Laboratoire Génomique, Bioinformatique, et Chimie Moléculaire, EA7528, Conservatoire National des Arts et Métiers, HESAM Université, Paris, France.
Université Paris Est Créteil, INSERM U955, IMRB, Laboratoire Neuro-Psychiatrie translationnelle, Créteil, France.
Front Immunol. 2023 Dec 11;14:1305856. doi: 10.3389/fimmu.2023.1305856. eCollection 2023.
We have reanalyzed the genomic data of the International Collaboration for the Genomics of HIV (ICGH), centering on HIV-1 Elite Controllers.
We performed a genome-wide Association Study comparing 543 HIV Elite Controllers with 3,272 uninfected controls of European descent. Using the latest database for imputation, we analyzed 35,552 Single Nucleotide Polymorphisms (SNPs) within the Major Histocompatibility Complex () region.
Our analysis identified 2,626 SNPs significantly associated (p<5. 10-8) with elite control of HIV-1 infection, including well-established signals such as the rs2395029-G allele which tags . A thorough investigation of SNPs in linkage disequilibrium with rs2395029 revealed an extensive haploblock spanning 1.9 megabases in the region tagging , comprising 379 SNP alleles impacting 72 genes. This haploblock contains damaging variations in proteins like NOTCH4 and DXO and is also associated with a strong differential pattern of expression of multiple genes such as , and . The study was expanded to include two cohorts of seropositive African-American individuals, where a haploblock tagging the allele was similarly associated with control of viral load. The mRNA expression profile of this haploblock in African Americans closely mirrored that in the European cohort.
These findings suggest that additional molecular mechanisms beyond the conventional antigen-presenting role of class I HLA molecules may contribute to the observed influence of alleles on HIV-1 elite control. Overall, this study has uncovered a large haploblock associated with alleles, providing novel insights into their massive effect on HIV-1 elite control.
我们重新分析了国际 HIV 基因组合作组织（ICGH）的基因组数据，重点关注 HIV-1 精英控制者。
我们进行了全基因组关联研究，将 543 名 HIV 精英控制者与 3272 名无感染的欧洲血统对照进行了比较。使用最新的数据库进行单核苷酸多态性（SNP）的推测，我们分析了主要组织相容性复合体（MHC）区域内的 35552 个 SNP。
我们的分析确定了 2626 个与 HIV-1 感染精英控制显著相关（p<5.10-8）的 SNP，包括如 rs2395029-G 等位基因标记的 等已确立的信号。对与 rs2395029 连锁不平衡的 SNP 的深入研究揭示了一个跨越 1.9 兆碱基的广泛单倍型块，该单倍型块在 区域标记 ，包含影响 72 个基因的 379 个 SNP 等位基因。该单倍型块包含如 NOTCH4 和 DXO 等蛋白质的有害变异，并且还与多个 基因的强烈差异表达模式相关，如 、 和 。该研究扩展到包括两个感染艾滋病毒的非裔美国人队列，其中标记 等位基因的单倍型块与病毒载量的控制也有类似的关联。该单倍型块在非裔美国人中的 mRNA 表达谱与欧洲队列非常相似。
这些发现表明，除了传统的 I 类 HLA 分子的抗原呈递作用之外，可能还有其他分子机制有助于观察到 等位基因对 HIV-1 精英控制的影响。总体而言，这项研究揭示了与 等位基因相关的一个大的单倍型块，为它们对 HIV-1 精英控制的巨大影响提供了新的见解。
