Proposed here is a Phase II research program designed to provide the candidate the opportunity to obtain research experience, initiate a research program, and develop into an independent investigator able to successfully compete for NIH research support. Feline immunodeficiency virus (FIV) induces a moderate to severe acute disease followed by a long clinical latency that, in nature, culminates in terminal acquired immunodeficiency syndrome (AIDS). While some experimentally infected cats do progress to AIDS, many do not, providing the opportunity to compare a successful to an unsuccessful host immune response against an immunodeficiency-inducing lentivirus. Two hypotheses are proposed to explain this dichotomy. Firstly, a primarily cellular immune response may predominate in FIV-infected cats that remain in a clinically latent phase, while animals progressing to AIDS may have a diminished cellular immune response. Whether an immune response is primarily cellular (T- helper lymphocyte type 1(Th1) predominates) or humoral (Th2 predominates) is reflected in the cytokine profile and may determine whether the immune system can contain viral replication and disease progression or not. Therefore, by quantitating viral DNA and RNA, as well as, mRNA levels of IL2, IL4, IL10, and INF-g in peripheral blood mononuclear cells and lymphoid tissues of experimentally FIV-infected cats at various time post inoculation, the correlation of particular cytokine profiles with status and degree of viral replication can be determined. By similarly evaluating naturally infected cats with AIDS to identify cytokine profiles characteristic of end-stage disease, changes in cytokine levels that may be indicative of a shift from Th1 to Th2 predominance. A second hypothesis is that maintenance of normal TNF-a levels may explain why cats remain in the clinically latent phase of disease. TNF-a is elevated in HIV-infected people with AIDS and approximately 50% of patients with ARC as well as in some individuals with lymphadenopathy. However, while serum TNF-a levels of FIV-infected cats are transiently elevated during the acute phase of infection, levels return to normal. These data suggest TNF-a may be play an important role in the progression of immune- deficiency. This hypothesis will be tested by administering TNF-a continuously to FIV-infected cats in clinical latency using subcutaneous osmotic pumps, and measuring viral DNA, viral RNA and cytokine mRNA production as well as monitoring the clinicopathologic condition of cats to see if TNF-a induces end-stage disease (AIDS).
