Mauritian Cynomolgus Macaques Share Two Exceptionally Common Major Histocompatibility Complex Class I Alleles That Restrict Simian Immunodeficiency Virus-Specific CD8+ T Cells
Mauritian Cynomolgus Macaques Share Two Exceptionally Common Major Histocompatibility Complex Class I Alleles That Restrict Simian Immunodeficiency Virus-Specific CD8+ T Cells
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DOI：
10.1128/jvi.00199-09
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发表时间：
2009-06-15
影响因子：
5.4
通讯作者：
O'Connor, David H.
中科院分区：
文献类型：
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作者：
Burwitz, Benjamin J.;Pendley, Chad J.;O'Connor, David H.
引起CD8(+) t细胞反应的疫苗在进入临床试验之前，通常在非人类灵长类动物中进行免疫原性测试。不幸的是，由于主要组织相容性（MHC） I类遗传的异质性，在目前利用的非人灵长类动物群体中，疫苗引发的t细胞反应的强度和特异性是可变的。我们最近发现毛里求斯食蟹猴（MCM）具有异常简单的MHC遗传，三个共同的单倍型编码一对共享的MHC IA类等位基因，Mafa-A*25和Mafa-A*29。基于单倍型频率，我们假设这些MHC I类等位基因限制的CD8(+) t细胞反应将在几乎所有MCM中检测到。我们在这里检查了这两个等位基因的频率和功能，显示88%的MCM表达Mafa-A*25和Mafa-A*29，携带这些等位基因的动物会产生三种新定义的猿猴免疫缺陷病毒特异性CD8(+) t细胞反应。这些应答所识别的表位累积了与免疫逃逸一致的取代，表明这些应答发挥了抗病毒的选择压力。Mafa-A*25和Mafa-A*29限制几乎所有MCM共有的CD8(+) t细胞应答，这表明这些动物是比较引起CD8(+) t细胞应答的疫苗的免疫原性的有利的非人灵长类动物模型。
Vaccines that elicit CD8(+) T-cell responses are routinely tested for immunogenicity in nonhuman primates before advancement to clinical trials. Unfortunately, the magnitude and specificity of vaccine-elicited T-cell responses are variable in currently utilized nonhuman primate populations, owing to heterogeneity in major histocompatibility (MHC) class I genetics. We recently showed that Mauritian cynomolgus macaques (MCM) have unusually simple MHC genetics, with three common haplotypes encoding a shared pair of MHC class IA alleles, Mafa-A*25 and Mafa-A*29. Based on haplotype frequency, we hypothesized that CD8(+) T-cell responses restricted by these MHC class I alleles would be detected in nearly all MCM. We examine here the frequency and functionality of these two alleles, showing that 88% of MCM express Mafa-A*25 and Mafa-A*29 and that animals carrying these alleles mount three newly defined simian immunodeficiency virus-specific CD8(+) T-cell responses. The epitopes recognized by each of these responses accumulated substitutions consistent with immunologic escape, suggesting these responses exert antiviral selective pressure. The demonstration that Mafa-A*25 and Mafa-A*29 restrict CD8(+) T-cell responses that are shared among nearly all MCM indicates that these animals are an advantageous nonhuman primate model for comparing the immunogenicity of vaccines that elicit CD8(+) T-cell responses.