The purpose of this study is to identify the various populations of activated cells that are produced during an immune response to an antigen, such as tetanus toxoid, or a superantigen (SA), and to determine why some activated cells do become infected with HIV and others do not. These cells include both antigen-specific and bystander activated cells, which are cells that do not recognize the antigen that initiated the response but are activated due to the release of mediators and other activation events that occur during the antigen-specific response. The various populations of activated cells will be studied in multiple in vitro model systems, including cocultures of dendritic cells and CD4+ T cells, an experimental protocol that mimics the interactions that occur in the paracortical regions of lymphoid organs, which are the main site of antigen-specific T-cell activation and HIV replication. We will also study stimulated peripheral blood mononuclear cells (PBMCs) to determine their infectability with HIV of various strains and tropisms. Both in vivo, tetanus immunized subjects, and in vitro, superantigen and environmental antigen-activated cells will be studied. The populations of activated cells produced during an immune response will be evaluated by surface antigen and chemokine receptor expression and the ability to be infected by M- and T-tropic HIV. Preliminary data suggest that antigen-specific cells are resistant to infection and viral replication is occurring primarily in the bystander activated cells. This may be due to the fact that activation of CD4+ T cells leads to a down regulation of both CCR5 and CXCR4 in the cells responding to antigen, whereas the bystander activated cells do not down-regulate either HIV co-receptor. The mechanisms responsible for the inability of HIV to infect these cells will be explored. The different mechanisms of activation of antigen-specific versus bystander populations will then be studied to determine the cytokines and receptor interactions that are responsible for the activation of the bystander cells.
