Van Weyenbergh Johan, Assone Tatiane, Racine Isaac, Menezes Soraya, Gonçalves Fernanda, Folgosi Víctor, Marcusso Rosa, Haziot Michel, Smid Jerusa, Dahy Flavia, Gascon Maria, Paiva Arthur, Galvao-Castro Bernardo, Araújo Thessika, Grassi Maria, Sousa Maísa, Puccioni-Sohler Marzia, Nukui Youko, Kashima Simone, Dierckx Tim, Twizere Jean-Claude, Murphy Edward, Bruhn Roberta, Pannecouque Christophe, Claes Sandra, Vanderlinden Evelien, Schols Dominique, Vercauteren Jurgen, Alvarez Carolina, Lopez Giovanni, Talledo Michael, Gotuzzo Eduardo, Oliveira Augusto, Cleynen Isabelle, Casseb Jorge
KU Leuven.
Faculdade de Medicina/USP.
Res Sq. 2025 Apr 29:rs.3.rs-5960764. doi: 10.21203/rs.3.rs-5960764/v1.
HTLV-1 is an enigmatic retrovirus triggering a debilitating neuroinflammatory disease, HTLV-1-associated myelopathy (HAM), with unknown pathogenesis. Both HTLV-1 infection and HAM predominantly affect women and non-white neglected populations. HAM is lacking disease-modifying treatment, as current treatment is mostly symptomatic and inspired by either HIV-1 or multiple sclerosis therapeutic strategies. We used systems biology analyses of novel and publicly available data comprising (epi)genomics, transcriptomics, metabolomics and proteomics of multi-ancestry cohorts from a total of > 2500 People Living with HTLV-1 from 5 countries (Brazil, Peru, Japan, UK, US). Leveraging an unique admixed Brazilian cohort, genome-wide association study (GWAS) revealed African-specific variants in inflammasome sensor with genome-wide significance (p < 5x10). Suggestive loci (p > 5x10) corresponding to metabolic, immune and neuronal genes were validated using published Japanese GWAS. Polygenic risk score and proviral load were independent disease predictors across ancestries. Systems biology analysis revealed neuronal/synaptic signaling, monocyte count, glucose/lipid metabolism, and neurocognition/depression as genetically linked to HAM. drug screening identified estrogen blocker Fulvestrant as the top hit, while also confirming existing (pre)clinical data for HDAC inhibitors and immunosuppressants. Validated GWAS genes were overexpressed in HAM patients' whole blood and CD4 T-cells, as well as in spinal cord astrocytes, oligodendrocytes, and microglia by single-cell RNAseq. We experimentally confirmed decreased ApoA1/lipid/cholesterol levels, higher monocyte levels and lower neurocognitive scores in multi-ancestry cohorts. We found striking biological similarities between retroviral Hbz/Tax overexpression, Hbz interactome and HAM multi-omics findings: enrichment for lipid/cholesterol metabolism, estrogen signaling, neurodegenerative diseases, and viral pathways including EBV, recently identified as the major driver of multiple sclerosis. In conclusion, our data-driven approach uncovers novel disease mechanisms and therapeutic targets, and a validated polygenic risk score allowing targeted surveillance for high-risk individuals. A strong molecular overlap to other neurodegenerative/neuroinflammatory diseases reveals shared neuropathogenic pathways between unrelated viruses.
人类嗜T淋巴细胞病毒1型（HTLV-1）是一种神秘的逆转录病毒，可引发使人衰弱的神经炎性疾病——HTLV-1相关脊髓病（HAM），其发病机制尚不清楚。HTLV-1感染和HAM主要影响女性以及被忽视的非白人人群。HAM缺乏改善病情的治疗方法，因为目前的治疗大多只是对症治疗，且借鉴了HIV-1或多发性硬化症的治疗策略。我们对来自巴西、秘鲁、日本、英国、美国5个国家的2500多名HTLV-1感染者的多血统队列的新的公开可用数据进行了系统生物学分析，这些数据包括（表观）基因组学、转录组学、代谢组学和蛋白质组学。利用独特的巴西混合队列，全基因组关联研究（GWAS）揭示了炎症小体传感器中具有全基因组意义（p<5×10）的非洲特异性变异。利用已发表的日本GWAS对与代谢、免疫和神经元基因相对应的提示性基因座（p>5×10）进行了验证。多基因风险评分和前病毒载量是不同血统中独立的疾病预测指标。系统生物学分析显示，神经元/突触信号传导、单核细胞计数、葡萄糖/脂质代谢以及神经认知/抑郁与HAM存在基因关联。药物筛选确定雌激素阻断剂氟维司群为最佳靶点，同时也证实了HDAC抑制剂和免疫抑制剂的现有（临床前）数据。通过单细胞RNA测序，验证的GWAS基因在HAM患者的全血和CD4 T细胞以及脊髓星形胶质细胞、少突胶质细胞和小胶质细胞中均有过表达。我们通过实验证实了多血统队列中载脂蛋白A1/脂质/胆固醇水平降低、单核细胞水平升高以及神经认知评分降低。我们发现逆转录病毒Hbz/Tax过表达、Hbz相互作用组与HAM多组学研究结果之间存在显著的生物学相似性：脂质/胆固醇代谢、雌激素信号传导、神经退行性疾病以及包括EBV在内的病毒途径富集，EBV最近被确定为多发性硬化症的主要驱动因素。总之，我们的数据驱动方法揭示了新的疾病机制和治疗靶点，以及经过验证的多基因风险评分，可用于对高危个体进行有针对性的监测。与其他神经退行性/神经炎性疾病的强烈分子重叠揭示了不相关病毒之间共享的神经致病途径。
