Background:  Naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys do not progress to AIDS despite chronically high viral loads. Pathogenic HIV/SIV infections of humans/rhesus macaques are associated with early, severe, and irreversible CD4⁺ T cell depletion from mucosal associated lymphoid tissues (MALT). We have shown that chronic SIV infection of sooty mangabeys is associated with variable but significant depletion of MALT CD4⁺ T cells. The aim of this study was to define the kinetics of CD4⁺ T cell depletion in SIV-infected sooty mangabeys.

Methods:  We infected 5 sooty mangabeys with uncloned SIV_smm derived from a naturally SIV-infected sooty mangabey. Longitudinal analyses of T-cell immunophenotype in MALT (rectal biopsy, RB, and broncho-alveolar lavage), lymph nodes and peripheral blood were performed by flow cytometry. Viral load was measured by real time polymerase chain reaction (RT-PCR). Plasma lipopolysaccharide levels were assessed by Limulus Amebocyte assay. Cytokine production in response to lipopolysaccharide, lipid A, and HKSA stimulation of whole blood was measured by cytokine bead arrays.

Results:  All SIV-infected sooty mangabeys remained asymptomatic, with peak and set-point viral loads of 10⁶ to 10⁸ and 10⁴ to 10⁶copies/mL plasma, respectively. While only a minor decline in the level of CD4⁺ T cells in peripheral blood and lymph nodes was observed, all animals underwent a rapid, significant, and persistent depletion of CD4⁺ T cells in both RB and broncho-alveolar lavage. This depletion involved all subsets of CD4⁺ T cells, including the CD28^–CD95⁺ “effectors,” and was temporally associated with a moderate increase in systemic and mucosal immune activation. An early increase in plasma lipopolysaccharide levels was observed in the 2 SIV-infected sooty mangabeys with the most profound CD4⁺ T-cell depletion in RB, indicating a transient loss of mucosal immune barrier integrity. However, we found that the ex vivo production of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in response to lipopolysaccharide was significantly reduced in sooty mangabeys compared to rhesus macaques, suggesting that sooty mangabeys have adapted to attenuate the inflammatory response to systemic translocation of intestinal microflora.

Conclusions:  These data indicate that non-pathogenic SIV infection of sooty mangabeys is similar to pathogenic HIV/SIV infections in terms of the pattern of target cell depletion, as it is associated with an early and severe loss of CD4⁺ T cells in mucosal tissues. However, the lack of sustained immune activation and maintenance of mucosal immune function in the presence of fewer CD4⁺ T cells may protect SIV-infected sooty mangabeys from systemic CD4⁺ T cell depletion and progression to AIDS.