Jay Rappaport
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Office: Department of Biology Center for Neurovirology and Cancer Biology 203 Biological Life Sciences Building Phone: (215) 204-0605 |
The focus of this laboratory is the development of novel therapeutics for the treatment of HIV infection. In order to effectively address therapeutic design and application, a further understanding of the mechanism of pathogenesis of HIV is required. Toward this end, we have carried out studies to determine factors which contribute to progression versus clinical stability in HIV infected individuals. In collaboration with Jean-Francois and Daniel Zagury (Institute Pierre and Marie Curie, Paris) we have characterized a cohort of Fast and Slow progressors with HIV infection. Two important observations have come out of this work. Our results demonstrate that the genetics of the CCR-5 chemokine receptor influences disease progression. In addition, anti-Tat antibodies correlate inversely with viral antigen in sera of infected patients and serves as an important predictor of non-progression. We are currently measuring T cell proliferative histories by telomeric length analysis and measuring thymic output in these individuals. Our recent results demonstrate that thymic output in HIV infection is reduced, and more severly in rapid progressors. Proliferation of extra-thymic T cells is also increased which may partially compensate for the thymic defect. These observation supports our efforts toward a therapeutic HIV vaccine targeting Tat protein. HIV-1 Tat is a viral transactivator that increases the rate of viral transcription. Tat also is secreted from infected cells and has immunosuppressive properties affecting T cells. T cells from HIV infected individuals, even at early stages of HIV infection, undergo programmed cell death in response to antigen stimulation. Tat inhibits proliferation and induces apoptosis in response to an antigen stimulus. These activities support the notion that Tat may be an ideal vaccine target. Since 1995, this Investigator has been working closely with Daniel Zaguryâs group (Paris), to develop a Tat vaccine. This work has progressed to a completed Phase I clinical trial in Milan, demonstrating a significant increase in CD4+ cells. This laboratory is now working toward a proof of concept study in macaques to demonstrate the efficacy of this approach as a protective vaccine for uninfected subjects. Studies are also in progress to further characterize the epitope specificity of anti-Tat antibodies in vaccinated patients and long-term non-progressors and to determine the ability of these sera to recognize diverse strains of HIV Tat protein. We have also isolated Tat genes from HIV subtypes common to areas outside of the US and Europe in order to further our immunologic studies and to provide a framework for engineering Tat based vaccines for potential application in Asia and Africa. In addition to HIV vaccine strategies, we are interested in the application of RNA and DNA molecules toward treatment of viral-induced neurological disorders and brain tumors; molecular pathogenesis of HIV-1 induced neurological disorders, specifically related to the role of Tat and chemokines. Our working hypothesis is that HIV induced chemokine secretion (perhaps induced by Tat) is responsible for the infiltration of activated macrophages into the CNS leading to a disease process involving astrocyte activation, upregulation of adhesion molecules, alteration of the blood brain barrier and neuronal cell death. Our recent studies demonstrate the localization of HIV-Tat and chemokines in CNS tissue from patients with HIV associated CNS disorders. Additional efforts are directed toward the development of chemokine molecules which bind, but do not signal their corresponding receptors. Such molecules could be used to prevent CNS infiltration in HIV as well as in a variety of CNS diseases. |
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