cell Subsets and Pathways to HIV Latency. AIDS Res Hum Retroviruses. 2018 Sep; 34(9):780-789. PMID: 29869531.
- Published on 6/28/2017
Graci JD, Michaels D, Chen G, Schiralli Lester GM, Nodder S, Weetall M, Karp GM, Gu Z, Colacino JM, Henderson AJ. Identification of benzazole compounds that induce HIV-1 transcription. PLoS One. 2017; 12(6):e0179100. PMID: 28658263.
- Published on 6/9/2017
Miller CM, Akiyama H, Agosto LM, Emery A, Ettinger CR, Swanstrom RI, Henderson AJ, Gummuluru S. Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells. J Virol. 2017 Jul 01; 91(13). PMID: 28424288.
- Published on 9/16/2016
Agosto LM, Hirnet JB, Michaels DH, Shaik-Dasthagirisaheb YB, Gibson FC, Viglianti G, Henderson AJ. Porphyromonas gingivalis-mediated signaling through TLR4 mediates persistent HIV infection of primary macrophages. Virology. 2016 Dec; 499:72-81. PMID: 27639573.
- Published on 8/26/2016
Papadopoulos G, Shaik-Dasthagirisaheb YB, Huang N, Viglianti GA, Henderson AJ, Kantarci A, Gibson FC. Immunologic environment influences macrophage response to Porphyromonas gingivalis. Mol Oral Microbiol. 2017 Jun; 32(3):250-261. PMID: 27346827.
- Published on 9/30/2015
Agosto LM, Gagne M, Henderson AJ. Impact of Chromatin on HIV Replication. Genes (Basel). 2015; 6(4):957-76. PMID: 26437430.
- Published on 9/14/2015
Kaczmarek Michaels K, Wolschendorf F, Schiralli Lester GM, Natarajan M, Kutsch O, Henderson AJ. RNAP II processivity is a limiting step for HIV-1 transcription independent of orientation to and activity of endogenous neighboring promoters. Virology. 2015 Dec; 486:7-14. PMID: 26379089.
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