Temporal loss of Nef-epitope CTL recognition following macaque lipopeptide immunization 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 immunized with a mixture of seven lipopeptides derived from SIV Nef and Gag proteins and showed a bispecific antiviral CTL response directed toward Nef 169-178 and 211-225 peptides. After SIV infection, CTL activity against the Nef 169-178 epitope was no longer detectable, as assessed from peripheral blood mononuclear cells stimulated by autologous SIV. CTL activity against the 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 proviral 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 169-178 showed only two mutations among all viral sequencing performed. We conclude that in this macaque, bispecific CTL exerted a strong selective pressure and escape virus mutants finally emerged. We identified CTL recognizing a conserved Nef epitope 112-119 (SYKLAIDM), essential for viral replication, which could be associated with a prolonged AIDS-free period. These results stress the importance of the induction of broader multispecific CTLs directed against highly conserved and functional T-cell epitopes by vaccination, with the aim of keeping HIV infection in check.
Mortara
L
L
Laboratoire d'Immunologie des Pathologies Infectieuses et Tumorales, Institut Cochin de Génétique Moléculaire (ICGM), INSERM U445, 27 rue du Faubourg Saint-Jacques, Paris, 75014, France.
Letourneur
F
F
Villefroy
P
P
Beyer
C
C
Gras-Masse
H
H
Guillet
J G
JG
Bourgault-Villada
I
I
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D015693:Gene Products, nef / Q000737:chemistry / Q000276:immunology*; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D016133:Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D014765:Viral Vaccines; D014766:Viremia / Q000276:immunology
D000939:Epitopes; D015693:Gene Products, nef; D010446:Peptide Fragments; D014765:Viral Vaccines