Background:  Natural SIV infection of sooty mangabeys is non-pathogenic despite chronic, high levels of viremia. The mechanisms underlying the disease resistance of simian immunodeficiency virus (SIV)-infected sooty mangabeys are still unclear, although a key feature of this infection is the absence of the generalized immune activation associated with HIV infection. Here we tested the hypothesis that SIV-infected sooty mangabeys avoid CD4⁺ T cell depletion and AIDS because the in vivo lifespan of virus-infected cells is longer or the fraction of virus produced by long-lived cells is higher than in pathogenic HIV/SIV infections. To this end we measured the kinetics of viral load decline after ART and inferred the percentage of viral replication occurring in short-lived infected cells as well as the average in vivo half-life of infected cells.

Methods:  We treated 6 naturally SIV-infected sooty mangabeys subcutaneously for 6 weeks with the reverse transcriptase inhibitors tenofovir and emtricitabine at a dose of 30 mg/kg/day. Plasma viremia was measured by real-time polymerase chain reaction at day 0, 1, 2, 4, 7, and twice/week thereafter. A longitudinal immunophenotypical analysis of lymphocytes derived from peripheral blood, lymph nodes, bone marrow, and mucosal tissues was performed using 7-color flow cytometry.

Results:  Treatment was well tolerated in all SIV-infected sooty mangabeys, with no discernible side effects. ART suppressed viral replication below detectable limit in 5 of 6 animals, with a decline of 2.8 Log in the sooty mangabeys with detectable viremia. All treated SIV-infected sooty mangabeys showed a rapid post-ART suppression of viral replication with average decline in plasma viremia of 0.51 Log after 2 days and 0.86 Log after 4 days. The rapid-phase of viremia decline lasted <7 days and accounted for >90% of viral replication in all animals. From the rate of decline we estimated that on average the half-life of productively infected cells is at most 1.07±0.28 days. Termination of treatment was followed by a rapid rebound of viremia to levels similar to those observed prior to ART. Suppression of viral replication was followed by a transient increase of CD4⁺ T cell counts in 4 of 6 sooty mangabeys.

Conclusions:  Similar to pathogenic HIV/SIV infections, natural SIV infection of sooty mangabeys is characterized by rapid viral turnover, the vast majority of viral replication occurring in short-lived infected cells. These findings indicate that the AIDS resistance of SIV-infected sooty mangabeys is unlikely to be related to a longer lifespan of infected cells.