CD8 T Cell Response Maturation Defined by Anentropic Specificity and Repertoire Depth Correlates with SIV Delta nef-induced Protection: e1004633

The live attenuated simian immunodeficiency virus (LASIV) vaccine SIV Delta nef is one of the most effective vaccines in inducing protection against wild-type lentiviral challenge, yet little is known about the mechanisms underlying its remarkable protective efficacy. Here, we exploit deep sequencing technology and comprehensive CD8 T cell epitope mapping to deconstruct the CD8 T cell response, to identify the regions of immune pressure and viral escape, and to delineate the effect of epitope escape on the evolution of the CD8 T cell response in SIV Delta nef-vaccinated animals. We demonstrate that the initial CD8 T cell response in the acute phase of SIV Delta nef infection is mounted predominantly against more variable epitopes, followed by widespread sequence evolution and viral escape. Furthermore, we show that epitope escape expands the CD8 T cell repertoire that targets highly conserved epitopes, defined as anentropic specificity, and generates de novo responses to the escaped epitope variants during the vaccination period. These results correlate SIV Delta nef-induced protection with expanded anentropic specificity and increased response depth. Importantly, these findings render SIV Delta nef, long the gold standard in HIV/SIV vaccine research, as a proof-of-concept vaccine that highlights the significance of the twin principles of anentropic specificity and repertoire depth in successful vaccine design.