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Member Information
Bruce Freedman, VMD, PhD
Assistant Professor, Department of Animal Biology
Office Phone:
Office Fax:
Email: bruce@vet.upenn.edu
Website(s):
Education: V.M.D. 1987 University of Pennsylvania ; Ph.D. 1992 University of Pennsylvania
Keywords: HIV-1, gp120
Research and/or Clinical Interests:
Mechanism of HV-1 gp120-induced capping on primary human macrophages.
Summary:
Macrophage (M)-tropic HIV-1 strains use CD4 and the chemokine receptor (CKR) CCR5 as coreceptors for entry, while T cell line (T)-tropic strains use CD4 and CXCR4. Macrophages express both CCR5 and CXCR4, along with CD4, although it is not known why macrophage CXCR4 generally fails to support entry by T-tropic strains. Although HIV-1 has subverted them for its own use, the CKR's are 7TM G protein-coupled receptors (GPCR) that normally mediate responses to their natural chemokine ligands. The receptors' signaling functions appear to be dispensable for viral entry in transfected cell lines, but recent studies suggest that signaling may have some role in primary cells. The question of how CKRJEnv interactions contribute to HIV pathogenesis, beyond mediating fusion, represents a significant gap in our understanding. Because GPCR often couple to ionic signaling pathways we investigated the ionic signaling response to HIV-1 gpl20. In preliminary studies, we identified several novel gpl20-activated ionic signaling pathways in primary human macrophages. In addition, we have demonstrated that gpl20 bound to macrophages undergoes focal cappina, which is denendent on gpl20/CKRactivated Cl- channels and Cat+ signals. The goals of this pilot proposal are to defne the mechanisms of gpl20-mediated capping, determine the role of CD4 and the CKR's in capping, and deine the role of CKR-mediated ionic signaling in capping, fusion and viral entry in macrophages. We anticipate that this line of investigation will help us better understand the role that ionic signaling plays in virus replication, post-entry steps of macrophage tropism, and altered macrophage function.
Representative Publications:
Liu, Q-H, Williams, D. A., McManus, C., Baribaud, F., Doms, R. W., Kotlikoff, M. I., Collman R. G., and Freedman B. D., 2000. HIV-1 gpl20 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation. an press, PNAS)
Collman, R.G., Yi, Y., Liu, Q-H, and Freedman, B.D., 2000. Chemokine signaling and HIV1 fusion mediated by macrophage CXCR4: Implications for target cell tropism. (submitted)
Freedman, B.D., Fleischmann, B.K., Yui, K., Maier, C., Gaulton, G., and Kotlikoff, M.I., 2000. Distinct changes in Kv channel expression are associated with CD4+ T cell proliferation and anergy. (submitted).
Liu, Q., Manzke, O., Peters T., Freedman B.D., Diehl, V., Hescheler, J., Bohlen, H., and Fleischmann, B.K., 2000. Activation of P2X and Icrac Ca2+ influx contributes to the immunological action of cytotoxic T-lymphocytes mediated by bispecific antibodies. (in preparation)
