Co-administration of Rapamycin with a DNA/MVA SIV Vaccine Improves Memory CD8 T Cell Response and Enhances Control of SIV251 Infection

Background: Recent studies in mice and macaques demonstrated generation of higher frequency and better quality memory CD8 T cells by inhibiting the mTOR pathway using rapamycin. In this study, we tested the effect of rapamycin on the immunogenicity and efficacy of a DNA/MVA SIV vaccine in rhesus macaques. Methods: Macaques were primed with a DNA/SIV vaccine on weeks 0 and 8, and boosted with a MVA/SIV vaccine on weeks 16 and 24 in the absence (DM) or presence of rapamycin either during MVA boosts or during primes and boosts. Rapamycin treatment was given for a period of 32 days starting from day -3 of each immunizationwhere used. Macaques were challengedwith SIV251 intrarectally at about 21–24 weeks after the final MVA boost. Results: Rapamycin treatment did not increase the magnitude but reduced contraction of effector CD8 T cell response that resulted in higher frequencies of SIV-specific memory CD8 T cells with enhanced quality as determined by higher expression of CCR7 and BCl-2 ex vivo and higher proliferative capacity in vitro. Rapamycin treatment did not significantly alter the memory CD4 T cell response. Post SIV251 infection, rapamycin-treated macaques demonstrated a marked expansion of SIV-specific CD8 T cells reaching up to 50% in blood and 25% in gut and this enhanced expansion in rapamycin-treated groups was associated with a markedly lower (2-logs compared to unvaccinated and 1log compared to DM) set-point viral loads, better preservation of central memory T cells in blood and enhanced survival compared to unvaccinated and DM-vaccinated macaques. Conclusion: Inhibiting mTOR pathway during MVA boosts of a DNA/MVA vaccine regimen enhances the functional quality of vaccine-elicited memory CD8 T cell response that is capable of markedly restricting a highly pathogenic SIV replication.