Ron Collman
Professor, Dept of Medicine

Microbiology, Virology and Parasitology Program

Address

522 Johnson Pavilion
3610 Hamilton Walk
Philadelphia, PA 19104

Office tel.: 215 898-0913
Lab tel.: 215 898-0912
Fax: 215 573-4446
E-mail: collmanr@mail.med.upenn.edu

Link(s)

Dr. Collman's Dept of Medicine Profile

Education

Boston University: BS (Biology), 1981.

Boston University: MD (Medicine), 1981.

Research Interests

• Mechanisms of HIV-1 entry and target cell tropism, and their role in pathogenesis.
• Intracellular signal transduction events triggered by viral Env/receptor interactions.

Key words: HIV, virus, tropism, signal transduction, gp120, viral envelope, macrophage.

Search PubMed for articles

Description of Research

Our lab studies the molecular pathogenesis of HIV-1 infection, focusing on the mechanisms of entry into different target cells and how viral target cell tropism influences disease. HIV-1 infects both macrophages and lymphocytes. Macrophage-tropic variants are responsible for person-to-person HIV-1 transmission, maintenance of infection during the asymptomatic phase, and virus entry and replication in the brain and lung, which leads to serious neurologic and pulmonary complications in AIDS. The other class of HIV-1 variants, T cell tropic variants, emerge in vivo as disease progresses, and are responsible for accelerated immune destruction. Target cell tropism of different HIV-1 strains is encoded by the viral envelope glycoprotein, and results from the choice between two different cellular chemokine receptors (CCR5 or CXCR4) that the virus utilizes in conjunction with CD4 as co-receptors for entry.

Our work is directed at defining how these cellular receptors are used by HIV-1 to enter primary cells infected in vivo, T lymphocytes and macrophages, and the molecular basis for M-tropic to T-tropic evolution. We identified a prototype HIV-1 variant that is an intermediate strain in this process of evolution, and are utilizing it to define the mechanisms of macrophage versus T cell infection and phenotypic evolution. We also showed that primary isolates of HIV-1 (ie, those isolated from patients rather than lab-adapted strains) vary in their ability to use the two principal coreceptors in macrophages and lymphocytes, and are studying how this may influence target cells infected in vivo. A related focus is understanding how HIV-1 alters macrophage function apart from direct infection to contribute to disease. We recently showed that when the viral envelope binds to chemokine receptors on macrophages, it activates them much like their natural ligands to trigger intracellular signaling cascades. We believe that these pathways are an important way that HIV-1 activates the immune system, and also causes disease in the brain and lung where activated macrophages play a central role. We are studying the signal transduction pathways activated by virus binding to its receptors, and how this leads to changes in cell function that contribute to pathogenesis.

Recent Publications

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-1a and R5 HIV-1 gp120 in human macrophages. Blood.  108:1145-50, 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. Leuk. Biol. 78:1016-1023, 2005.

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.

Lab

Rotation Projects

1. Compare the pathways used by different HIV-1 strains for entry into target cells from lymphoid tissues.
2. U. Determine the changes in entry efficiency that develop over time during virus evolution in infected people.
3. Define the signaling cascades activated in macrophages by envelope glycoproteins from HIV-1 isolates of patients with dementia.

Lab personnel:

• Lamorris Loftin (graduate student)
• Nadeene Riddick (graduate student)
• Rick Cheung (Postdoctoral Researcher)
• Mobeen Malick (Postdoctoral Researcher)
• Yanjie Yi (Senior Research Investigator)
• Lingshu Wang (Research Associate)
• Jesse Isaacman-Beck (Technician)
• Martha Kienzle (Technician)
• Farida Shaheen (Senior Research Investigator)