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Member Information
Ronald Collman, MD
Professor, Pulmonary, Allergy & Critical Care Section
Department of Medicine and Department of Microbiology (secondary)
Office Phone: 215-898-0913
Office Fax: 215-573-4446
Email: collmanr@mail.med.upenn.edu
Website(s): http://www.med.upenn.edu/camb/faculty/mv/collman.html
Education: MD 1981, Boston University
Keywords: Tropism, Viral Entry, Macrophage, NeuroAIDS, HIV Encephalopathy, AIDS Dementia, Pulmonary Disease in AIDS
Research and/or Clinical Interests:
Defining the mechanisms of HIV-1 tropism, entry into macrophages, and consequences of virus-cell interactions for macrophage function.
Summary:
Our goal is to better understand the mechanisms of HIV-1 infection of human macrophages, and how macrophage infection contributes to pathogenesis in sites such as the brain.
One aspect of our work is to understand the cellular receptors used on macrophages for entry and infection. Along with CCR5, the chemokine receptor that functions along with CD4 as the principal fusion co-receptor for macrophage (M)-tropic HIV-1 strains, we have determined that CXCR4 is expressed by macrophages and also supports entry by some primary isolates of HIV-1 but not by the prototype T cell line (T)-tropic strains that use CXCR4 in other cell types. Studies are currently focused on (a) identifying the viral envelope determinants of macrophage CXCR4 utilization, (b) the cellular determinants that control CXCR4 co-receptor function in a cell-specific manner, and (c) the role of other chemokine receptor molecules to support entry into primary macrophages. A closely related area of research is determining the cellular signaling pathways that are activated in primary macrophages by HIV-1 envelope interaction with the chemokine receptors. Along with identifying the pathways involved, we are studying the functional consequences for macrophages, and how thes activation pathways may contribute to pathogenesis including in the development of neurological complications in AIDS.
Representative Publications:
Yi, Y., Loftin, L., Wang, L., Ratcliffe, S.J., Isaacman-Beck, J., Collman, R.G. Entry coreceptor use and fusion inhibitor T20 sensitivity of dual-tropic R5X4 HIV-1 in primary macrophage infection. J. Acquired Immune Deficiency Synd. (in press).
Twigg, H.L., Weiden, M., Valentine, F., Schnizlein-Bick, C.T., Bassett, R., Wheat, J., Day, R.B., Rominger-Grubbs, H., Collman, R.G., Fox, L., Brizz, B., Dragavon, J., Coombs, R.W., Bucy, R.P., for the AIDS Clinical Trials Group Protocol 723 Team. Effect of highly active antiretroviral therapy on viral burden in the lungs of HIV-infected subjects. J. Infectious Diseases. 197:109-116, 2008.
Tomkowicz, B., Lee, C., Ravyn, V., Cheung, R., Ptasznik, A., Collman, R.G. The Src kinase lyn is required for CCR5 signaling in response to MIP-1b and R5 HIV-1 gp120 in human macrophages. Blood. 108:1145-50, 2006.
Goodenow, M.M., Collman, R.G. HIV-1 coreceptor preference is distinct from target cell tropism: A dual parameter nomenclature to define viral phenotypes. J. Leukocyte Biol. 80:965-972, 2006.
Yi, Y., Shaheen, F., Collman, R.G. Preferential use of CXCR4 by R5X4 HIV-1 isolates for infection of primary lymphocytes. J. Virol. 79:1480-1486, 2005.
Lee, C., Tomkowicz, B., Freedman, B.D., Collman, R.G. HIV-1 gp120-induced TNF-a production by primary human macrophages is mediated by phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways. J. Leukocyte Biol. 78:1016-1023, 2005.
Yi, Y., Singh, A., Cutilli, J., Collman, R.G. Use of dual recombinant vaccinia virus vectors to assay viral glycoprotein-mediated fusion with transfection-resistant primary cell targets. Methods in Molecular Biology. 269:333-46, 2004.
Tomkowicz, B., Collman, R.G. HIV-1 entry inhibitors: Closing the front door. Expert Opinion in Therapeutic Targets. 8:65-78, 2004.
Yi, Y., Chen, W., Frank, I., Cutilli, J., Singh, A., Starr-Spires, L., Sulcove, J., Kolson, D.L., Collman, R.G. An unusual syncytia-inducing HIV-1 primary isolate from the central nervous system that is restricted to CXCR4, replicates efficiently in macrophages, and induces neuronal apoptosis. J. Neurovirology. 9:433-441, 2003.
Yi, Y., Singh, A., Shaheen, F., Louden, A., Lee, C., Collman, R.G. Contrasting use of CCR5 structural determinants by R5 and R5X4 variants within an HIV-1 primary isolate quasispecies. J. Virol. 77;12057-12066, 2003.
Novina, C.D., Murray, M.F., Dykzhoorn, D., Beresford, P.J., Zhang, D., Riess, J., Collman, R.G., Lieberman, J., Shankar, P., Sharp, P.A. siRNA-directed host and viral gene silencing inhibits HIV infection. Nature Medicine. 8:681-686, 2002.
Del Corno, M., Liu, Q.-H., Schols, D., de Clercq, E., Gessani, S., Freedman, B.D., Collman, R.G. HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein (MAP) kinases in primary macrophages mediated by chemokine receptors through a calcium-dependent, pertussis toxin-insensitive pathway. Blood. 98:2909-2916, 2001.
