DataSheet_2_The 2000HIV study: Design, multi-omics methods and participant characteristics.docx

BackgroundEven during long-term combination antiretroviral therapy (cART), people living with HIV (PLHIV) have a dysregulated immune system, characterized by persistent immune activation, accelerated immune ageing and increased risk of non-AIDS comorbidities. A multi-omics approach is applied to a large cohort of PLHIV to understand pathways underlying these dysregulations in order to identify new biomarkers and novel genetically validated therapeutic drugs targets.MethodsThe 2000HIV study is a prospective longitudinal cohort study of PLHIV on cART. In addition, untreated HIV spontaneous controllers were recruited. In-depth multi-omics characterization will be performed, including genomics, epigenomics, transcriptomics, proteomics, metabolomics and metagenomics, functional immunological assays and extensive immunophenotyping. Furthermore, the latent viral reservoir will be assessed through cell associated HIV-1 RNA and DNA, and full-length individual proviral sequencing on a subset. Clinical measurements include an ECG, carotid intima-media thickness and plaque measurement, hepatic steatosis and fibrosis measurement as well as psychological symptoms and recreational drug questionnaires. Additionally, considering the developing pandemic, COVID-19 history and vaccination was recorded. Participants return for a two-year follow-up visit. The 2000HIV study consists of a discovery and validation cohort collected at separate sites to immediately validate any finding in an independent cohort.ResultsOverall, 1895 PLHIV from four sites were included for analysis, 1559 in the discovery and 336 in the validation cohort. The study population was representative of a Western European HIV population, including 288 (15.2%) cis-women, 463 (24.4%) non-whites, and 1360 (71.8%) MSM (Men who have Sex with Men). Extreme phenotypes included 114 spontaneous controllers, 81 rapid progressors and 162 immunological non-responders. According to the Framingham score 321 (16.9%) had a cardiovascular risk of >20% in the next 10 years. COVID-19 infection was documented in 234 (12.3%) participants and 474 (25.0%) individuals had received a COVID-19 vaccine.ConclusionThe 2000HIV study established a cohort of 1895 PLHIV that employs multi-omics to discover new biological pathways and biomarkers to unravel non-AIDS comorbidities, extreme phenotypes and the latent viral reservoir that impact the health of PLHIV. The ultimate goal is to contribute to a more personalized approach to the best standard of care and a potential cure for PLHIV.

即使在长期的联合抗逆转录病毒治疗（cART）期间，艾滋病毒携带者（PLHIV）的免疫系统仍存在失调，表现为持续的免疫激活、免疫老化加速及非艾滋病合并症风险增加。本研究采用多组学方法对大量PLHIV进行深入研究，旨在解析这些失调背后的通路，以识别新的生物标志物和经基因验证的新型治疗药物靶点。研究方法：2000HIV研究是对接受cART的PLHIV进行的纵向队列研究。此外，还招募了未经治疗的HIV自发控制者。将进行深入的全面多组学特征描述，包括基因组学、表观遗传学、转录组学、蛋白质组学、代谢组学和宏基因组学，功能免疫学检测和广泛的免疫表型分析。此外，将通过细胞相关的HIV-1 RNA和DNA以及部分个体的全长前病毒测序来评估潜伏病毒库。临床测量包括心电图、颈动脉内膜中层厚度和斑块测量、肝脂肪变性及纤维化测量，以及心理症状和娱乐药物问卷调查。鉴于正在发展的流行病，还记录了COVID-19病史和疫苗接种情况。参与者将在两年后进行随访。2000HIV研究包括在独立地点收集的发现和验证队列，以立即在独立队列中验证任何发现。结果：总体而言，分析纳入了来自四个地点的1895名PLHIV，其中发现队列1559名，验证队列336名。研究人群代表了西方欧洲HIV人群，包括288名（15.2%）跨性别女性、463名（24.4%）非白人和1360名（71.8%）男性同性恋者（MSM）。极端表型包括114名自发控制者、81名快速进展者和162名免疫非反应者。根据Framingham评分，321名（16.9%）在未来10年内心血管风险超过20%。234名（12.3%）参与者记录了COVID-19感染，474名（25.0%）个体接种了COVID-19疫苗。结论：2000HIV研究建立了一个1895名PLHIV的队列，利用多组学发现新的生物通路和生物标志物，以揭示影响PLHIV健康的非艾滋病合并症、极端表型和潜伏病毒库。最终目标是贡献于更个性化的最佳护理标准和PLHIV潜在治愈方案。