Background: Naturally SIV-infected sooty mangabeys (SMs) do not develop CD4⁺ T-cell depletion and AIDS despite chronic high levels of virus replication, limited anti-SIV CTL responses measured ex-vivo, and a short in vivo lifespan of infected CD4⁺ T-cells. We proposed that CTL responses do not contribute to control of virus replication and, in fact, their absence is beneficial in enabling SIV-infected SMs to avoid CD4⁺ T-cell depletion and AIDS.

Methods: To test this hypothesis, we have assessed the overall level of cellular immune responses in 19 naturally SIV-infected SMs by measuring the expression of activation (e.g., CD69, CD25, HLA-DR) and proliferation (e.g., Ki67) markers, as well as the production of cytokines in peripheral blood- and lymph node-derived T-cells. In addition, we have performed the same analyses, as well as the in situ study of Ki67 expression in lymph nodes during acute experimental SIVsm infection of SMs and rhesus macaques (RM). Finally, the role of CD8⁺ T-cell mediated responses was studied by measuring the effect of CD8⁺ T-cell depletion on the level of plasma viremia in naturally SIV-infected SMs.

Results: 1) Naturally SIV-infected SMs show minimal levels of CD8⁺ T-cell activation and proliferation and low levels of CD8⁺ T-cell mediated production of pro-inflammatory cytokines such as IFN-γ and TNF; 2) Experimental SIV-infection of SMs elicited little, if any, CD8⁺ T-cell activation during both the acute and chronic phases of infection. In contrast, RMs infected in parallel exhibited substantial and persistent T-cell activation. Following peak viremia, greater suppression of virus replication was observed in RMs (despite the fact that RMs, but not SMs, manifest CD4⁺ T-cell depletion and AIDS) and found to be correlated with elevated CD8⁺Ki67⁺ T-cells. This finding suggests that CD8⁺ T-cell proliferation during acute infection represents a measure of the SIV-specific cellular immune response; and 3) CD8⁺ T-cell depletion during chronic SIV-infection of SMs results only in a modest increase of viremia (3-fold).

Conclusions: These complimentary sets of data indicate that in SIV-infected SMs CD8⁺ T-cell mediated cellular immune responses are highly unlikely to play a major role in determining the levels of virus replication and/or the clinical course of the infection.