SIV escape mutants in rhesus macaques vaccinated with NEF-derived lipopeptides and challenged with pathogenic SIVmac251

Abstract

Background: Emergence of viral variants that escape CTL control is a major hurdle in HIV vaccination unless such variants affect gene regions that are essential for virus replication. Vaccine-induced multispecific CTL could also be able to control viral variants replication. To explore these possibilities, we extensively characterized CTL responses following vaccination with an epitope-based lipopeptide vaccine and challenge with pathogenic SIVmac251. The viral sequences corresponding to the epitopes present in the vaccine as well as the viral loads were then determined in every macaque following SIV inoculation.

Results: In most cases, the emergence of several viral variants or mutants within vaccine CTL epitopes after SIV challenge resulted in increased viral loads except for a single macaque, which showed a single escape viral variant within its 6 vaccine-induced CTL epitopes.

Conclusion: These findings provide a better understanding of the evolution of CD8+ epitope variations after vaccination-induced CTL expansion and might provide new insight for the development of an effective HIV vaccine.

Figure 1

Cytotoxic activities detected in the 7 responder macaques against long peptides after lipopeptide vaccination. Only the positive cytotoxic responses against long peptide-sensitized target cells of the responder macaques are shown, all long peptides having been tested in each monkey.

Figure 2

Evaluation of plasma viral RNA levels and cell-associated viremia in SIV-challenged macaques. a- Plasma viral load in 8 lipopeptide-vaccinated (102, 105, 109, 117, 120, 125, 127, 129) and 3 naive (954, 956, 959) macaques was evaluated up to week 35 post-SIV infection using SIVmac bDNA assay. b- Cell-associated viremia was evaluated in 8 lipopeptide-vaccinated (102, 105, 109, 117, 120, 125, 127, 129) and 3 control (954, 956, 959) macaques up to 35 weeks post-SIV inoculation.

Figure 3

Post-challenge CTL responses of lipopeptide-vaccinated macaques 109 and 129, evaluated at weeks 10 and 53 for macaque 109, weeks 13 and 47 for macaque 129. The target cells were autologous B-LCL cells alone (○) or sensitized by short epitopic peptides: NEF 101–110 (□), NEF 116–126 (◆), NEF 128–136 (▲), NEF 169–178 (X), NEF 201–211 (*), NEF 211–219 (-), NEF 215–225 (●) and GAG 266–275 (+).