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Member Information
David Weiner, PhD
Professor, Pathology and Laboratory Medicine
Office Phone: 215-349-8365
Office Fax: 215-573-9436
Email: dbweiner@mail.med.upenn.edu
Website(s): http://mail.med.upenn.edu/~dbwlab/
Education: PhD 1986, University of Cinncinnatti
Keywords: HIV, DNA Vaccines
Research and/or Clinical Interests:
One focus of the laboratory is developing novel DNA vaccines for HIV-1. This includes developing immunogens for multiple subtypes to combat viral diversity as well as engineering new improved vaccines thorough inclusion of immune modulatory molecules as part of the vaccine cassettes. The basic biology of vaccination is a focus of the laboratory.
Summary:
Our laboratory has focused on the development of a DNA vaccine for HIV-1. Over the past 13 years DNA vaccines have moved from a laboratory curiosity to an important immunization approach. We have recently reported in a therapy study in the context of HAART that DNA vaccines induce CD8 T cell responses and result in lower viral loads in humans. However, the quality and longevity of the responses induced even with highly optimized plasmid cassettes is still significantly below that of vector live approaches. Enhancing potency is critically important. The laboratory has taken several steps to improve the potency of these vaccines. These include new investigations into understanding the basic mechanisms of plasmid transfer to mammalian cells during the vaccination process. In addition studies focus on increasing the amount of antigen produced from an individual plasmid vaccine. Other focuses are targeting the antigens produced to specific intracellular compartments to study these effects on the resulting immune responses. One very important tool for increasing the potency of the induced immune responses is to engineer molecular adjuvants into the vaccines themselves. Through many different studies we have observed that cytokines such as IL-12 or IL-15 have dramatic ability to improve on the DNA induced immune responses. We are currently evaluating these approaches in non human primate models as well as in clinical studies. Additionally the functions of the HIV accessory genes and how they impact the host cell are also an important focus of the laboratory.
Representative Publications:
Ayyavoo, V., A. Mahboubi, S. Mahalingam, R. Ramalingam, S. Kudchodkar, W. V. Williams, D. R. Green, and D. B. Weiner. 1997. HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor kappa B [see comments]. Nat Med. 3:1117-1123.
Boyer, J. D., K. E. Ugen, B. Wang, M. Agadjanyan, L. Gilbert, M. L. Bagarazzi, M. Chattergoon, P. Frost, A. Javadian, W. V. Williams, Y. Refaeli, R. B. Ciccarelli, D. McCallus, L. Coney, and D. B. Weiner. 1997. Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination [see comments]. Nat Med. 3:526-532.
Kim, J. J., M. L. Bagarazzi, N. Trivedi, Y. Hu, K. Kazahaya, D. M. Wilson, R. Ciccarelli, M. A. Chattergoon, K. Dang, S. Mahalingam, A. A. Chalian, M. G. Agadjanyan, J. D. Boyer, B. Wang, and D. B. Weiner. 1997. Engineering of in vivo immune responses to DNA immunization via codelivery of costimulatory molecule genes. Nat Biotechnol. 15:641-6.
Mahalingam, S., V. Ayyavoo, M. Patel, T. Kieber-Emmons, G. D. Kao, R. J. Muschel, and D. B. Weiner. 1998. HIV-1 Vpr interacts with a human 34-kDa mov34 homologue, a cellular factor linked to the G2/M phase transition of the mammalian cell cycle. Proc Natl Acad Sci U S A. 95:3419-3424.
Weiner, D. B., and R. C. Kennedy. 1999. Genetic vaccines. Sci Am. 281:50-57.
Kim, J. J., J. S. Yang, T. C. VanCott, D. J. Lee, K. H. Manson, M. S. Wyand, J. D. Boyer, K. E. Ugen, and D. B. Weiner. 2000. Modulation of antigen-specific humoral responses in rhesus macaques by using cytokine cDNAs as DNA vaccine adjuvants. J Virol. 74:3427-3429.
Boyer, J. D., A. D. Cohen, S. Vogt, K. Schumann, B. Nath, L. Ahn, K. Lacy, M. L. Bagarazzi, T. J. Higgins, Y. Baine, R. B. Ciccarelli, R. S. Ginsberg, R. R. MacGregor, and D. B. Weiner. 2000. Vaccination of seronegative volunteers with a human immunodeficiency virus type 1 env/rev DNA vaccine induces antigen-specific proliferation and lymphocyte production of beta-chemokines. J Infect Dis. 181:476-483.
Chattergoon, M., J.J. Kim, J.S. Yang, T. M. Robinson, D.J. Lee, T. Dentchev, D.M. Wilson, V. Ayyavoo, and D. B. Weiner. 2000.Targeted antigen delivery to antigen-presenting cells including dendritic cells by engineered fas-mediated apoptosis. Nat. Biotechnol. 18:974-979.
Kim, J., Yang, J.S., Nottingham, L.K., Lee, D.J., Kelledy, H., Manson, M., Wyand. M., Boyer, J.D., Ugen, K.E., Weiner, D.B., 2001. Protection from Immunodeficiency Virus Challenges in Rhesus Macaques by Multicomponent DNA Immunization. Virology 285, 204-217.
Muthumani K , Zhang D, Hwang DS, Kudchodkar S, Dayes NS, Malik AS , Yang JS, Chattergoon MC, Desai BM, Maguire Jr HC and David B. Weiner. Adenovirus encoding HIV-1 Vpr activates Caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. Oncogene (2002) 11;21(30):4613-25.
MacGregor, RR., Ginsberg, R., Ugen, KE., Baine, Y., Kang, C., Tu, XM., Higgins, T., Weiner, DB ., Boyer, JD., T cell Responses Induced in Normal Volunteers Immunized with a DNA Based Vaccine Containing HIV-1 Env and Rev, AIDS, 16:2137-2143, 2002.
Muthumani K, Hwang DS, Desai BM, Zhang D, Dayes NS, Green DR , Weiner DB. HIV-1 Vpr Induces apoptosis through caspase 9 in T cells and peripheral blood mononuclear cells. Journal of Biological Chemistry (2002). 227(40): 37820-37831.
Ramanathan, P, and D. B. Weiner, Carboxy terminus of hVIP/mov34 is critical for Vpr interaction and glucocorticoid mediated signaling. J. Biological Chemistry, v277: 47854-47860, 2002.
