School of Human Sciences, University of Western Australia, Crawley, Australia.
Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia.
PLoS Pathog. 2024 Jul 9;20(7):e1012359. doi: 10.1371/journal.ppat.1012359. eCollection 2024 Jul.
A strong genetic predictor of outcome following untreated HIV-1 infection is the carriage of specific alleles of human leukocyte antigens (HLAs) that present viral epitopes to T cells. Residual variation in outcome measures may be attributed, in part, to viral adaptation to HLA-restricted T cell responses. Variants of the endoplasmic reticulum aminopeptidases (ERAPs) influence the repertoire of T cell epitopes presented by HLA alleles as they trim pathogen-derived peptide precursors to optimal lengths for antigen presentation, along with other functions unrelated to antigen presentation. We investigated whether ERAP variants influence HLA-associated HIV-1 adaptation with demonstrable effects on overall HIV-1 disease outcome. Utilizing host and viral data of 249 West Australian individuals with HIV-1 subtype B infection, we identified a novel association between two linked ERAP2 single nucleotide polymorphisms (SNPs; rs2248374 and rs2549782) with plasma HIV RNA concentration (viral load) (P adjusted = 0.0024 for both SNPs). Greater HLA-associated HIV-1 adaptation in the HIV-1 Gag gene correlated significantly with higher viral load, lower CD4+ T cell count and proportion; P = 0.0103, P = 0.0061, P = 0.0061, respectively). When considered together, there was a significant interaction between the two ERAP2 SNPs and HLA-associated HIV-1 adaptation on viral load (P = 0.0111). In a comprehensive multivariate model, addition of ERAP2 haplotypes and HLA associated adaptation as an interaction term to known HLA and CCR5 determinants and demographic factors, increased the explanatory variance of population viral load from 17.67% to 45.1% in this dataset. These effects were not replicated in publicly available datasets with comparably sized cohorts, suggesting that any true global epistasis may be dependent on specific HLA-ERAP allelic combinations. Our data raises the possibility that ERAP2 variants may shape peptide repertoires presented to HLA class I-restricted T cells to modulate the degree of viral adaptation within individuals, in turn contributing to disease variability at the population level. Analyses of other populations and experimental studies, ideally with locally derived ERAP genotyping and HLA-specific viral adaptations are needed to elucidate this further.
在未经治疗的 HIV-1 感染后，对结果有强烈遗传预测作用的是携带人类白细胞抗原（HLA）特定等位基因，这些等位基因将病毒表位呈递给 T 细胞。结果测量的剩余差异部分归因于病毒对 HLA 限制的 T 细胞反应的适应性。内质网氨肽酶（ERAPs）的变体影响 HLA 呈递的 T 细胞表位的 repertoire，因为它们将病原体衍生的肽前体修剪成最佳的抗原呈递长度，以及与抗原呈递无关的其他功能。我们研究了 ERAP 变体是否会影响与 HLA 相关的 HIV-1 适应性，以及对整体 HIV-1 疾病结果的明显影响。利用来自 249 名澳大利亚西部感染 HIV-1 亚型 B 的个体的宿主和病毒数据，我们发现两个连锁的 ERAP2 单核苷酸多态性（SNPs；rs2248374 和 rs2549782）与血浆 HIV RNA 浓度（病毒载量）之间存在新的关联（两个 SNP 的调整后 P 值均为 0.0024）。HIV-1 Gag 基因中与 HLA 相关的 HIV-1 适应性更高，与更高的病毒载量、更低的 CD4+T 细胞计数和比例显著相关；P = 0.0103，P = 0.0061，P = 0.0061。当一起考虑时，两个 ERAP2 SNP 与 HLA 相关的 HIV-1 适应性对病毒载量的交互作用有显著意义（P = 0.0111）。在一个综合的多变量模型中，将 ERAP2 单倍型和 HLA 相关适应性作为相互作用项添加到已知的 HLA 和 CCR5 决定因素以及人口统计学因素中，增加了该数据集人群病毒载量的解释方差，从 17.67%增加到 45.1%。在具有可比规模队列的公开可用数据集中没有复制这些效果，这表明任何真正的全球上位性可能依赖于特定的 HLA-ERAP 等位基因组合。我们的数据提出了这样一种可能性，即 ERAP2 变体可能塑造呈递给 HLA 类 I 限制的 T 细胞的肽 repertoire，以调节个体内病毒适应性的程度，从而在人群水平上导致疾病变异性。需要对其他人群进行分析，并进行理想的本地 ERAP 基因分型和 HLA 特异性病毒适应性的实验研究，以进一步阐明这一点。
