One reason HIV-1-infected subjects fail to control viremia is due to the high rate of mutation of HIV-1, with consequent escape from the immune response, especially from neutralizing antibodies. Approximately 8% of the human genome is composed of human endogenous retroviruses (HERVs). Most HERVs are fixed in the human genome, defective in replication, and transcriptionally silent in normal cells. Previous studies have shown members of the HERV-K (HK) family are reactivated during HIV-1 infection. This reactivation leads to the production of viral proteins that may become stable antigens on HIV-1-infected cells. Interestingly, Garrison/Jones et al. from the Nixon and Ostrowski labs have shown a specific T cell response against HK epitopes in HIV-1 infected patients. Our preliminary results have demonstrated a humoral response against two domains of HK present on the viral envelope in both HIV-1-infected subjects and healthy controls. The humoral response to one of these domains is specific for HIV-1-infected patients. I propose, in this grant, to study and characterize this humoral response in HIV-1-infected patients to determine if these antibodies have a role in HIV-1 pathogenesis or could be exploited as a therapeutic tool. To assess this hypothesis, I will identify the immunodominant domain of the HK viral proteins and isolate B-cells that have been EBV immortalized which produce antibodies against different HK epitopes, to evaluate their ability to specifically bind HIV-1 or infected cells and induce their lysis. The understanding of the immune response directed against human endogenous retroviruses may have a broad impact on the concept of immunodominancy in the HIV-1 immune response. Furthermore, it may lead to a new concept of a "non-HIV" HIV-1 vaccine or therapeutic.