The Koralnik laboratory is studying the pathogenesis of the polyomaviruses JC, BK, and SV40. Current areas of investigations include:
Cellular immunity to JC virus in AIDS-associated Progressive Multifocal Leukoencephalopathy (PML):
PML is a deadly demyelinating disease of the central nervous system caused by JC virus (JCV) in immunosuppressed individuals. JCV infects most healthy adults without causing any disease, but its reactivation leads to a productive and lytic infection of oligodendrocytes, the myelin producing cells in the central nervous system. We are currently studying the cellular immune response against JCV mediated by both CD8+ and CD4+ T lymphocytes in patients with PML, and we are characterizing genetic markers of the host associated with favorable outcome of PML. We are studying how this immune response cross-reacts with BK virus, the etiologic agent of polyomavirus nephropathy. Since there is no cure for PML, our laboratory is now developing a dendritic cell-based immunotherapy for this disease.
Latency and reactivation of JC virus:
We are studying the molecular and cellular mechanisms leading to the reactivation of JCV in bone marrow and peripheral blood samples, as well as the phenotype of JCV-infected cells in immunosuppressed individuals including patients with AIDS, leukemias, transplant recipients and multiple sclerosis patients treated with novel immunomodulatory medications.
Characterization of a granule cell neuron-tropic JC virus variant:
Our laboratory has shown that JC virus could also infect and destroy granule cell neurons of the cerebellum, and cause cerebellar atrophy and associated neurological dysfunction. This granule cell neuron tropic JCV variant has a unique mutation in the gene encoding the major capsid protein of JCV. We are now characterizing the phenotype of this JCV variant in vitro.
A nonhuman primate model of AIDS-associated PML:
Since JCV does not infect animals, we are developing an animal model of PML and neuronal infection using the JCV-related simian virus 40 (SV40) in SHIV immunosuppressed rhesus macaques.
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References:
Pfister LA, Letvin NL, Koralnik IJ. JC virus regulatory region tandem repeats in plasma and CNS isolates correlate with poor outcome in patients with Progressive Multifocal Leukoencephalopathy. J. Virol 2001; 75: 5672-76.
Du Pasquier RA, Corey S, Margolin DH, Williams K, Pfister LA, De Girolami U, McKey JJ, Wüthrich C, Joseph J, Koralnik IJ. Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. Neurology 2003, 61:775-82.
Du Pasquier, RA, Kuroda M, Zheng Y, Jean-Jacques J, Letvin NL, Koralnik IJ. A prospective study demonstrates an association between JC virus-specific cytotoxic T lymphocytes and the early control of Progressive Multifocal Leukoencephalopathy. Brain 2004, 127(9):1970-1978.
Dang X, Axthelm M, Letvin N, Koralnik IJ. Rearrangement of SV40 regulatory region is not required for induction of progressive Multifocal Leukoencephalopathy in immunosuppressed monkeys. J Virol 2005, 79: 1361-1366.
Koralnik IJ, Wüthrich C, Dang X, Rottnek M, Gurtman A, Simpson D, Morgello S. JC virus granule cell neuronopathy: a novel clinical syndrome distinct from PML. Ann Neurol 2005; 57:576-80.
Dang X, Koralnik. IJ. A granule cell neuron-associated JC virus variant has a unique deletion in the VP1 gene. J Gen Virol 2006, 87: 2533-2537.
Chen Y, Trofe J, Gordon J, Du Pasquier RA, Roy-Chaudhury P, Kuroda MJ, Woodle ES, Khalili K, Koralnik IJ. Interplay of cellular and humoral immune responses against BK virus in kidney transplant recipients with polyomavirus nephropathy. J Virol 2006, 80:3495-3505.
Lima MA, Marzocchetti A, Autissier P, Tompkins T, Chen Y, Gordon J, Clifford DB, Gandhi RT, Venna N, Berger JR, Koralnik IJ. Frequency and phenotype of JC virus-specific CD8+ T lymphocytes in the peripheral blood of patients with progressive multifocal leukoencephalopathy. J. Virol 2007, 81:3361-8.
Dang X, Wüthrich C, Axthelm MK, Koralnik IJ. Productive SV40 infection of neurons in immunosuppressed rhesus monkeys JNEN 2008, in press
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