Ángel Bayón-Gil, Inmaculada Hernández, Judith Dalmau, Juan C Nieto, Víctor Urrea, Lidia Garrido-Sanz, Ginevra Caratú, Maria C García-Guerrero, Cristina Gálvez, María Salgado, Itziar Erkizia, Fernando Laguía, Patricia Resa-Infante, Marta Massanella, Raúl Tonda, Jordi Morata, Kai Ying Hong, Jane Koshy, Aaron R Goldman, Leila Giron, Mohamed Abdel-Mohsen, Holger Heyn, Javier Martinez-Picado, Maria C Puertas
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引用次数: 0
摘要
背景:无病毒进展者(VNPs)是 HIV-1 感染者中一个特殊且不常见的亚群,其特点是尽管病毒复制不受控制,但 CD4+ T 细胞数量仍能显著保持正常--这让人联想到猿类免疫缺陷病毒的自然宿主。主要由于缺乏综合研究,人类 VNPs 规避 HIV-1 致病机理的机制仍然难以捉摸:方法:我们采用了一种新颖的单细胞和多组学方法,在 16 例 VNPs 和 29 例 HIV+ 进展者中全面描述了驱动这种极为罕见的疾病表型的病毒、基因组、转录组和代谢组因素:CCR5Δ32杂合度较高,这与较低的CCR5表达水平和较低的外周循环感染细胞频率有关。我们还观察到 VNPs 的肠道破坏血浆标志物水平降低,干扰素反应减弱。这些因素可能推动了这一人群免疫保护的其他表型特征,包括色氨酸代谢特征未发生改变、细胞毒性淋巴细胞活化减少以及旁观者 CD4+ T 细胞凋亡减少:总之,我们的综合分析确定了与 VNPs 独特的免疫病理平衡共同相关的复杂因素,揭示了管理 HIV 发病机制的潜在治疗探索途径:这项工作得到了西班牙科学与创新部(Spanish Ministry of Science and Innovation)和美国国立卫生研究院(NIH)的资助。
Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors.
Background: Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4+ T cell counts despite uncontrolled viral replication-a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies.
Methods: We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors.
Findings: Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4+ T cell apoptosis.
Conclusions: In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis.
Funding: The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH).
期刊介绍:
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.