This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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 Leukoencephalopathy (PML) is emerging as a cause of death in individuals with acquired immunodeficiency syndrome (AIDS), with survival limited to an average of 10.5 months after diagnosis. Further, the incidence of JC human polyomavirus (JCV)-induced 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 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. Simian virus 40 (SV40) is a rhesus macaque polyomavirus closely related to the human JCV. We have isolated and characterized variant SV40 strain 18429 from a simian-human immunodeficiency virus (SHIV)-infected rhesus macaque that developed PML-like CNS lesions. The goal of this study is to produce a nonhuman primate 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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