HIV Immunopathogenesis: Inhibition of CD4+ T Cell Activation

Human immunodeficiency virus (HIV) infection causes profound impairment of CD4+ T cell immunity. Anti-retroviral therapy (ART) restores CD4+ T cell responses to common antigens, but HIV-specific responses remain deficient. The immunization of chronically HIV infected, ART treated subjects also leads to poor HIV-specific CD4+ T cell responses. The mechanisms are not fully understood. In this thesis, I demonstrate that HIV envelope glycoprotein (Env), when delivered in the form of a vaccine or when present on free viral particles, suppresses antigen-stimulated CD4+ T cell proliferation. I investigate the potential involvement of human T regulatory cells (Treg) using an in vitro model system. I show that Env exposure neither changes the frequency nor the suppressive activity of Treg cells in human PBMC, and that Env-induced suppression of CD4+ T cell proliferation is independent of Tregs. The studies of HIV-induced inhibition of CD4+ T cell immunity were then moved to an in vivo model to determine physiological significance. A macaque model of HIV-infected individuals treated with ART during chronic infection was used to study the effect of SIV antigen stimulation in lymph nodes early after immunization. CMV seropositive rhesus macaques were infected with pathogenic SIVmac251 and after 4 months, treated with D4T and PMPA for viral control and immune reconstitution. I studied the immune and viral responses to SIV and CMV antigen immunization in draining lymph nodes. Animals were immunized with both SIV gag and CMV pp65 encoding plasmids in both arms and legs, which allowed draining lymph nodes for each antigen to be obtained at the same time, thus allowing direct comparisons of the effect of each antigen stimulation in the same animal. I observed that both SIV and CMV antigen immunizations stimulated antigen-specific T cell responses in draining lymph nodes. The CMV-specific responses were found in the periphery for 50 days post-immunization, while the SIV-specific responses transiently appeared. The SIV antigen stimulation also induced transient SIV viral replication in the draining lymph nodes, suggesting a mechanism for the early loss and poor HIV-specific CD4+ T cell response observed in HIV-infected progressors