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 â-chemokines and also elevated levels of both Th1 and Th2 type cytokines. This immune activation was associated with the accumulation of CD8+ T-cells that expressed granzyme A but not perforin.

The presence of a selective impairment in the expression of perforin, in spite of increased levels of several immune activating cytokines, lead us to investigate potential factors that could interfere with efficient cell mediated immunity. One such factor is regulatory T-cells (Treg), characterized by the constitutive expression of the transcription factor, FOXP3. Indeed, active HIV-replication was associated with a significant accumulation of Treg within lymphoid tissue and subsequently increased expression of mediators associated with Treg suppressive function, such as CTLA-4, TGF-B and the tryptophan catabolising enzyme, IDO. Furthermore, the accumulation of Treg within lymphoid tissue was correlated with plasma viral load in HIV infected individuals, suggesting a link between Treg viral load and disease progression.

We also showed that the accumulation of Treg and mediators associated with Treg function in lymphoid tissue was only evident in individuals with a progressive HIV infection and thus absent in HIV infected subjects with a non progressing type of infection, who are naturally able to control virus replication. Similar results were also obtained in a cohort of SIV infected rhesus macaques. It is likely that the accumulation of Treg can have negative influence on antiviral cell mediated immunity since we found that a high perforin/FOXP3 ratio in lymphoid tissue was associated with a non progressing type of infection in both SIV infected rhesus macaques and HIV infected individuals.

Novel therapeutic approaches aimed at enhancing immune function in HIV-infected patients should likely be targeted to the manipulation of Treg numbers and/or function in order to improve immunity.