Background: The pathogenesis of AIDS is related to both the direct cytopathic effect of HIV on infected CD4⁺ T-cells and indirect mechanisms of lymphocyte depletion such as increased apoptosis of uninfected T-cells and impaired regeneration of lymphocytes. Naturally SIV-infected sooty mangabeys (SMs) do not progress to AIDS despite high levels of virus replication and a short in vivo lifespan of infected CD4⁺ T-cells. We proposed that the absence of indirect mechanisms of immunodeficiency is instrumental in avoiding AIDS in SIV-infected SMs. We have previously shown that HIV-infection is associated with specific perturbations of cell cycle control (called Cell Cycle Disease, CCD), consisting of 1) increased cyclin B/p34 cdc2 activity, and 2) abnormal nucleolar structure. We hypothesized that CCD is a biological link between hyper-immune activation and apoptosis and represents an important indirect mechanism leading to CD4⁺ T-cell depletion and AIDS.

Methods: We performed a comparative study of cyclin B expression and nucleolar structure in 20 SMs and 20 RMs (10 SIV-infected and 10 uninfected). The analysis of in vivo susceptibility to apoptosis was performed by measuring CD95, CD95L, and Apo2.7 expression on T-cells, and in situ TUNEL staining in lymph nodes, while the analysis of in vitro susceptibility to apoptosis was performed using Annexin V/7AAD staining.

Results: We found that while SIV infection of RMs is associated with levels of CCD that are similar to what was observed in HIV-infected humans, no signs of CCD were found in lymphocytes isolated from SIV-infected SMs, with levels of cyclin B expression and AgNOR staining similar to that observed in uninfected controls. Consistent with the lack of CCD in freshly isolated lymphocytes, we did not find an increased propensity to spontaneous and activation-induced apoptosis in vitro in lymphocytes from SIV-infected SMs.

Conclusions: The finding that neither CCD nor increased susceptibility to apoptosis are present in the non-pathogenic SIV-infection of SMs supports the hypotheses that 1) the lack of indirect mechanisms of immunodeficiency is instrumental in protecting SIV-infected SM from the development of AIDS, and 2) that CCD represents a key molecular mechanism determining the increased sensitivity to apoptosis of uninfected T-lymphocytes in pathogenic HIV and SIV infections.