A Novel Protective MHC-I Haplotype Not Associated with Dominant Gag-Specific CD8+ T-Cell Responses in SIVmac239 Infection of Burmese Rhesus Macaques

Naofumi Takahashi,Tetsuro Matano,Teiichiro Shiino,Tsugumine Shu,Tatsuhiko Igarashi,Yusuke Takahara,Takushi Nomura,Hiroto Hara,Yoshio Koyanagi,Akiko Takeda,Mamoru Hasegawa,Akihiro Iida,Hiromi Sakawaki,Tomoyuki Miura,Taeko K Naruse,Makoto Inoue,Hiroyuki Yamamoto,Akinori Kimura

doi:10.1371/journal.pone.0054300

Abstract

Several major histocompatibility complex class I (MHC-I) alleles are associated with lower viral loads and slower disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. Immune-correlates analyses in these MHC-I-related HIV/SIV controllers would lead to elucidation of the mechanism for viral control. Viral control associated with some protective MHC-I alleles is attributed to CD8+ T-cell responses targeting Gag epitopes. We have been trying to know the mechanism of SIV control in multiple groups of Burmese rhesus macaques sharing MHC-I genotypes at the haplotype level. Here, we found a protective MHC-I haplotype, 90-010-Id (D), which is not associated with dominant Gag-specific CD8+ T-cell responses. Viral loads in five D+ animals became significantly lower than those in our previous cohorts after 6 months. Most D+ animals showed predominant Nef-specific but not Gag-specific CD8+ T-cell responses after SIV challenge. Further analyses suggested two Nef-epitope-specific CD8+ T-cell responses exerting strong suppressive pressure on SIV replication. Another set of five D+ animals that received a prophylactic vaccine using a Gag-expressing Sendai virus vector showed significantly reduced viral loads compared to unvaccinated D+ animals at 3 months, suggesting rapid SIV control by Gag-specific CD8+ T-cell responses in addition to Nef-specific ones. These results present a pattern of SIV control with involvement of non-Gag antigen-specific CD8+ T-cell responses.

Highlights

Virus-specific CD8+ T-cell responses play a central role in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication [1,2,3,4,5]
Previous studies have found several protective major histocompatibility complex class I (MHC-I) alleles associated with lower viral loads and slower disease progression in HIV/SIV infection [7,13,14,16,17]
Elucidation of the mechanisms of viral control associated with individual protective MHC-I alleles would contribute to HIV cure and vaccine-based prevention

Summary

Introduction

Virus-specific CD8+ T-cell responses play a central role in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication [1,2,3,4,5]. In some MHC-1 alleles associating with lower viral loads and slower disease progression, certain CD8+ T-cell responses restricted by these MHC-I molecules have been shown to be responsible for HIV control [11,12,13]. Recent studies have indicated great contribution of CD8+ T-cell responses targeting Gag epitopes to reduction in viral loads in HIV/SIV infection [18,19,20,21]. CD8+ T-cell responses specific for the HLA-B*57-restricted Gag240249 TW10 and HLA-B*27-restricted Gag263272 KK10 epitopes exert strong suppressive pressure on HIV replication and frequently select for an escape mutation with viral fitness costs, leading to lower viral loads [22,24,25,26,27]. Accumulation of our knowledge on the potential of these non-Gag-specific as well as Gag-specific CD8+ T-cell responses for HIV/SIV control should be encouraged for elucidation of viral control mechanisms

Methods

Results

Conclusion