Protection afforded by live attenuated SIV is associated with rapid killing kinetics of CTLs.

Live attenuated SIV vaccines are highly efficacious, but how they mediate protection is poorly understood. A feature of the effectiveness of live attenuated vaccines is their ability to control high dose challenge viruses early, without a large peak of acute viraemia. We hypothesized that long-lived antigen exposure from live attenuated SIV may result in CD8+ cytotoxic T lymphocytes persistently capable of rapidly cytolytic potential. We employed a kinetic degranulation assay to study multiple tetramer+ SIV-specific CTL specificities before and after the SIVmac251 challenge of pigtail macaques inoculated with a live attenuated SIV. Live attenuated SIV-vaccinated animals rapidly controlled a subsequent challenge, with minimal viraemia after exposure. For over 9 months after the initial vaccination with live attenuated SIV we could detect both Gag- and Tat-specific CTLs that maintained a long-term capacity to rapidly degranulate (CD107a expression) and release granzyme B within 30 minutes of antigen exposure. This rapid cytolytic phenotype was maintained throughout the early period after challenge, despite the absence of a marked enhancement in CTL frequencies. Our results suggest that highly functional CTLs may contribute to the remarkable efficacy of live attenuated SIV vaccines. Studying the killing kinetics of CTLs induced by other, safer, HIV vaccines could facilitate a better understanding of the requirements for an effective HIV vaccine.