Background:  Sooty mangabeys are natural hosts of the simian immunodeficiency virus (SIV) and do not manifest with AIDS despite sustained high viral loads. In contrast to pathogenic lentiviral infection, neither increased T-lymphocyte turnover nor increased immune activation is detected in SIV-infected sooty mangabeys, suggesting the possibility that SIV does not induce bystander cell destruction and immunopathology in its natural host. To determine whether sooty mangabeys fail to mount a cellular immune response to SIV, we prospectively evaluated the magnitude and breadth of SIV-specific CD4⁺ and CD8⁺ T-lymphocyte responses in a cohort of naturally SIV-infected sooty mangabeys.

Method:  The T-lymphocyte response to pools of overlapping peptides spanning all 9 SIV_mac239 proteins was measured in the peripheral blood mononuclear cells (PBMC) of 25 sooty mangabeys by the interferon-g ELISpot assay. The contribution of CD4⁺ and CD8⁺ T lymphocytes to the SIV-specific response was determined in 9 sooty mangabeys by the intracellular cytokine staining assay and/or ELISpot assays performed on CD4- and CD8-depleted PBMC.

Results:  An interferon-g ELISpot response >100 spot-forming cells (SFC)/10⁶ PBMC directed to 1 or more SIV proteins (median number 4, range 1 to 6) was detected in 24/25 animals. Although positive Th2 cytokine (IL-4, IL-5, and IL-13) ELISpot responses were detected following mitogen or superantigen stimulation, they were absent or >10-fold lower than interferon-g ELISpot responses following SIV-specific stimulation. The magnitude of the total interferon-g SIV-specific response ranged between 510 and 5244 SFC/10⁶ PBMC (median 1738 SFC/10⁶ PBMC) in 24 naturally infected sooty mangabeys, and was comparable to that observed in 4 rhesus macaques infected for more than 1 year with SIV_mac251 (range 634 to 3952 SFC/10⁶ PBMC; median 2336 SFC/10⁶ PBMC). In the majority of sooty mangabeys, the interferon-g responses to SIV Gag or Env proteins accounted for at least two thirds of the total SIV-specific response. In 9 mangabeys examined, the interferon-g responses to Gag and Env were predominantly mediated by high avidity CD8⁺ T lymphocytes.

Conclusions:  Naturally SIV-infected sooty mangabeys mount a substantial SIV-specific cellular immune response, suggesting that immune tolerance is neither a feature nor a requirement for maintenance of nonpathogenic infection in this natural host of SIV infection.

Keywords: sooty mangabeys; cellular immunology