Herpesvirus saimiri (HVS) has been used in recent years as a tool in the study of human T cells. The PI has shown that HVS can be used to immortalize CD4+ and CD8+ T cell clones from HIV-1 infected nonprogressors and AIDS patients with high frequency. HVS- immortalized cells appear to maintain normal, functional phenotype. However, all CD4+ clones from nonprogressors, but not from AIDS patients, produced high levels of b-chemokines, RANTES, MIP-1a, and MIP-1b and were resistant to infection with non-syncytium-inducing (NSI) viruses. Interestingly, selected CD4+ clones from nonprogressors were also resistant to infection by syncytium-inducing (SI) viruses whereas other clones from the same donor were highly susceptible. Resistance to SI viruses was not mediated through surface co-receptors (CXCR4) or by over production of SDF-1. However, viral DNA could be detected in the resistant cells after nonproductive infection with SI viruses suggesting that the block to virus replication occurred at a post-entry level. Additionally, resistant clones but not susceptible clones from the same donor elaborated soluble factors that could protect other susceptible cells against infection with SI viruses and could inhibit virus production from chronically-infected cells. These data suggest a novel mechanisms of host resistance against SI viruses mediated, in part through soluble factors that act after virus entry and integration. The overall goal of this application is to further validate this mechanism by developing CD4+ clones from AIDS patients and nonprogressors by the same techniques followed by identification, characterization and molecular cloning of resistance factors.
