For Protection from HIV-1 Infection, More Might Not Be Better: a Systematic Analysis of HIV Gag Epitopes of Two Alleles Associated with Different Outcomes of HIV-1 Infection
For Protection from HIV-1 Infection, More Might Not Be Better: a Systematic Analysis of HIV Gag Epitopes of Two Alleles Associated with Different Outcomes of HIV-1 Infection
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DOI：
10.1128/jvi.05721-11
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发表时间：
2012-01-01
影响因子：
5.4
通讯作者：
Plummer, Francis A.
中科院分区：
文献类型：
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作者：
Luo, Ma;Daniuk, Christina A.;Plummer, Francis A.
1985年在肯尼亚内罗毕建立的普姆瓦尼性工作者队列中，有一部分妇女尽管通过积极的性工作反复暴露于高风险（艾滋病毒暴露，血清阴性[HESN]），但仍未受到感染。这种HESN表型与人类白细胞抗原（HLA）的几个等位基因以及对HIV-1的特异性CD 8（+）和CD 4（+）T细胞应答相关。HLA等位基因与不同HIV-1感染的相关性很可能是由于它们呈递抗原的能力不同以及它们诱导的免疫应答不同。因此，与HIV-1感染的不同结果相关的HLA等位基因的表位特征可能为开发有效的疫苗提供重要线索。在这项研究中，我们系统地分析了HIV-1进化枝A和D Gag CD 8（+）T细胞表位的两个HLA I类等位基因与HIV-1感染的不同结果。确定所鉴定的表位的结合亲和力和解离速率。γ干扰素（IFN-γ）酶联免疫斑点（ELISpot）测定与患者外周血单核细胞（PBMC）验证的表位。表位特异性CD 8（+）T细胞进一步用四聚体染色针对记忆标志物进行表型分型。我们的研究表明，保护性等位基因A*01：01只识别三个Gag表位。相比之下，与易感性相关的等位基因B*07：02结合30个表位变体。这两个等位基因最重要的不同之处在于它们可以呈现的Gag表位的谱，而不是亲和力、解离速率、表位的位置或表位特异性Tem/Tcm频率。更多表位的结合和强IFN-γ ELISpot应答与HIV-1感染的易感性相关，而更集中的多亚型抗原识别具有保护性。合理的疫苗设计应考虑这些观察结果。
A subset of women in the Pumwani Sex Worker Cohort, established in 1985 in Nairobi, Kenya, remains uninfected despite repeated high-risk exposure (HIV-exposed, seronegative [HESN]) through active sex work. This HESN phenotype is associated with several alleles of human leukocyte antigens (HLAs) and specific CD8(+) and CD4(+) T cell responses to HIV-1. The associations of HLA alleles with differential HIV-1 infection are most likely due to their different abilities to present antigen and the different immune responses they induce. The characteristics of epitopes of HLA alleles associated with different outcomes of HIV-1 infection might therefore point to a vital clue for developing an effective vaccine. In this study, we systematically analyzed HIV-1 clade A and D Gag CD8(+) T cell epitopes of two HLA class I alleles associated with different outcomes of HIV-1 infection. Binding affinity and off-rates of the identified epitopes were determined. Gamma interferon (IFN-gamma) enzyme-linked immuno-spot (ELISpot) assays with patient peripheral blood mononuclear cells (PBMCs) validated the epitopes. Epitope-specific CD8(+) T cells were further phenotyped for memory markers with tetramer staining. Our study showed that the protective allele A*01:01 recognizes only three Gag epitopes. By contrast, B*07:02, the allele associated with susceptibility, binds 30 epitope variants. These two alleles differ most importantly in the spectrum of Gag epitopes they can present and not in affinity, off-rates, the location of the epitopes, or epitope-specific Tem/Tcm frequencies. The binding of more epitopes and strong IFN-gamma ELISpot responses are associated with susceptibility to HIV-1 infection, while more focused antigen recognition of multiple subtypes is protective. Rational vaccine design should take these observations into account.