Botey-Bataller Javier, van Unen Nienke, Blaauw Marc, Vos Willem A J W, van Eekeren Louise, Vadaq Nadira, Matzaraki Vasiliki, Verbon Annelies, Groenendijk Albert L, Dos Santos Jéssica C, Cleophas Maartje C P, Stalenhoef Janneke E, Berrevoets Marvin A H, Jiang Xun, Gupta Manoj K, Nguyen Nhan, Xu Cheng-Jian, Joosten Leo A B, Netea Mihai G, van der Ven André J A M, Li Yang
Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
Nat Med. 2025 Aug 20. doi: 10.1038/s41591-025-03887-1.
People living with HIV (PLHIV) have an increased susceptibility to non-AIDS comorbidities. In this study, we systematically profiled 1,342 PLHIV across five omics layers and immune function. We found latent factors, resulting from integrating epigenomics, transcriptomics, proteomics, metabolomics and immune responses, linked to cardiovascular diseases, the presence of carotid plaque and chronic obstructive pulmonary disease in PLHIV. Mapping four omics layers to genetic variation identified 5,962 molecular quantitative trait loci, illustrating a common genetic regulation in PLHIV compared to healthy individuals. By performing Mendelian randomization, we uncovered host genetic-driven changes in baseline molecules causally related to immune responses upon stimulation with inactivated pathogens. Lastly, we uncovered that the inflammasome, genetically regulated by the NLRP12 locus, contributes to systemic inflammation across multiple molecular layers. This study offers a unique catalog of genetic and molecular determinants of immune function in PLHIV and elucidates molecular pathways driving inter-individual variation in immune response and comorbidities.
人类免疫缺陷病毒感染者（PLHIV）对非艾滋病合并症的易感性增加。在本研究中，我们系统地分析了1342名PLHIV在五个组学层面和免疫功能方面的情况。我们发现，整合表观基因组学、转录组学、蛋白质组学、代谢组学和免疫反应后得出的潜在因素，与PLHIV的心血管疾病、颈动脉斑块的存在以及慢性阻塞性肺疾病有关。将四个组学层面映射到基因变异上，确定了5962个分子数量性状位点，这表明与健康个体相比，PLHIV存在共同的基因调控。通过进行孟德尔随机化，我们发现宿主基因驱动的基线分子变化与用灭活病原体刺激后的免疫反应存在因果关系。最后，我们发现由NLRP12基因座进行基因调控的炎性小体在多个分子层面促成了全身炎症。这项研究提供了一份关于PLHIV免疫功能的遗传和分子决定因素的独特目录，并阐明了驱动个体间免疫反应和合并症差异的分子途径。
