Background: We reported previously on the emergence and clinical implications of simian immunodeficiency virus (SIVmac251) mutants with a K65R mutation in reverse transcriptase (RT), and the role of CD8+ cell-mediated immune responses in suppressing viremia during tenofovir therapy. Because of significant sequence differences between SIV and HIV-1 RT that affect drug susceptibilities and mutational patterns, it is unclear to what extent findings with SIV can be extrapolated to HIV-1 RT. Accordingly, to model HIV-1 RT responses, 12 macaques were inoculated with RT-SHIV, a chimeric SIV containing HIV-1 RT, and started on prolonged tenofovir therapy 5 months later.

Simian immunodeficiency virus (SIV) infection of infant macaques is a useful animal model of pediatric HIV infection to evaluate the potential of chemoprophylactic regimens to reduce mother-to-infant transmission of HIV. Previous studies have demonstrated that short-term subcutaneous administration of the reverse transcriptase inhibitor tenofovir was highly effective in protecting newborn macaques against infection after a single high-dose oral inoculation with virulent SIVmac251. In the current study, we mimicked HIV transmission through breast-feeding by repeatedly feeding infant macaques low doses of SIVmac251. Topical administration of a low dose of the second-generation tenofovir prodrug GS-7340 did not have detectable prophylactic efficacy. Oral administration of tenofovir disoproxil fumarate (DF; 10 mg/kg SID) lowered the infection rate at birth, but had lower efficacy against virus infection at 4 weeks of age, most likely because drug levels became suboptimal relative to those obtained with the current tenofovir DF regimen in humans. These prophylactic results further underscore the relevance of the current tenofovir DF prevention trials in pediatric and adult populations.

Infection of macaques with the avirulent molecular clone SIVmac1A11 results in transient low viremia and no disease. To investigate if this low viremia is solely due to intrinsic poor replication fitness or is mediated by efficient immune-mediated control, 5 macaques were inoculated intravenously with SIVmac1A11. Three animals that were depleted of CD8+ cells at the start of infection had more prolonged viremia with peak virus levels 1 to 2 logs higher than those of 2 animals that received a non-depleting control antibody. Thus, CD8+ cell-mediated immune responses play an important role in controlling SIVmac1A11 replication during acute viremia.