The goal of this proposal is to advance our understanding of papovaviral persistent infection in general and, to elucidate those processes which might underlie papovaviral persistence and pathogenesis in the human slow virus disease, progressive multifocal leukoencephalopathy (PML). Because this neurodegenerative disease is the only human illness in which papovaviruses are clearly implicated, we also seek to identify those factors which might predispose the central nervous system to papovaviral persistence or, more likely, to chronic disease. Toward these ends we will evaluate basic parameters of simian virus 40 (SV4Q), BK virus, and JC virus (the primary etiologic agent of PML) persistent infections established in cultures of human neuroblastoma and glioblastoma cell lines, in explants of human oligodendrogliomas, and in cell cultures of non-neural origin. We will determine the proportion of cells which either produce virus, or which support only limited viral gene expression, or which contain completely latent viral genomes. We will assess the temporal relationship between viral replication and cell killing. We will determine the states of the viral genomes (e.g. integrated versus free, defective versus nondefective) in latently infected clonal isolates and assess whether there is a relationship between those states and the probability of reactivation of the productive infection. We will analyze viral variants which might emerge, particularly with respect to their capacities to modulate the productive infection. We will evaluate cellular factors which might act to regulate the infection and we will determine whether those factors are related to the physiological state of the cells or to their level of differentiation. To advance our understanding of the PML disease process we will determine if persistent infection leads to specific impairment of the specialized functions expressed by the neuronal-like and glial-like cell cultures. Specialized functions to be examined include enzyme activities of neurotransmitter metabolism, neurotransmitter receptor functions, electrophysiological activity, and the expression by glial cells of extrinsic influences which promote and maintain the functional competence of neuronal cells.
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