HIV-1 infection is associated with progressive and ultimately profound immunosuppression, resulting in the development of opportunistic infections and neoplasm in the later stage of illness. Despite strong virus-specific humoral and cellular responses, disease progression ensues in the vast majority of infected persons indicating that the immune responses are incapable of clearing the infection. Virus-specific CD4+ T helper lymphocytes are critical to maintain effective immunity in a number of chronic viral infections, but are characteristically weak or undetectable in chronic HIV-1 infection representing the most notable defect in the immunological repertoire against HIV-1. A better understanding of HIV-1-specific lymphocyte proliferative responses is likely to be highly relevant to understanding the immunopathogenesis of HIV-1 and may provide valuable insight into therapeutic interventions and vaccine development. The goals of this proposal are to determine the breadth, magnitude, specificity, and immunological function of HIV-1-specific proliferative responses in persons infected with HIV-1. Additionally, to determine whether intervention with anti-retroviral therapy during primary HIV-1 infection that impact on the generation of virus-specific lymphocyte proliferative responses. Blood sample will be obtained from individuals with long-term non- progressive infection and from persons with primary HIV-1 infection and early seroconversion. CD4+ lymphocytes will be tested in standard lymphocyte proliferation assays to HIV-1 specific antigens. When responses are detected, in-depth immunological studies including cytokine and chemokine production, fine epitope specificity and HLA restriction will be performed using bulk and cloned cells. In persons with primary HIV-1, potent anti-retroviral therapy will be initiated and subjects will be monitored for the development of an HIV-specific lymphocyte proliferative response. The development of HIV-1 specific lymphocyte responses will be correlated HIV-1 plasma, RNA viral load, and the generation and maintenance of virus-specific cytotoxic T lymphocyte activity. Insight into the immunological function of CD4+ HIV-1 specific lymphocytes may provide valuable information for immunotherapeutic and vaccine development.
