Temporal loss of Nef-epitope CTL recognition following macaque lipopeptideimmunization and SIV challenge

To address the subtle interactions between antiviral cytotoxic T-cell (CTL) immune responses and the evolution of viral quasispecies variants in vivo, we performed a longitudinal study in a simian immunodeficiency virus (SIV) -infected rhesus macaque that had a long experimental SIV infection before developing simian AIDS. Before being infected with SIV, this animal was imm unized with a mixture of seven lipopeptides derived from SIV Nef and Gag pr oteins and showed a bispecific antiviral CTL response directed toward Nef 1 69-178 and 211-225 peptides. After SIV infection, CTL activity against the Nef 169-178 epitope was no longer detectable, as assessed from peripheral b lood mononuclear cells stimulated by autologous SIV. CTL activity against t he 211-225 epitope was lost after 3 months, and an additional CTL response to the amino acids 112-119 Nef epitope emerged. Analysis of the Nef provira l sequence revealed the presence of immune escape variants first in the 211 -225 epitope and much later in the 112-119 epitope. In contrast, epitope 16 9-178 showed only two mutations among all viral sequencing performed. We co nclude that in this macaque, bispecific CTL exerted a strong selective pres sure and escape virus mutants finally emerged. We identified CTL recognizin g a conserved Nef epitope 112-119 (SYKLAIDM), essential for viral replicati on, which could be associated with a prolonged AIDS-free period. These resu lts stress the importance of the induction of broader multispecific CTLs di rected against highly conserved and functional T-cell epitopes by vaccinati on, with the aim of keeping HIV infection in check. (C) 2000 Academic Press .