Li Nan, He Chuan
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Shenyang, Liaoning, China.
NHC Key Laboratory of AIDS Prevention and Treatment, Shenyang, Liaoning, China.
Sci Rep. 2025 Jul 2;15(1):23618. doi: 10.1038/s41598-025-07962-y.
The acquisition of human immunodeficiency virus (HIV) is influenced by environmental and genetic factors, such as viral inoculum dose, host behavior, and immune responses. Despite advances in understanding HIV pathogenesis, no effective vaccine exists, underscoring the urgent need to deepen our comprehension of host immune mechanisms to enhance preventive strategies. Genetic predisposition and certain immunity characteristics of the host might play essential roles in the risk of HIV-1 acquisition. Mendelian randomization (MR) and colocalization analysis are utilized to investigate the causal relationships between immune responses and HIV-1 risk, aiming to identify targets for potential eradication strategies. We employed a two-sample MR approach to explore the causal links between 731 immunophenotypes and HIV-1 acquisition, using genetic variants from publicly available GWAS summary statistics as instrumental variables. Sources included GWAS data for immune traits and a meta-analysis from European cohorts for HIV-1 acquisition. We validated our findings using Summary-data-based MR analysis, integrating eQTL and mQTL data from the GTEx project. Bayesian colocalization analysis was conducted to identify shared causal variants. Functional and pathway enrichment analysis employing Metascape and Enrichr websets were performed to elucidate potential biological pathways linking immunephenotypes to HIV-1 risk. Our MR analysis identified significant causal associations between 26 specific immunophenotypes and HIV-1 acquisition, indicating a causal association with HIV risk. Colocalization analysis showed that none demonstrated genome-wide evidence of genetic colocalization (regional PP.H4.abf > 0.70). SMR and HEIDI analysis confirmed pleiotropic associations, particularly noting CCR2 on granulocytes as significant. Functional enrichment analysis of 39 SMR-identified genes revealed critical pathways linking immunophenotypes to HIV-1 susceptibility. The "NABA MATRISOME ASSOCIATED" canonical pathway emerged as the most significant pathway using Metascape. Protein-protein interaction networks demonstrated 5 functionally cohesive clusters. Multi-database analyses using Enrichr Analysis revealed functionally similar pathway enrichment: Cell cycle regulation ("G2 Phase", Reactome; "G1/S Control", WikiPathways), shedding light on crucial immune regulation mechanisms potentially instrumental in HIV-1 acquisition.
人类免疫缺陷病毒（HIV）的感染受环境和遗传因素影响，如病毒接种剂量、宿主行为和免疫反应。尽管在理解HIV发病机制方面取得了进展，但尚无有效的疫苗，这突出表明迫切需要加深我们对宿主免疫机制的理解，以加强预防策略。宿主的遗传易感性和某些免疫特征可能在HIV-1感染风险中起重要作用。孟德尔随机化（MR）和共定位分析用于研究免疫反应与HIV-1风险之间的因果关系，旨在确定潜在根除策略的靶点。我们采用两样本MR方法，利用公开可用的全基因组关联研究（GWAS）汇总统计中的遗传变异作为工具变量，探索731种免疫表型与HIV-1感染之间的因果联系。数据来源包括免疫性状的GWAS数据以及欧洲队列中HIV-1感染的荟萃分析。我们使用基于汇总数据的MR分析验证了我们的发现，整合了来自基因型-组织表达（GTEx）项目的表达数量性状基因座（eQTL）和甲基化数量性状基因座（mQTL）数据。进行贝叶斯共定位分析以识别共享的因果变异。使用Metascape和Enrichr网站进行功能和通路富集分析，以阐明将免疫表型与HIV-1风险联系起来的潜在生物学途径。我们的MR分析确定了26种特定免疫表型与HIV-1感染之间的显著因果关联，表明与HIV风险存在因果关系。共定位分析表明，没有一个显示出全基因组范围内的遗传共定位证据（区域后验概率PP.H4.abf＞0.70）。单变量MR（SMR）和异质性检验（HEIDI）分析证实了多效性关联，特别指出粒细胞上的CCR2具有显著性。对39个SMR鉴定基因的功能富集分析揭示了将免疫表型与HIV-1易感性联系起来的关键途径。使用Metascape分析，“NABA基质体相关”经典途径成为最显著的途径。蛋白质-蛋白质相互作用网络显示出5个功能凝聚簇。使用Enrichr分析进行的多数据库分析揭示了功能相似的通路富集：细胞周期调控（“G2期”，Reactome；“G1/S控制”，WikiPathways），这揭示了可能对HIV-1感染有重要作用的关键免疫调节机制。
