Background:. Natural SIV infection of sooty mangabeys (SM) does not induce AIDS despite chronic high levels of virus replication and the short in vivo lifespan of infected cells. However, significant variations can be observed between individual animals with respect to CD4⁺ T-cell count. The aim of this study was to identify determinants of low CD4⁺ T-cell counts in SIV-infected SM.

Methods:  We conducted a cross-sectional survey of 110 naturally SIV-infected SM (age 6 to 28 years) hosted at the Yerkes Primate Center. All animals were evaluated for AIDS-related symptoms. Viral load was measured by reverse transcriptase-polymerase chain reaction. Expression of markers of T- cell activation (CD69, CD25, CD95, HLA-DR), proliferation (Ki67), differentiation (CCR7, CD62L, CD45RA, CD27, CD28, CD127), and SIV co-receptors (CCR5, CXCR4, Bob, and Bonzo) was studied by flow cytometry.

Results:  The nonpathogenic nature of SIV infection of SM was confirmed by the consistent absence of AIDS-related symptoms in all animals and the finding of an average CD4⁺ T-cell count of 1,076 + 589/cmm despite many years of infection with a highly replicating virus (mean viremia of 171,000 copies/mL). No correlation was found between CD4⁺ T-cell counts and age (which can be used as a surrogate marker for the length of infection) or level of viral replication. A significant inverse correlation was found between CD4⁺ T-cell count and the expression of several markers of CD4⁺ and CD8⁺ T-cell activation (i.e., expansion of CD28-neg cells). The study also found a loss of IL-7R/CD127 expression, up-regulation of CD95, and reduced fraction of naïve and/or central memory T cells. A CD4⁺ T-cell count lower than 500/cmm was observed in 14 animals, of which 3 showed a CD4 count lower than 200/cmm). Interestingly, the 2 SIV-infected SM with lowest CD4⁺ T-cell counts (i.e., < 50/cmm) showed relatively normal levels of viral replication and immune activation, suggesting a complex pathogenesis for this rare phenotype that may involve viral factors as well as failure in CD4⁺ T-cell regeneration.

Conclusions:  We observed an association between decreased CD4⁺ T-cell counts and increased T-cell activation, indicating that in naturally SIV-infected SM the overall level of immune activation is an important determinant of CD4⁺ T-cell count. In addition, the occurrence of severe CD4⁺ T-cell depletion is a rare event during natural SIV infection of SM and, when present, is not associated with any AIDS-related symptoms.

Keywords: SIV infection of natural hosts; Immune Activation; CD4 T-cell Depletion