Association of Major Histocompatibility Complex Class I Haplotypes with Disease Progression after Simian Immunodeficiency Virus Challenge in Burmese Rhesus Macaques

Abstract

Nonhuman primate AIDS models are essential for the analysis of AIDS pathogenesis and the evaluation of vaccine efficacy. Multiple studies on human immunodeficiency virus and simian immunodeficiency virus (SIV) infection have indicated the association of major histocompatibility complex class I (MHC-I) genotypes with rapid or slow AIDS progression. The accumulation of macaque groups that share not only a single MHC-I allele but also an MHC-I haplotype consisting of multiple polymorphic MHC-I loci would greatly contribute to the progress of AIDS research. Here, we investigated SIVmac239 infections in four groups of Burmese rhesus macaques sharing individual MHC-I haplotypes, referred to as A, E, B, and J. Out of 20 macaques belonging to A + ( n = 6), E + ( n = 6), B + ( n = 4), and J + ( n = 4) groups, 18 showed persistent viremia. Fifteen of them developed AIDS in 0.5 to 4 years, with the remaining three at 1 or 2 years under observation. A + animals, including two controllers, showed slower disease progression, whereas J + animals exhibited rapid progression. E + and B + animals showed intermediate plasma viral loads and survival periods. Gag-specific CD8 + T-cell responses were efficiently induced in A + animals, while Nef-specific CD8 + T-cell responses were in A + , E + , and B + animals. Multiple comparisons among these groups revealed significant differences in survival periods, peripheral CD4 + T-cell decline, and SIV-specific CD4 + T-cell polyfunctionality in the chronic phase. This study indicates the association of MHC-I haplotypes with AIDS progression and presents an AIDS model facilitating the analysis of virus-host immune interaction.

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

“…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).…”

“…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.…”

“…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).…”