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Member Information
Drew Weissman, MD, PhD
Associate Professor of Medicine, Division of Infectious Diseases
Office Phone: 215-614-0291
Office Fax: 215-349-5111
Email: dreww@mail.med.upenn.edu
Website(s): http://www.uphs.upenn.edu/idd/
Education: MD, PhD 1987, Boston University
Keywords: dendritic cell, siRNA, immunopathogenesis, Env binding proteins, trans-infection, gp-340, RNA vaccine, Env induced apoptosis
Research and/or Clinical Interests:
The focus of Dr. Weissman's laboratory is to understand the factors responsible for and the immune controls that regulate the initiation and propagation of HIV infection.
Summary:
Currently three major projects related to HIV immunopathogenes are ongoing. The first project studies antigen presentation by dendritic cells (DC). Our hypothesis is that autologous dendritic cells (DC) may be utilized for the presentation of HIV antigens, which will then result in strong cellular immune responses. The goal of this research is to optimize the delivery of candidate antigens to DC and the resulting activation of T cells to generate a vaccine/immune adjuvant. We are currently studying mRNA that encodes antigen(s) as a delivery agent for loading DC.
The second project studies host and viral factors at the site of heterosexual transmission of HIV, the genital mucosa. In Thailand , Asia, and Africa , over 90% of new infections are acquired heterosexually. Preliminary studies have identified an infiltration of activated CD4+ T cells expressing high levels of HIV in Thai but not US women (84% versus <10%). Our hypothesis is that genital epithelial inflammation containing activated CD4+ T cells is a cause of increase male to female and female to male transmission.
The third project studies the populations of CD4+ T cells that actively replicate HIV during an antigen-specific immune response. We previously demonstrated that during an in vivo immune response to a vaccine or infection, antigen-specific T cells are activated and viral replication increases. Preliminary data suggests that, in fact, the bystander activated cells replicate HIV while antigen-specific are protected. Our hypothesis is that immune stimulation and consequent cell-cell interactions result in local immune activation, HIV-1 replication in specific cellular subsets, and immune cell depletion and dysfunction.
Representative Publications:
Weissman, D., Ni, H, Scales, D, Dude, A., Capodici, J, McGibney, K, AbdoolA., Isaacs, S.N., Cannon, G., Karikó, K. HIV gag mRNA transfection of dendritic cells delivers encoded antigen to MHC class I and II molecules, causes DC maturation, and induces a potent human in vitro primary immune response. J. Immunol. 165:4710-4717, 2000.
Scales, D, Ni, H., Capodici, J., Cannon, G., Weissman, D. Unactivated, non-proliferating CD4+ T cells actively replicate HIV in a lymphoid environment. J. Immunol. 166:6437-6443, 2001.
Cohn, M.A., Frankel, S., Rugpao, S., Vahey, M., Young, M.,Wollett, G., Tovanabutra, S., Suriyanon, V., VanCott, T., Barrick, S., Nelson, K., and Weissman, D. Chronic Inflammation with Increased HIV RNA Expression in the Vaginal Epithelium of HIV-infected Thai women. J. Inf. Dis. 184:410-419, 2001.
Venkatesan, S., Petrovic, A., Kim, Y-O., Weissman, D., and Murphy, P.M. Membrane proximal basic domain followed by a cysteine cluster constitutes a bi-partite motif critical for cell surface expression of the chemokine receptor, CCR5. J. Biol. Chem. 276: 40133-40145, 2001.
Venkatesan, S., Petrovic, A., Van Ryk, D.I., Locati, M., Weissman, D., and . Murphy, P.M. Reduced cell surface expression of CCR5 in 32 heterozygotes is mediated by gene dosage, not by receptor sequestration. J. Biol. Chem. 277:2287-2301, 2002
Soilleux, E.J., Morris, L.S., Leslie, G., Chehimi, J., Trowsdale||, J., Montaner, L.J., Doms, R.W., Weissman, D., Coleman, N., Lee, B-H., DC-SIGN is expressed on tissue dendritic cells, on specialized macrophages and on a sub-population of plasmacytoid blood dendritic cells. J. Leuk. Biol. 71:445-457, 2002.
Ni, H., Communi, D., Boeyannes, J-C, Kariko, K., Weissman, D., mRNA induces dendritic cell activation and differentiation by signaling through P2Y nucleotide receptors. J. Biol. Chem. 277:12689-12696, 2002
Capodici, J., Karikó, K., and Weissman, D. Inhibition of HIV infection and replication by small interfering RNA mediated RNA interference. J. Immunol. 169: 5196-5201, 2002.
Weissman, D. and L. J. Montaner. Immune reconstitution. Clin Lab Med 22:719, 2002.
Lin, G. Baribaud, F., Ni, H., Haggarty, H., Pöhlmann, S., Weissman, D., Hoxie, J.A., and Doms, R.A. DC-SIGN and DC-SIGNR Differentially Interact with T Cell and Macrophage Derived HIV Due to Differences in N-linked Carbohydrate Composition of Env Proteins . J. Virol. 77:1337, 2003.
Kariko, K., Bhuyan, P, Capodici, J., Ni, H., and Weissman, D. siRNA treatment of mammalian cells induces specific and non-specific suppression Journal of Gene Medicine. In Press.
Kariko, K., Ni, H., Capodici, J, Lampheir, M., Weissman, D., mRNA is an endogenous ligand for Toll-like receptor 3, Submitted Immunity.
Cannon, G., Van Ryk, D.I., Chaiken, I., Cutilli, J.R., Wu, Z, Ni, H., Scales, D.A., Malamud, D., Weissman, D.,HIV envelope binding by macrophage expressed gp-340 promotes HIV-1 infection. Submitted J. Immunology
Weissman, D., Rabin, R., Arthros, J., Dybul, M., Rubbert, A., Venkatesan, S., Farber, J., Fauci, A.S.: Macrophage tropic HIV and SIV gp160 signals through CCR5. Nature 389:981-6, 1997.
Rubbert, A., Combadiere, C., Ostrowski, M., Dybul, M., Machado, E., Cohn, M., Hoxie, J.A., Murphy, P.M., Fauci, A.S., Weissman, D.: Dendritic cells express multiple chemokine receptors used by HIV as coreceptors for entry. J Immunol 160:3933-41, 1998.
Lee, B., Sharron, M., Montaner, L.J., Weissman, D., and Doms, R.W. Quantification of CD4, CCR5, and CXCR4 on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc. Natl. Acad, Sci. USA 96:5512-20, 1999.
Weissman, D., Dybul, M., Davey, R.T.Jr., Walker, R.E., Kovacs, J.A. Interleukin-2 Upregulates Expression of the HIV Fusion Coreceptor CCR5 by CD4+ Lymphocytes in vivo. In Press Journal Infectious Diseases.
Cohn, M.A., Frankel, S., Rugpao, S., Vahey, M., Young, M.,Willett, G., Tovanabutra, S., Suriyanon, V., VanCott, T., Bhoopat, L., Barrick, S., Nelson, K., and Weissman, D. Chronic Vaginal Mucosal Inflammation and HIV Expression: A Mechanism for Increased Heterosexual Transmission of HIV-1. Submitted Nature Med.
