Andrew J. Henderson PhD
Professor, Infectious Diseases
Assistant Dean, Oral Health Sciences
650 Albany St | (617) 414-5240
BU-BMC Cancer Center
Evans Center for Interdisciplinary Biomedical Research
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.
Associate Professor, Microbiology
Biomedical Sciences, PhD, University of California, Riverside, 1991
Biology, MS, University of California, Riverside, 1988
Biology, BS, University of California, Riverside, 1984
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.Published on 5/22/2019
Gagne M, Michaels D, Schiralli Lester GM, Gummuluru S, Wong WW, Henderson AJ. Strength of T cell signaling regulates HIV-1 replication and establishment of latency. PLoS Pathog. 2019 05; 15(5):e1007802. PMID: 31116788.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 05; 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 08 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 08 01; 128(8):3439-3444. PMID: 29723162.
Published on 3/8/2021
Published on 3/1/2020View full list of 2 media mentions.