David Margolis, MD

David Margolis, MD

Professor
Department of Medicine
2016 Genetic Medicine Bldg
CB#7042
919-966-6388



Research

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.

Lab Website

Publications

Garrido C, Spivak AM, Soriano-Sarabia N, Checkley MA, Barker E, Karn J, Planelles V, Margolis DM. HIV Latency-Reversing Agents Have Diverse Effects on Natural Killer Cell Function. Front Immunol. 2016; 7:356. PubMed PMID:27708642; PubMed Central PMCID: PMC5030263.

Soriano-Sarabia N, Archin NM, Bateson RE, Dahl NP, Crooks AM, Kuruc JD, Garrido C, Margolis DM. Peripheral gd T cells are a novel reservoir of latent HIV infection. PLoS Pathog 2015; 11(10): e1005201. PMID:26473478

Sung JA, Pickeral P, Liu L, Stanfield-Oakley SA, Lam C-YK, Garrido C, Pollara J, LaBranche C, Bonsignori M, Moody AM, Yang Y, Parks R, Archin NM, Allard B, Kirchherr J, Kuruc JD, Gay CL, Cohen M, Ochsenbauer C, Soderberg K, Liao H-X, Montefiori D, Moore P, Johnson S, Koenig S, Haynes BF, Nordstrom JL, Margolis DM, Ferrari G. Dual Affinity Re-Targeting (DART) proteins direct T cells to mediate cytolysis of patients’ latently HIV-infected cells. J Clin Invest. 2015; 125(11):4077-90.doi:10.1172/JCI82314. PMID: 26413868

Tripathy MK, McManamy MEM, Burch BD, Archin NM, Margolis DM. H3K27 demethylation at the proviral promoter sensitizes latent HIV to the effects of vorinostat in ex-vivo cultures of resting CD4+ T cells. J. Virol. 2015; 89(16):8392-405. PMID:26041287

Sung JAM, Lam S, Garrido C, Archin NM, Rooney CM, Bollard CM, and Margolis DM. Expansion of Cytotoxic T Cell Lymphocytes Ex-Vivo to Clear Latent HIV Infection. J Infect Dis. 2015; 212(2):258-63. PMID:25589335

Soriano-Sarabia N, Bateson R, Dahl NP, Crooks AM, Kuruc JD, Margolis DM, Archin NM. The quantitation of replication-competent HIV-1 in populations of resting CD4+ T cells. J Virol. 2014; 88(24):14070-7. PMID: 25253353

N.M. Archin; R. Bateson; M. Tripathy; A.M. Crooks; K.H. Yang; N.P. Dahl; M.F. Kearney; E.M. Anderson; J.M. Coffin; M.C. Strain; D.D. Richman; K.R. Robertson; A.D. Kashuba; R.J. Bosch; D.J. Hazuda; J.D. Kuruc; J.J. Eron; D.M. Margolis. HIV-1 Expression within Resting CD4 T-Cells Following Multiple Doses of Vorinostat. J Infectious Dis 2014; 210(5):728-35. PMID:24620025

Barton KM, Margolis DM. Selective targeting of the repressive transcription factors YY1 and cMyc to disrupt quiescent human immunodeficiency viruses. AIDS Res Hum Retroviruses. 2012; 29:289-98. PubMed PMID: 22866663.

Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012; 487:482-5. PMID:22837004

Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, Kearney MF, Cohen MS, Coffin JM, Bosch RJ, Gay CL, Eron JJ, Margolis DM, Perelson AS. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A. 2012;109(24):9523-8. PMCID: PMC3386138

Anderson J, Archin 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; 85(10):5220-3. PMCID: PMC3126162

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. PMCID: PMC2853863

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.

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, Archin, N, Lehrman, G, Bosch, RJ, Margolis, DM.  Coaxing Human Immunodeficiency Virus Type 1 from Resting CD4+ T Cells:  histone deacetylase inhibition allows latent viral expression.  AIDS 2004; 18:1101-1108. PMID: 15166525.

He, G, Margolis, DM.  Counter-regulation of Chromatin Acetylation and Histone Deacetylase Occupancy at the Integrated Promoter of Human Immunodeficiency Virus Type 1 by the HIV-1 Activator Tat and the HIV-1 Repressor YY1.  Mol. Cell. Biol. 2002; 22:2965-2973. PMCID: PMC133763.

Coull, J, Romerio, F, Sun, J-M, Volker, JM, Galvin, KM, Davie, JR, Shi, Y, Hansen, U, Margolis, DM.  The human factors YY1 and LSF repress the human immunodeficiency virus type-1 long terminal repeat via recruitment of histone deacetylase 1.  J. Virology 2000; 74:6790–6799. PMCID: PMC112196.

Cocchi, F, DeVico, AL, Yarchoan, R, Redfield, R, Cleghorn, F, Blattner, WA, Garzino-Demo, A, Colombini-Hatch, S, Margolis, DM, Gallo, RC.  Higher macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta levels  from CD8+ T cells are associated with asymptomatic HIV-1 infection.  Proc. Natl. Acad. Sci. USA 2000; 97:13812-13817. PMCID: PMC17658.

Romerio, F, Gabriel, M, Margolis, DM.  Repression of HIV-1 through the novel cooperation of the human factors YY1 and LSF. J. Virology 1997; 71:9375-9382. PMCID: PMC230241.

Margolis, DM, Somasundaran, M, Green, MR.  Human transcription factor YY1 represses HIV-1 transcription and virion production.  J. Virology 1994; 68:905-910. PMCID: PMC236527.

Margolis, DM, Ostrove, JM, Straus, SE. HSV-1 activation of HIV-1 transcription is augmented by a cellular protein that binds near the initiator element.  Virology 1993; 192:370-374.

Complete list of publications

Accomplishments

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

Affiliations

School of Medicine
School of Public Health-Dept. of Epidemiology
Department of Microbiology and Immunology

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