Identification of Immunodominant HIV-1 Epitopes Presented by HLA-C*12:02, a Protective Allele, Using an Immunopeptidomics Approach
Identification of Immunodominant HIV-1 Epitopes Presented by HLA-C*12:02, a Protective Allele, Using an Immunopeptidomics Approach
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DOI：
10.1128/jvi.00634-19
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发表时间：
2019-09-01
影响因子：
5.4
通讯作者：
Takiguchi, Masafumi
中科院分区：
文献类型：
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作者：
Chikata, Takayuki;Paes, Wayne;Takiguchi, Masafumi
尽管事实上HLA-C在未感染和HIV感染细胞上的细胞表面表达水平低于HLA-A和-B，但越来越多的证据表明HLA-C和HLA-C限制性CD 8（+）T细胞应答在决定HIV-1感染个体的病毒控制效率中具有重要作用。尽管如此，HLA-C限制性T细胞应答比HLA-A/B限制性T细胞应答研究得少得多，并且已经确定了相对较少的由HLA-C等位基因限制的最佳HIV-1 CD 8（+）T细胞表位。最近改进的灵敏度质谱（MS）为基础的方法来分析免疫肽组提出了一个机会，表位发现的大规模。在这里，我们采用了基于MS的免疫肽组策略来表征由保护性等位基因HLA-C*12：02呈递的HIV-1肽。我们总共鉴定了10，799种独特的8- 12-mer肽，包括15种HIV-1肽。后者包括2个先前报道的免疫显性HIV-1表位，对检测到的其他HIV-1肽的T细胞应答的分析揭示了另外的免疫显性表位。这些发现说明了基于MS的方法用于表位定义的实用性，并强调了HLA-C在HIV感染个体中呈递免疫显性T细胞表位的能力，这表明进一步评估HLA-C限制性应答以鉴定HIV-1预防和治疗策略的新靶点的重要性。来自病原体的结合肽，但迄今为止只进行了非常有限的HIV-1免疫肽组的分析。值得注意的是，越来越多的证据最近开始表明HLA-C在HIV-1感染中的保护作用，这可能表明，尽管HLA-C在未感染和HIV-1感染的细胞上的表达水平低于HLA-A/B的表达水平，但HLA-C仍然有效地将表位呈递给CD 8（+）T细胞。为了探索这一点，我们分析了HLA-C*12：02限制的HIV-1肽的HIV-1感染的细胞只表达HLA-C*12：02（一个保护性等位基因）使用液相色谱串联质谱（LC-MS/MS）。我们确定了一些新的HLA-C*12：02结合的HIV-1肽，并表明，虽然他们中的大多数人没有引起T细胞的反应，在自然感染的日本队列，他们包括三个免疫显性表位，强调HLA-C的贡献表位介绍艾滋病毒感染的细胞。
Despite the fact that the cell surface expression level of HLA-C on both uninfected and HIV-infected cells is lower than those of HLA-A and -B, increasing evidence suggests an important role for HLA-C and HLA-C-restricted CD8(+) T cell responses in determining the efficiency of viral control in HIV-1-infected individuals. Nonetheless, HLA-C-restricted T cell responses are much less well studied than HLA-A/B-restricted ones, and relatively few optimal HIV-1 CD8(+) T cell epitopes restricted by HLA-C alleles have been defined. Recent improvements in the sensitivity of mass spectrometry (MS)-based approaches for profiling the immunopeptidome present an opportunity for epitope discovery on a large scale. Here, we employed an MS-based immunopeptidomic strategy to characterize HIV-1 peptides presented by a protective allele, HLA-C*12:02. We identified a total of 10,799 unique 8- to 12-mer peptides, including 15 HIV-1 peptides. The latter included 2 previously reported immunodominant HIV-1 epitopes, and analysis of T cell responses to the other HIV-1 peptides detected revealed an additional immunodominant epitope. These findings illustrate the utility of MS-based approaches for epitope definition and emphasize the capacity of HLA-C to present immunodominant T cell epitopes in HIV-infected individuals, indicating the importance of further evaluation of HLA-C-restricted responses to identify novel targets for HIV-1 prophylactic and therapeutic strategies.IMPORTANCE Mass spectrometry (MS)-based approaches are increasingly being employed for large-scale identification of HLA-bound peptides derived from pathogens, but only very limited profiling of the HIV-1 immunopeptidome has been conducted to date. Notably, a growing body of evidence has recently begun to indicate a protective role for HLA-C in HIV-1 infection, which may suggest that despite the fact that levels of HLA-C expression on both uninfected and HIV-1-infected cells are lower than those of HLA-A/B, HLA-C still presents epitopes to CD8(+) T cells effectively. To explore this, we analyzed HLA-C*12:02-restricted HIV-1 peptides presented on HIV-1-infected cells expressing only HLA-C*12:02 (a protective allele) using liquid chromatography-tandem MS (LC-MS/MS). We identified a number of novel HLA-C*12:02-bound HIV-1 peptides and showed that although the majority of them did not elicit T cell responses during natural infection in a Japanese cohort, they included three immunodominant epitopes, emphasizing the contribution of HLA-C to epitope presentation on HIV-infected cells.