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

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.

Biphasic CD8 + T-Cell Defense in Simian Immunodeficiency Virus Control by Acute-Phase Passive Neutralizing Antibody Immunization

“…While macaque R03-013 experienced a transient viral rebound between weeks 16 and 32, it showed stringent control thereafter, and no SIV controllers experienced late-phase breakthrough infection. We previously noted that some 90-120-Ia ϩ and 90-010-Id ϩ naive macaques showed lower viral loads (19,20), but they only rarely become spontaneous aviremic controllers. This indicated that the passive NAb conferred robust SIV control.…”

“…We first retrospectively performed a longterm follow-up of previously SIV mac239 -infected, NAb-immunized rhesus macaques that showed undetectable set point viral loads (less than 4 ϫ 10 2 copies/ml) (17,19,20). Four pairs of rhesus macaques that were identified as sharing different MHC-I haplotypes (21) Counterparts had been passively infused intravenously with 300 mg of polyclonal anti-SIV neutralizing IgG at day 7 postinfection.…”

“…R06-019 and R06-038 had been infused with 300 mg of nonspecific control IgG at week 1. The dotted lines show geometric mean viral loads for the previously reported haplotype-possessing naive infected animals (n Ն 5) (19,20). (B) Comparison of peak (weeks 1 and 2), set point (week 12), and chronic-phase (geometric [geo] mean after year 1) pVL in NAb-uninfused and infused animals (paired t tests).…”

“…Most of the animals had been used for our previous experiments, and their viral loads in the early phase were previously reported (17,19,20). In the present study, we conducted a longterm follow-up and in-depth analysis on T-cell responses throughout the period of observation (up to approximately 2 years).…”

“…The present study used frozen peripheral blood mononuclear cell (PBMC) samples derived from Burmese rhesus macaques (Macaca mulatta) for retrospective analysis of SIV-specific T-cell responses. Previous SIV mac239 challenge experiments using the animals (17,19,20) were conducted at the Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), with the help of the Corporation for Production and Research of Laboratory Primates. These studies were approved by the Committee on the Ethics of Animal Experiments of NIBIOHN under the guidelines for animal experiments at NIBIOHN and the National Institute of Infectious Diseases, which are in accordance with the Guidelines for Proper Conduct of Animal Experiments established by the Science Council of Japan (http://www.scj.go.jp/ja/info/kohyo/pdf/kohyo-20-k16-2e .pdf).…”