Mason Sara J, Sreeram Sheetal, Niazi Farshad, Leskov Konstantin, Levine Alan D, Karn Jonathan, Valadkhan Saba
Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, 44106, USA.
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
bioRxiv. 2025 May 8:2025.05.08.651477. doi: 10.1101/2025.05.08.651477.
HIV-associated neurocognitive disorders (HAND) persist in milder forms despite anti-retroviral therapy, leading to premature and exacerbated aging-related cognitive disorders. We investigated the interplay between HAND and aging in microglia, which constitute the main brain HIV reservoir. We compared the transcriptomic patterns associated with normal aging in healthy humans to those observed following HIV infection in both ex vivo and in vivo models. Single cell and bulk transcriptomic patterns revealed that HIV infection induces a pattern of cellular senescence, with strong parallels to the transcriptomic signature of normal aging. Both processes were characterized by p53 pathway activation, upregulation of inflammatory genes and downregulation of proliferative genes while maintaining mTOR signaling, a pattern characteristic of cellular senescence. Importantly, both actively HIV infected and bystander microglia showed the cellular senescence patterns. Our results provide a mechanistic basis for the observed premature brain aging in HAND, and identify senescence-associated pathways as potential therapeutic targets.
尽管有抗逆转录病毒疗法，与艾滋病病毒相关的神经认知障碍（HAND）仍以较轻的形式存在，导致过早出现并加剧与衰老相关的认知障碍。我们研究了构成大脑中主要艾滋病病毒储存库的小胶质细胞中HAND与衰老之间的相互作用。我们将健康人类正常衰老相关的转录组模式与在体外和体内模型中感染艾滋病病毒后观察到的转录组模式进行了比较。单细胞和整体转录组模式显示，艾滋病病毒感染会诱导一种细胞衰老模式，与正常衰老的转录组特征有很强的相似性。这两个过程的特征都是p53通路激活、炎症基因上调和增殖基因下调，同时维持mTOR信号传导，这是细胞衰老的一种特征模式。重要的是，无论是活跃感染艾滋病病毒的小胶质细胞还是旁观小胶质细胞都显示出细胞衰老模式。我们的研究结果为HAND中观察到的大脑过早衰老提供了一个机制基础，并将衰老相关通路确定为潜在的治疗靶点。
