Acute-Phase CD8 T Cell Responses That Select for Escape Variants Are Needed to Control Live Attenuated Simian Immunodeficiency Virus

Max Harris,Charles M Burns,Thomas C Friedrich,Emma Gostick,Shelby L O'Connor,Andrew T Braasch,David A Price,Randall C Johnson,Ericka A Becker,Karl W Broman

doi:10.1128/jvi.00909-13

Abstract

The overall CD8 T cell response to human/simian immunodeficiency virus (HIV/SIV) targets a collection of discrete epitope specificities. Some of these epitope-specific CD8 T cells emerge in the weeks and months following infection and rapidly select for sequence variants, whereas other CD8 T cell responses develop during the chronic infection phase and rarely select for sequence variants. In this study, we tested the hypothesis that acute-phase CD8 T cell responses that do not rapidly select for escape variants are unable to control viral replication in vivo as well as those that do rapidly select for escape variants. We created a derivative of live attenuated SIV (SIVmac239Δnef) in which we ablated five epitopes that elicit early CD8 T cell responses and rapidly accumulate sequence variants in SIVmac239-infected Mauritian cynomolgus macaques (MCMs) that are homozygous for the M3 major histocompatibility complex (MHC) haplotype. This live attenuated SIV variant was called m3KOΔnef. Viremia was significantly higher in M3 homozygous MCMs infected with m3KOΔnef than in either MHC-mismatched MCMs infected with m3KOΔnef or MCMs infected with SIVmac239Δnef. Three CD8 T cell responses, including two that do not rapidly select for escape variants, predominated during early m3KOΔnef infection in the M3 homozygous MCMs, but these animals were unable to control viral replication. These results provide evidence that acute-phase CD8 T cell responses that have the potential to rapidly select for escape variants in the early phase of infection are needed to establish viral control in vivo.

Highlights

The CD8 T cell response to human/simian immunodeficiency virus (HIV/SIV) is an aggregate of multiple, discrete epitopespecific responses
Since few CD8 T cell epitopes restricted by molecules encoded by the M3 major histocompatibility complex (MHC) haplotype had been identified when we began this study, we reasoned that high-frequency variants shared between virus populations isolated from these three M3 homozygous Mauritian cynomolgus macaques (MCMs) progressors would have adequate replicative fitness and contain effective escape mutations in commonly recognized CD8 T cell epitopes
Even though CD8 T cell responses targeting these five epitopes were absent, we detected reproducible CD8 T cell responses targeting three additional epitopes that remained intact in m3KO⌬nef, two of which typically do not select for escape variants until the chronic infection phase in M3 homozygous MCMs infected with SIVmac239

Summary

Introduction

The CD8 T cell response to human/simian immunodeficiency virus (HIV/SIV) is an aggregate of multiple, discrete epitopespecific responses. It is nearly impossible to evaluate the in vivo antiviral efficacy of acute-phase CD8 T cell responses that do not rapidly select for variants in HIV-positive individuals. These studies typically focus on responses restricted by a single MHC class I. Control of pre-escaped SIV replication has been inconsistent and unpredictable in these studies [10,11,12] and the antiviral efficacy of acute-phase CD8 T cell responses targeting invariant epitopes could not be evaluated. With such exquisite knowledge of host MHC genetics and epitope-specific CD8 T cell immunity, this model can be customized to evaluate the antiviral efficacy of CD8 T cell responses that do not rapidly select for escape variants

Methods

Results

Conclusion