Almost half of the human genome is composed of transposable retroelements. These include human endogenous retroviruses (HERV), which are thought to be remnants or fossils of ancient viral infections. Previously, we have identified HERV-specific CD8+ T cell responses in HIV-1 infected adults. For some HIV-1-positive individuals, the strength of their responses against HERV was associated with lower HIV-1 viral loads, suggesting that these responses contribute to immune containment of HIV. However, nothing is known about HERV-specific CD4+ T cell responses. In the present study, we plan to measure these responses in 20 HIV-1 infected adults and 20 HIV-1 uninfected adults using an interferon-? ELISPOT assay, cytokine flow cytometry and T cell proliferation assays. We will also determine whether HERV-specific CD4+ T cell responses are preserved over time or affected by antiretroviral therapy in a longitudinal study of four different timepoints from each HIV-1 infected individual. Finally, we hope to demonstrate that these responses play a vital role in providing help for the cytotoxic function of HIV-1-specific CD8+ T cells. These experiments will be conducted over a 12-month period and the results will be analyzed using standard statistical tools such as the Fisher's Exact test and Mann-Whitney U test. This study has important implications for new directions in HIV-1 vaccine research. One of the key obstacles to creating an effective HIV-1 vaccine is overcoming the ability of viral variants to continually evade HIV-specific immune responses. HERV sequences are fixed in the human genome and can therefore provide a stable vaccine target. If HERV-specific T cells can kill HIV-1-infected cells or enhance the function of HIV-specific cytotoxic T lymphocytes (CTL), vaccination with these conserved antigens could be a new approach to an HIV-1 vaccine.