Human herpesvirus type 8 (HHV-8) is a gamma family herpesvirus discovered in 1994 by Chang and Moore. The virus has been strongly implicated by serologic antibody studies and PCR detection as the etiologic agent of Kaposi's sarcoma (KS) as well as multicentric Castleman's disease and body cavity lymphomas. Based on the well-documented role of T cell immune responses in herpesvirus infections, we hypothesize that T cell immunity is induced by HHV-8 infection. We postulate further that cytotoxic T lymphocyte (CTL) activity specific for the virus is central to control of HHV-8 infection, and failure of this surveillance mechanism results in development of HHV-8 related disease. Knowledge regarding CTL responses to HHV-8 may be important in development of adequate treatment and prevention methods for this agent. Therefore, we propose the following specific aims for this project: (1) Characterize the longitudinal T cell immmunologic responses (by lytic activity, gamma interferon producing cells and tetramer staining) to regulatory, structural and latent proteins of HHV-8 during primary infection of normal adults subjects, including T cell phenotype, HLA restriction and peptide epitope mapping; (2) Define the role of the anti-HHV-8CTL response in the development of KS in HIV-1 infected subjects; (3) Determine the CTL response in situ to viral proteins related to lytic, latent and transforming properties of HHV-8, and determine if KS tumor cells are capable of suppressing CTL activity; and (4) Determine if the transforming protein K1 elicits HHV-8 clade- specific CTL responses. Application of these methodologies in our laboratories for assessing cellular immunity and HHV-8 expression, combined with access to a longitudinal cohort of HHV-8 seroconvertors in the Multicenter AIDS Cohort Study, offers a unique opportunity to advance our understanding of anti-HHV-8 CTL responses in primary infection and development of KS. Such information is also important for understanding the immune correlates of protection against HHV-8 infection as the basis for development of therapeutic regimens and prophylatic vaccines
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