This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Life expectancy has been prolonged in HIV-1-infected individuals due to improved clinical management of the primary retroviral and opportunistic infections. Nevertheless, Progressive Multifocal Leuko-encephalopathy (PML) is emerging as a persistent cause of death in individuals with AIDS, with survival limited to an average of 10.5 months after diagnosis. A recent study showed that the incidence of PML among HIV-infected patients receiving combination drug therapy for HIV-1 has increased. While new treatment strategies are reasonably successful in abating the progression of acquired immunodeficiency disease (AIDS), there is currently no effective treatment for PML. Therefore, the development of an animal model of PML would be a tremendous asset for studying mechanisms involved in myelin damage that characterizes PML and for devising better treatments for the disease. Reactivation of the JC human polyomavirus (JCV) in the central nervous system (CNS) of immunosuppressed patients can cause progressive loss of myelin that characterizes PML. Simian virus 40 (SV40) is a rhesus macaque polyomavirus closely related to the human JCV. We have isolated and characterized a variant strain of SV40 from a simian-human immunodeficiency virus (SHIV)-infected rhesus macaque that developed PML-like CNS lesions. Further, SV40-naive, SHIV-infected rhesus macaques experimentally co-infected with variant SV40 strain 18429 developed PML-like CNS disease. The goal of this study is to produce a nonhuman primate animal model of PML suitable for studying the mechanisms involved in myelin destruction and for testing new treatment strategies. To accomplish this goal we will: 1) attempt to induce PML in SHIV-infected rhesus macaques using a full-length molecular clone of SV40 strain 18249, and 2) create SV40/JCV hybrid viruses using the strain 18429 molecular clone of SV40 and a PML isolate of JCV to explore viral genetic determinants of CNS cell tropism in monkey and human cells in vitro.
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