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Member Information
Robert Doms, PhD
Chair, Department of Microbiology
Office Phone: 215 573-6780
Office Fax: 215 898-9557
Email: doms@mail.med.upenn.edu
Website(s): http://www.med.upenn.edu/micro/faculty/doms.html
Education: MD/PhD 1988, Yale University
Keywords: HIV Pathogenesis and Vaccine Development
Research and/or Clinical Interests:
How HIV engages cell surface receptors to infect cells; mechanisms of action by which entry inhibitors block HIV infection
Summary:
In order for HIV-1 to enter a cell, the viral Env protein must bind to CD4, the primary virus receptor. However, CD4 binding alone is not sufficient to trigger the conformational changes in Env that lead to membrane fusion and virus entry. For this to occur, the virus must also interact with the appropriate coreceptor. We found that macrophage-tropic virus strains, which are involved in transmission and are the predominant virus type isolated from infected individuals, require the chemokine receptor CCR5 in addition to CD4 for infection to occur. The importance of CCR5 in vivo was shown by our finding that approximately 1% of Caucasian individuals lack CCR5; these individuals are extraordinarily resistant to HIV-1 infection. Over time, T-cell tropic virus strains emerge in some infected individuals; these viruses typically require the chemokine receptor CXCR4 in conjunction with CD4. The discovery of HIV-1 specific coreceptors has important implications for understanding viral tropism pathogenesis, and for the development of novel anti-viral agents.
Current projects involve the use of specific inhibitors of virus entry, many of which are now in clinical trials including the membrane fusion inhibitor T20, which received FDA approval in early 2003. By studying the entry process, we hope to characterize why some virus strains are more sensitive to certain classes of entry inhibitors than other virus strains and to determine if these differences correlate with virus tropism or pathogenesis. This information could also be used to help guide clinical therapy. In addition, now that the structure of the HIV Env protein is better understood and the receptors with which it interacts have been identified, it is now possible to rationally modify the Env protein through genetic means in the hopes of eliciting more effective immunogens. We use both HIV-1, HIV-2 and SIV systems to address these points, comparing closely related virus strains that differ markedly in their pathogenic potential to understand how specific structural alterations can impact virus replication in vivo. Finally, we study virus attachment factors such as DC-SIGN, a lectin like protein expressed at high levels on some types of dendritic cells. DC-SIGN efficiently captures HIV and presents it to adjoining T-cells, resulting in highly efficient virus infection. Other pathogens also utilize DC-SIGN, including Ebola and HCV.
Representative Publications:
Turville, S.G., P.U. Cameron, A. Handley, G. Lin, S. Pöhlmann, R.W. Doms and A.L. Cunningham. 2002. Diversity of receptors binding HIV on dendritic cell subsets. Nat. Immunol. 3:975-983.
Baribaud, F., S. Pöhlmann, G. Leslie, F. Mortari and R.W. Doms. 2002. Quantitative expression and virus transmission analysis of DC-SIGN on monocyte-derived dendritic cells. J. Virol., 76:9135-9142.
Reeves, J.D., S.A. Gallo, N. Ahmad, J. Miamidian, P. Harvey, M. Sharron, S. Pöhlmann, J.N. Sfakianos, C.A. Derdeyn, R. Blumenthal, E. Hunter and R.W. Doms. 2002. Sensitivity of HIV-1 to entry inhibitors correlates with envelope:coreceptor affinity, receptor density and fusion kinetics. Proc. Natl. Acad. Sci. USA 99:16249-16254.
Simmons, G., J.D. Reeves, C.C. Grogan, L.H. Vandenberghe, F. Baribaud, J.C. Whitbeck, , E. Burke, M.J. Buchmeier, E.J. Soilleux, J.L. Riley, R.W. Doms, P. Bates and S. Pöhlmann. 2003. DC-SIGN and DC-SIGNR bind Ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology, 305:115-123.
Lin, G., F. Baribaud, J. Romano, R.W. Doms and J.A. Hoxie. 2003. Identification of gp120 binding sites on CXCR4 using CD4-independent human immunodeficiency virus type 2 Env proteins. J. Virol., 77:931-942.
Lin, G., G. Simmons, S. Pöhlmann, F. Baribaud, H. Ni, G.J. Leslie, B. Haggarty, P. Bates, D. Weissman, J.A. Hoxie and R.W. Doms. 2003. Differential N-linked glycosylation of HIV and Ebola virus envelope glycoproteins modulates interactions with DC-SIGN and DC-SIGNR. J. Virol., 77:1337-1346.
Blanpain, C., B.J. Doranz, A. Bondue, C. Govaerts, A. De Leener, G. Vassart, R.W., Doms, A. Proudfoot and M. Parmentier. 2003. The core domain of chemokines bind CCR5 extracellular domains while their amino-terminus interacts with the transmembrane helix bundle. J. Biol. Chem, 278:5179-5187.
Pöhlmann, S. J. Zhang, F. Baribaud, Z. Chen, G. Lin, A. Granelli-Piperno, R.W. Doms, C.M. Rice and J.A. McKeating. 2003. Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J. Virol., 77: 4070-4080.
Dehghani, H., Puffer, B.A., Doms, R.W. and Hirsch, V.M. 2003. Unique pattern of convergent envelope evolution in simian immunodeficiency virus-infected rapid progressor macaques: association with CD4-independent usage of CCR5. J. Virol., 77:6405-6418.
Sreekanth, H., Chalasani, S.H., F. Baribaud, C.M. Coughlan, M.J. Sunshine, V.M.Y. Lee, R.W. Doms, D.R. Littman and J.A. Raper. 2003. The chemokine SDF-1 promotes the survival of embryonic retinal ganglion cells. J. Neurosci. 23:4601-4612.
Moore, J.P. and R.W. Doms. 2003. The entry of entry inhibitors: A fusion of science and medicine. Proc. Natl. Acad. Sci. USA, In press.
Lee, B., M.P. Sharron, C, Blainpain, B.J. Doranz, J. Vakliki, P. Setoh, E. Berg, G. Liu, H.R. Guy, S.R. Durrel, M. Paramentier, C.N. Chang, K. Price, M. Tsang, and R.W. Doms. 1999. Epitope mapping of CCR5 reveals multiple conformational state and distinct but overlapping structures involved in chemokine and coreceptor function. J. Biol. Chem., 274:9617-9626.
Edinger, A.L., C. Blainpain, M. Parmentier, and R.W. Doms. 1999. Functional dissection of CCR5 coreceptor function through the use of CD4-independent SIV strains. J. Virol., 73:4062-4073.
Lee, B., M. Sharron, L.J. Montaner., D. Weissman., R.W. Doms. 1999. Quantification of CD4, CCR5 and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc. Natl. Acad. Sci. USA, 96:5215-5220.
Hoffman, T.L., C. Labranche, W. Zhang, G. Canziani, J. Robinson, I. Chaiken, J.A. Hoxie, R.W. Doms. 1999. Stable exposure of the coreceptor binding site in a CD4-independent HIV-1 envelope protein. Proc. Natl. Acad. Sci. USA, 96:6359-6364.
