Assessment of CD4+ T Cell Depletion and Monocyte Function During Nonpathogenic SIV Infection of Sooty Mangabeys

SIV-infected sooty mangabeys maintain low levels of chronic immune activation and do not progress to AIDS, making them an important model for elucidating the mechanisms contributing to AIDS pathogenesis. The studies presented here utilize the mangabey model of nonpathogenic SIV infection to assess the impact of CD4+ T cell depletion on immune activation in SIV-infected mangabeys and to assess the contribution of monocytes to nonpathogenic SIV infection. The Sodora laboratory previously identified a cohort of SIV-infected sooty mangabeys that experienced a virally-mediated severe decline in CD4+ T cells yet did not develop opportunistic infections or AIDS. Here, we assessed the immune competence of three mangabeys following viral passage from one CD4-low mangabey that resulted in a dramatic decline in CD4+ T cells within 21 days-post-infection. Despite the rapid depletion of CD4+ T cells, all mangabeys maintained low levels of chronic immune activation and mounted adaptive immune responses to SIV and influenza vaccination. To investigate the contribution of monocytes to the low levels of immune activation, we assessed the effector function of monocytes in SIV-infected CD4-low and CD4-healthy sooty mangabeys. We found that, compared to SIV-negative mangabeys, monocytes from SIV-infected mangabeys produced significantly less TNF-alpha upon stimulation with lipopolysaccharide (LPS). In contrast, hosts of a pathogenic infection, including SIV-infected macaques and HIV-infected humans, displayed no change in monocyte TNF-alpha responses relative to uninfected controls. In mangabey PBMC cultures, stimulation with LPS led to increases in CD8+ T cell activation that could be inhibited in a dose-dependent manner by TNF-alpha –blocking antibodies. Taken together, these results suggest that TNF-alpha production from monocytes can contribute to increases in immune activation and that SIV-infected sooty mangabeys regulate the monocyte response to LPS as one means to avoid chronic immune activation during SIV infection. These studies expand the current knowledge of the mechanisms by which SIV-infected natural hosts avoid progression to AIDS and underscore the importance of controlling immune activation during lentiviral infection, which may inform the next generation of therapies and vaccines for HIV patients.