The overall goal of our laboratory is to obtain new insights into the host-virus interaction, particularly in HIV infection, and translate discoveries in molecular biology and virology to the clinic to aid in the treatment of HIV infection. A subpopulation of HIV-infected lymphocytes is able to avoid viral or immune cytolysis and return to the resting state. While this latent reservoir of HIV infection is a significant clinical problem, the molecular mechanisms that underlie it are enigmatic.
Current work focuses on the molecular mechanisms that control the latent reservoir of HIV infection within resting T cells. We have found that cellular transcription factors widely distributed in lymphocytes can remodel chromatin and maintain quiescence of the HIV genome in resting CD4+ lymphocytes. Novel reagents allow us to direct modulate HIV expression in T cells obtained from HIV+ patients [Ylisastigui 2004], and attempt to deplete the latent reservoir of HIV infection in translational clinical experiments [Lehrman 2005].
These studies give insight into the basic molecular mechanisms of eukaryotic gene expression, as well as new therapeutic approaches for HIV infection. Novel histone deacetylase inhibitors and their effects on viral chromatin and gene expression, and host genes, are under study.
Anderson J,cArchin NA, Ince W, Parker D., Wiegand A, Coffin J, Kuruc J., Eron JJ, Swanstrom
R, Margolis DM. Residual HIV-1 Viremia In Patients on Intensified Antiretroviral Therapy Is Found in Circulating Resting CD4+ T Cells. J. Virol. 2011;
Margolis DM. Eradication Therapies for HIV Infection: Time to Begin Again. AIDS Res Hum Retroviruses. 2011; 27(4):347-53. PMCID: PMC3065332.
Archin NA, Cheema M, Parker D, Wiegand A, Bosch R, Coffin J, Eron J, Cohen M, and Margolis DM. Antiretroviral intensification and valproic acid have limited effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One 2010; 5:e9390. PMCID: PMC2826423.
Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz R. The Challenge of a Cure for HIV Infection. Science. 2009; 323:1304-1307.
Archin NM, Keedy KS, Espeseth AS, Dang H, Hazuda DJ, and Margolis DM. Expression of Latent Human Immunodeficiency Type-1 is Induced by Novel and Selective Histone Deacetylase Inhibitors. AIDS. 2009; 23:1799-806.PMID:19590405
Choudhary SK, Rezk NL, Ince WL, Cheema M, Zhang L, Su L, Swanstrom R, Kashuba AD, Margolis DM. Suppression of HIV-1 viremia with reverse transcriptase and integrase inhibitors, CD4+ T
cell recovery, and viral rebound upon therapy interruption in a new model for HIV treatment in the humanized Rag-/-gc-/- mice. J Virol. 2009.
83:8254 8258. PMCID: PMC2715775.
Keedy KS, Archin NM, Gates AT, Espeseth AS, Hazuda DJ, and Margolis DM. A limited group of class I histone deacetylases act to repress human
immunodeficiency virus type-1 expression. J Virol. 2009; 88:4749 4756. PMCID: PMC2682072.
Archin NM, Espeseth A, Parker D, Cheema C, Hazuda DJ, Margolis DM. Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid. AIDS Res Hum Retro. 2009; 25:207-212. PMCID: PMC2853863.
Vahey MT, Wang Z, Ockenhouse CF, Su Z, Nau ME, Krambrink A, Skiest DJ, Margolis DM. Differential
Expression of Genes Associated with the Regulation of Apoptosis Predicts Progression in Persons Who Discontinue Antiretroviral Therapy. AIDS Res Hum Retro. 2008; 24:1047-66. PMID: 18724805.
Archin NA, Eron JJ, Palmer S, Hartmann-Duff A, Martinson JA, Wiegand A, Bandarenko N, Schmitz JL, Bosch RJ, Landay AL, Coffin JM, Margolis DM. Standard ART and Valproic Acid Have Limited Impact on the Persistence of HIV Infection in Resting CD4+ T Cells. AIDS 2008; 22:1131-1135. PMID: 18525258.
Bowman MC, Ballard TE, Ackerson CJ, Feldheim DL, Margolis DM, Melander C. Inhibition of HIV Fusion with Multivalent Gold Nanoparticles. J Am Chem Soc 2008; 130:6896-7. PMCID: PMC2916654
Choudhary, S.K., Archin, N.M., Margolis, D.M. Hexamethylbisacetamide and Disruption of Human Immunodeficiency Virus Type 1 Latency in CD4+ T
Cells. J Infectious Diseases 2008; 197:1162 1170. PMID: 18419522.
Jiang G, Espeseth A, Archin NM, Hazuda DJ, and Margolis DM. c-Myc and Sp1 contribute to proviral latency by recruiting HDAC1 to the Human Immunodeficiency Virus Type 1 promoter. J. Virology
2007; 81:10914-23. PMCID: PMC2045540.
Klichko, V., Kaur, R.J., Archin, N., Lehrman, G, and Margolis, D.M. Hexamethylbisacetamide
remodels the Human Immunodeficiency Virus type 1 promoter and induces Tat-independent HIV-1 expression without cellular activation. J. Virology. 2006; 80:4570 4579. PMCID: PMC1472000.
Lehrman, G., Hogue, I.B., Palmer, S., Jennings, C., Spina, C.A., Wiegand, A., Landay, A.L., Coombs, R.W., Richman, D.D., Mellors, J.W., Coffin, J.M., Bosch, R.J., Margolis, D.M. Depletion of latent HIV
infection in vivo: a proof of concept study. Lancet 2005; 36:549-555. PMCID: PMC1894952.
Ylisastigui, L, Kaur, R, Volker, JL, Johnson, H, Hansen, U, Margolis, DM. Mitogen-Activated Protein Kinase Regulation of LSF Occupancy at the Integrated Promoter of HIV-1. J. Virology 2005; 79:5952-5962. PMCID: PMC1091734.
Honors and Awards:
Magna Cum Laude, Harvard College, 1981
Clinical Associates award, Am. Coll. Phys., 1988
NIH Physician-Scientist award (K-11), 1991-94
Fellow, American College of Physicians, 1996
IDSA young investigator, 1997
Fellow, Infectious Dis. Society of America, 2000
amfAR Basic Science award, 2001
Am. Society for Clinical Investigation, 2005
Nat'l Found. Infect. Dis. young investigator, 1996
Recent National Advisory and Review Committees:
NIAID AACTG Research Agenda Committees 1999-present;
V.A. Merit Review, Infectious Diseases subcommittee (ad hoc) 2000, 2004;
NIH special emphasis panel, Centers for AIDS Research 2001;
NIH AIDS and Related Research Study Sections 1 (ad hoc) 2001; NIAID/NCI Inter-Institute Program for Development of AIDS-related Therapeutics 2003, 2004;
NIAID AIDS Clinical Studies and Epidemiology Study Section (ad hoc) 2003, 2004;
amfAR Scientific Advisory board 2002-present;
NIAID AIDS Research Advisory Committee 2004-2008;
AIDS Clinical Trials Strategic Working Group 2006-2008