HIV infection inhibits granulysin expression by memory CD8+ T cells (128.26)

Abstract The hallmark of HIV infection is severe immuno-suppression and an increased susceptibility to many infectious agents including M. tuberculosis. Granulysin is expressed by cytotoxic T cells (CTL) and is strongly lytic against susceptible and drug resistant strains of M. tuberculosis. We hypothesized that the reduced CTL activity observed following HIV infection may, in part, be due to suppression of granulysin. We and others have shown that granulysin expression is regulated by common γc cytokines IL-2, IL-15 and IL-21. We used an in vitro model, in which we infected PBMC from healthy donors with HIV. We found that induction of granulysin in CD8+ T cells following stimulation with IL-2, IL-15 or IL-21 was reduced in PBMC infected with HIV. Moreover, we observed that phosphorylation of STAT5, a downstream signaling molecule crucial for the induction of granulysin by IL-2 and IL-15 was also reduced by HIV infection. In an antigen-specific memory response, using PBMC from PPD+ donors, we found that expression of granulysin by memory CD8+ T cells following PPD stimulation was inhibited in HIV-infected PBMC. Our results suggest that suppression of granulysin in response to γc cytokines and specific TB antigen by HIV may be one mechanism for the increased susceptibility of HIV+ patients to TB infection and could represent an important avenue for immune intervention.