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, Oral Health Sciences, Boston University School of Medicine, Graduate Medical Sciences
- Associate Professor, Microbiology, Boston University School of Medicine
- Member, BU-BMC Cancer Center, Boston University
- Member, Evans Center for Interdisciplinary Biomedical Research, Boston University
- Boston Medical Center
- Member, Genome Science Institute, Boston University
- Graduate Faculty (Primary Mentor of Grad Students) , Boston University School of Medicine, Graduate Medical Sciences
- University of California, Riverside, PhD
- University of California, Riverside, MS
- University of California, Riverside, BS
- Published on 5/20/2022
Ratnasekera IU, Johnson A, Powell EE, Henderson A, Irvine KM, Valery PC. Epidemiology of ascites fluid infections in patients with cirrhosis in Queensland, Australia from 2008 to 2017: A population-based study. Medicine (Baltimore). 2022 May 20; 101(20):e29217. PMID: 35608422.
- Published on 1/12/2022
Dalecki AG, Greer BD, Duverger A, Strange EL, Carlin E, Wagner F, Shi B, Lowman KE, Perez M, Tidwell C, Kaczmarek Michaels K, Giattina S, Bossmann SH, Henderson AJ, Hu H, Kutsch O. Host T Cell Dedifferentiation Effects Drive HIV-1 Latency Stability. J Virol. 2022 03 09; 96(5):e0197421. PMID: 35019721.
- Published on 12/28/2021
Kuniholm J, Armstrong E, Bernabe B, Coote C, Berenson A, Patalano SD, Olson A, He X, Lin NH, Fuxman Bass JI, Henderson AJ. Intragenic proviral elements support transcription of defective HIV-1 proviruses. PLoS Pathog. 2021 12; 17(12):e1009982. PMID: 34962974.
- Published on 11/2/2021
Ragan EJ, McCallum C, Marathe J, Cole M, Hofman M, Henderson AJ, Flack T, Miller NS, Burks EJ, Zhao GQ, Denis R, Lin NH, Jacobson KR, Andry CD, Pelton SI, Duffy ER, Bhadelia N. Pandemic Response Requires Research Samples: A U.S. Safety-Net Hospital's Experience and Call for National Action. Ann Intern Med. 2021 12; 174(12):1727-1732. PMID: 34724402.
- Published on 3/16/2021
Pedro KD, Agosto LM, Sewell JA, Eberenz KA, He X, Fuxman Bass JI, Henderson AJ. A functional screen identifies transcriptional networks that regulate HIV-1 and HIV-2. Proc Natl Acad Sci U S A. 2021 03 16; 118(11). PMID: 33836568.
- Published on 12/2/2020
Santoso CS, Li Z, Lal S, Yuan S, Gan KA, Agosto LM, Liu X, Pro SC, Sewell JA, Henderson A, Atianand MK, Fuxman Bass JI. Comprehensive mapping of the human cytokine gene regulatory network. Nucleic Acids Res. 2020 12 02; 48(21):12055-12073. PMID: 33179750.
- Published on 10/12/2020
Olson A, Basukala B, Lee S, Gagne M, Wong WW, Henderson AJ. Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9. Viruses. 2020 10 12; 12(10). PMID: 33053801.
- Published on 10/1/2020
He X, Eddy JJ, Jacobson KR, Henderson AJ, Agosto LM. Enhanced Human Immunodeficiency Virus-1 Replication in CD4+ T Cells Derived From Individuals With Latent Mycobacterium tuberculosis Infection. J Infect Dis. 2020 10 01; 222(9):1550-1560. PMID: 32417884.
- Published on 5/26/2020
Karagiannis TT, Cleary JP, Gok B, Henderson AJ, Martin NG, Yajima M, Nelson EC, Cheng CS. Single cell transcriptomics reveals opioid usage evokes widespread suppression of antiviral gene program. Nat Commun. 2020 05 26; 11(1):2611. PMID: 32457298.
- Published on 8/29/2019
Olson A, Basukala B, Wong WW, Henderson AJ. Targeting HIV-1 proviral transcription. Curr Opin Virol. 2019 10; 38:89-96. PMID: 31473372.
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