Background:  Simian immunodeficiency virus (SIV) infection of its natural host, sooty mangabeys (SM), results in high levels of plasma viremia in the absence of immune dysfunction and clinical AIDS. However, cross-species transmission of SIV to non-natural hosts (HIV in humans/SIV in macaques) generally results in high viral loads, low CD4+ T-cell levels, and clinical AIDS. Here a study of SIVsmm inoculation resulted in an unexpected decline of CD4 levels to below 100/ul of blood in two SM, although these animals still remain free of clinical AIDS symptoms.

Methods:  Six SM were IV inoculated with plasma from a naturally infected SM and followed longitudinally for viral and immunologic parameters. Flow cytometric analysis was utilized to assess CD4 T-cell levels and immune proliferation/activation/apoptosis (CD95, CD28, CD69, HLA-DR, Ki67, annexin V). Real-time polymerase chain reaction (PCR) was utilized to assess viral loads and T-cell receptor recombination excision circles (TREC) levels as a measure of recent thymic emigrants. Viral diversity was assessed by sequence analysis of the V1-V2 region of the SIV env gene.

Results:  CD4⁺ T-cell depletion to AIDS-defining levels was observed in 2 SIVsmm-inoculated SM (CD4⁺ T-cell loss not due to down-modulation of the CD4 molecule from the cell surface). Investigation of the causes of these AIDS-defining CD4⁺ T-cell levels did not identify a correlation with increased levels of proliferation/activation/apoptosis or a decline in the levels of recent thymic emigrants. The apparent health of the immune system was further verified due to the presence of SIV-specific antibodies in both CD4-normal and CD4-low SM. Experiments to assess the viral diversity within these SM identified a restriction in viral env sequences, suggesting that viral mutations in the CD4-low SM may be a contributing factor. Most importantly, the CD4-low phenotype did not result in clinical symptoms of AIDS after 3 years at levels <100 CD4⁺ T cells/ul of blood. 

Conclusions:  These data suggest that the CD4-low phenotype is the result of direct viral cytopathicity of the SIVsmm replicating in these 2 SM, as we did not identify any correlation between CD4 decline and immune activation. These CD4-low SM therefore represent a unique model to investigate the direct cytopathicity of SIV in the absence of aberrant immune activation as well as other immune components responsible for preventing progression to clinical AIDS in SM.

Keywords: SIV; mangabey; CD4 depletion