Effects of human immunodeficiency virus (HIV) infection of the CNS are a major health issue in this country. At present, neuropathogenesis associated with lentiviral infection remains largely unexplained. Lack of neuronal infection by HIV suggests indirect mechanisms of neurovirulence. Feline immunodeficiency virus (FIV) may serve as an excellent model to study lentiviral neuropathogenesis. Neural target cells for FIV are similar to those for HIV; both infect astrocytes and microglia but not neurons. The candidate's immediate career goal is to gain depth and experience in the field of neuroscience, specifically with the effects of viral infection of neuroglia. Dr. Zenger plans to explore the multistep model of lentiviral-induced neuropathogenesis presented in this application under the direct supervision of Dr. Evelyn Tiffany-Castiglioni (sponsor). The investigators propose to study the molecular changes that occur in astrocytes following FIV infection. Because altered cell membrane permeability is a likely early effect of viral infection and a likely common denominator resulting in abnormalities of many important estrocyte functions, we will also evaluate several parameters related to astrocyte membrane permeability: (1) plasma membrane fluidity, (2) neurotransmitter uptake and metabolism, and (3) alterations of calcium channel responsiveness. Further studies will investigate the effect on glutathione (GSH) activity and protection against viral effects by exogenous GSH. The candidate will exploit the powerful technology of interactive laser cytometry for developing highly sensitive essays that quantitate functional abnormalities end probe the disruption of cell metabolism at discrete sites. This approach will be combined with more traditional immunological and biochemical assays to obtain a broad coverage of molecular events transpiring in FIV-infected cells. The candidate's department is unique in that it has both state-of-the-art equipment end a highly trained support staff (headed by Dr. Robert Burghardt, co-sponsor of this proposal) required for effective use of the interactive laser cytometry technology. These experiments constitute Phase l of the research plan. In Phase II, the candidate plans to specifically address the question of the effects of individual FIV proteins in astroglial cultures through the use of viral protein expression vectors.
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