The human polyomavirus JC virus (JCV) is the etiologic agent of Progressive Multifocal Leukoencephalopathy (PML), a demyelinating disease of the central nervous system, which occurs in immunosuppressed individuals, including patients with AIDS. There is no specific treatment for PML, which remains one of the deadliest opportunistic infections in AIDS despite the introduction of highly active antiretroviral therapy. Due to the narrow host range of JCV, there is no adequate animal model for its study. The Simian Virus 40 (SV40) has 69% homology with JCV, and has been associated with a PML like disease in immunosuppressed monkeys. Since it is not likely that JCV infection of a laboratory animal will result in a disease that will exactly mimic PML, we will study a virus of this class such as SV40 that can produce a disease with CNS manifestations in immunosuppressed animals. We hypothesize that JCV/SV40 hybrid viruses may cause a CNS disease more closely resembling PML in monkeys. We have isolated a molecular clone of SV40 from the brain of an immunosuppressed rhesus monkey who died from SV40 associated brain disease, including PML and a meningoencephalitis. In the following studies, we will: I. inoculate this molecular clone in rhesus monkeys to verify that it is infectious and pathogenic in vivo II. create JCV/SV40 hybrid viruses using this infectious and pathogenic molecular clone of SV40 and a PML isolate of JCV and test their infectivity in monkey and human cells in vitro. Two SV40-negative rhesus monkeys will be injected iv with 10/7 TCID50 of this SV40 molecular clone. Two months later, they will be infected with SHIV 89.6P. We expect that this molecular clone will prove to be infectious and pathogenic. To combine the host range of SV40, and the restricted cell tropism and pathogenicity of JCV, JCV/SV40 hybrid viruses will be constructed, swapping JCV and SV40 regulatory regions and T regulatory protein sequences. These hybrid viruses will be tested for their ability to grow in monkey and human cells in vitro and compared to the previously described JCV M1-SVE (delta) hybrid. Selected hybrid viruses able to grow best in monkey adult glial cells will be used in future experiments. We expect that these hybrid viruses will produce a disease more closely resembling PML. The availability of an animal model of PML will allow new therapeutic interventions for this incurable disease.
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| Koralnik, Igor J; Schellingerhout, Dawid; Frosch, Matthew P (2004) Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 14-2004. A 66-year-old man with progressive neurologic deficits. N Engl J Med 350:1882-93 |
| Koralnik, Igor J (2004) New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 17:365-70 |
