On the immunopathogenesis of HIV infection

Abstract: CD8+ T-cell dependent clearance of microbial infections by perforin mediated killing of infected cells is a central component in the combat against viral infections. In HIV- 1 infected individuals the incidence of virus infected cells in lymphoid tissue, which is the major site for virus production, does not drop, but instead slowly increases as the disease progresses. This suggests that the function of HIV-specific CD8+ T-cells in the lymphoid tissue of HIV infected individuals is compromised. The work presented in this thesis has focused on the study of the immune response in lymphoid tissue of HIV infected individuals. The relation between granzyme A and perform expression in lymphoid CD8+ T-cells was assessed in HIV infected individuals, at the single cell level. While the expression of granzyme A in lymphoid tissue was extensively increased as compared to uninfected controls, no concomitant increase in the expression of perforin was noted. This was in contrast to expression in lymphoid tissue of individuals with acute EBV infection, where levels of granzyme A and perforin were concomitantly up regulated. The absence of perforin expression in lymphoid tissue of HIV infected individuals was not due to lack of infected cells since we showed that both intracellular HIV DNA and RNA levels were typically 10-100 times higher in lymphoid tissue as compared to peripheral blood. The low expression of perforin may depend on skewed production of cytokines required for the activation and maturation of efficient cytotoxic CD8+ T-cells. In order to address this we analyzed the expression of several chemokines and cytokines in the lymphoid tissue of individuals that were undergoing acute symptomatic HIV infection. A profound and early immune activation was evident during acute HIV infection, with increased expression of