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

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.

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

“…ϩ MCMs (9,12,18,(20)(21)(22). Some of these 14 epitopes accumulate variants during acute SIV infection, some accumulate variants during chronic infection, and some rarely accumulate variants.…”

“…This observation led us to hypothesize that similar conditional escape may occur during chronic SIV infection, when the comprehensive set of sequences present in the virus population is more complex and diverse than during acute infection. In this study, we deep sequenced SIV replicating in MCMs that were homozygous and heterozygous for the M3 MHC haplotype, and we evaluated variant accumulation in the 14 epitopes previously shown to be restricted by M3 MHC class I molecules (18,20).…”

Vaccination with Live Attenuated Simian Immunodeficiency Virus (SIV) Protects from Mucosal, but Not Necessarily Intravenous, Challenge with a Minimally Heterologous SIV

“…To test our hypothesis, we used seven Mauritian cynomolgus macaques (MCMs) that had been vaccinated with m3KO⌬nef, a live attenuated strain of SIV that differs from SIVmac239⌬nef by 24 amino acids (9). Four of these amino acid mutations are located in known CD8 T cell epitopes presented by MHC class I molecules expressed in the four M3-positive animals (animals cy0379, cy0381, cy0384, and cy0385) (9).…”

“…Four of these amino acid mutations are located in known CD8 T cell epitopes presented by MHC class I molecules expressed in the four M3-positive animals (animals cy0379, cy0381, cy0384, and cy0385) (9). gag viral loads were measured in these seven animals during the first 20 weeks after vaccination with m3KO⌬nef (9).…”

“…Viral loads were determined from plasma obtained from venous blood drawn into EDTA tubes. SIV gag loads were determined essentially as previously described (9,10). Viral RNA (vRNA) was isolated from plasma, reverse transcribed, and amplified with the SuperScript III Platinum one-step quantitative reverse transcription-PCR (qRT-PCR) system (Invitrogen).…”