The goal of this program project is to better understand the relationship between the persistence of neurotropic virus and the development of acute and chronic neurologic disease. The proposed program contains three specific projects, an administrative and a scientific core. The first project analyzes B cell responses in human multiple sclerosis (MS) brain. The second and third projects center, respectively, on highly neurotropic herpesvirus: varicella zoster virus (VZV) which causes serious morbidity and occasional mortality, particularly in elderly and immunocompromised humans, and simian varicella virus (SVV) which displays clinical , pathological and virologic features virtually identical to those of VZV in humans, thus allowing experimental manipulation not possible in humans. In all three projects, material from humans and monkeys will be studied clinically combined with virologic, molecular biologic and genetic techniques. We will analyze heavy chain IgG family and germline usage in acute MS brain. Based on our successful development of recombinant antibodies specific for measles virus from IgG sequences expressed in SSPE brain, we will generate recombinant IgG to demonstrate their specificity in MS brain. We will expand the analysis of varicella latency by infecting primates with SVV expressing a green fluorescent protein, identify the cell infected during latency, and determine the extent of varicella transcription in latently infected ganglia obtained before death in its natural host. Finally, we will study the molecular interactions of VZV genes known to be transcribed in latently infected human ganglia. This proposal melds the skills and strategies of investigators with expertise in neurology, virology, molecular genetics and clinical investigation. This concerted effort is focused on prospective studies to determine the cause and pathogenesis and eventual prevention of viral and demyelinative disease of the human nervous system.
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