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Associate Chairperson, Department of Neuroscience Director of Graduate Programs, Department of Neuroscience Professor, Neuroscience Professor, Neurovirology Location: Room 746 MERB Telephone: 215-707-6248 Fax: 215-707-4888 Email: jayrapp@temple.edu
Department of NeuroscienceCenter for Neurovirology
Molecular pathogenesis of HIV infection and the development of vaccines for prevention and treatment. Mechanisms of viral induced CNS disorders and the development of RNA and DNA based therapeutic strategies.
Research Summary
HIV Vaccine Development. The development of vaccines for HIV infection has been difficult for a number of reasons:
In order to address some of these issues, we are focusing our efforts to target the early (non-structural) proteins as vaccine targets. Efforts are in progress to develop and test vaccines targeting the retroviral Tat, Rev and Nef proteins, in combination with Gag. We are testing these subunits using specialized delivery methods to induce cytotoxic T-cell responses in non-human primates infected with simian immunodeficiency virus (SIV). Studies currently in progress include the evaluation of DNA, protein and adenovirus delivery systems. These studies will evaluate the efficacy of DNA vaccine administration in combination with cytokine adjuvants in the context of SIV infection during anti-retroviral therapy.
Pathogenesis of HIV Associated Dementia Complex/HIV Encephalitis (HIVE). In HIV infection, particularly during the latter stages of disease (AIDS) an increase in the number of activated monocytes in circulation is observed. These cells are often infected by HIV and can invade the CNS leading to neurological disorders. Our current studies are focused on defining the monocyte populations, which are infected by HIV in CNS and are also aimed at determining mechanisms responsible for abnormal activation and increased trafficking into organ compartments. It is likely that the mechanisms leading to monocyte activation not only promote CNS disease, but also promote further increases in virus replication and potentially contribute to drug resistant reservoirs in HIV infected patients. Results of our studies in human tissues derived from autopsy specimens demonstrates that the perivascular macrophage is the major reservoir for productive HIV infection in the CNS in HIV. In addition, cells with ramified microglial morphology in brain parenchyma are also productively infected. There is a large increase in both populations of macrophages/microglia in HIVE. Having ruled out proliferation as a mechanism for the increased number of these cells, our studies now focus on trafficking of monocyte/macrophages in HIVE. Indeed, other organs including kidney, liver, lymph node and spleen exhibit invasion of monocyte/macrophages in patients with HIVE. Viral genetic analysis of individual cell subsets is currently in progress to determine if HIV evolution is compartmentalized within the CNS or alternatively, if similar viral sequences are found in various organs and tissues.
Pathogenesis of Progressive Multifocal Leukoencephalopathy in HIV Infection. In this project, we focus on the role of Purα in viral CNS interaction. HIV-1 infection of the central nervous system induces a variety of clinical abnormalities including dementia, ataxia, and memory loss. Progressive multifocal leukoencephalopathy (PML) represents one of the most common neurological complications of HIV-1 infection. PML is a fatal demyelinating disease that results from the reactivation of the human neurotropic polyomavirus, JCV, and its infection of oligodendrocytes and astrocytes. Once a rare disorder, the higher incidence of PML among AIDS patients suggests cross-communication between HIV-1 and JCV in the brain. Results from molecular biology and virology studies have established the ability of Tat to augment the JCV genome. This event requires, at least in part, a cellular protein named Purα, a single stranded DNA and RNA binding protein whose expression is controlled during brain development. Purα also stimulates HIV-1 gene expression and its association with Tat augments Tat activation of the LTR. Furthermore, Purα, controls JCV DNA replication and gene expression in glial cells by interacting with the JCV early protein, T-antigen. Purα has an unusual structural feature allowing the protein to interact with various important cellular proteins in addition to nucleic acids. Ablation of Purα in animal models causes incomplete brain development. Our preliminary observations have shown the ability of Purα to control cell cycle progression and prolong cells with damaged DNA in S-phase. On the other hand, Purα has shown the ability to interact with Rad51 (a key factor in the homologous recombination pathway), decrease the level of Rad51 gene transcription, and interfere with the function of Ku70, one of the major components of the non-homologous end-joining pathway. These observations ascribed a new role for Purα as a gatekeeper of DNA repair, which ensures the efficient and appropriate repair of DNA with high levels of fidelity and accuracy by modulating cell cycle progression and the level of expression and activity of factors involved in cellular DNA repair machinery. Support for this observation stems from our results showing substantial chromosomal abnormalities associated with dysfunctional repair in cells lacking Purα. In light of these observations one can envision a model in which the physical interaction of Purα with the JCV regulatory protein, T-antigen, and the HIV-1 transactivator protein, Tat, will have a functional consequence on the ability of Purα to execute its role in DNA repair during the course of HIV-1 infection and JCV reactivation. In this project, experiments are proposed to delineate the effect of Purα on DNA repair mechanisms seen in astrocytes and oligodendrocytes, and determine the impact of JCV and HIV-1 upon Purα functions in cell cycle regulation and genomic stability. The outcome of these studies will provide important information which can be utilized to better understand the indirect communication of two distinct viruses by cellular proteins and their cooperative role in the progression of diseases in the CNS.
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Jay Rappaport, PhD