Analogies between the pathogenesis of clade B HIV-1 and other subtypes have been proposed but not proven, and the immunopathogenesis in non-B subtype HIV-1 infection remains inadequately explored. Cellular immunity in HIV-1 infection is believed to play a key role in viral control, and remains an important focus in vaccine development, in a region of the world where non-clade B infections predominate, it is crucial to characterize the immunopathogenesis of these viruses, because it is unclear whether they may elicit different immune responses and thus require different preventive and therapeutic approaches. Another geographic issue is the differential frequency of HLA alleles in different ethnic populations. Structured treatment interruptions (STI) of antiretroviral therapy (ARV) in the U.S. and Europe (where clade B predominates) have provided a unique opportunity to evaluate the role of cellular immune responses in the control of viremia. These studies have provided a model for the study of cellular immune control of viral replication in vivo. Until recently, such studies have not been feasible in many resource-poor settings where non-B clades predominate, particularly in Africa. Antiretroviral therapy has recently been introduced to Uganda, where two clinical studies evaluating ARV and STi, respectively, are currently ongoing at the Joint Clinical Research Centre in Kampala. These studies provide us a unique opportunity to evaluate the immune response in the setting of non-B clade HIV-1 infection and various ARV regimens. We hypothesize that the determinants antiviral cellular immunity could differ with the varying clades in distinct geographic regions. The goals of this proposal are to further dissect factors in non-B clade HIV infection, with potential implications in immunotherapeutics and vaccine development. Specifically, we propose: 1) To determine the T cell responses to clade A, and D viral strains in Uganda, in the context of the host HLA class alleles; 2) To perform mechanistic studies of antiviral function using CD8+ T cell clones; 3) To analyze the cellular immune responses in a cohort of Ugandan individuals Ireceiving continuous highly active antiretroviral therapy (HAART) and STI, and study the correlates of immune control in this population.
