Abstract：
Despite antiretroviral therapy (ART), HIV-associated peripheral neuropathy remains one of the most prevalent neurologic manifestations of HIV infection. The spinal cord is an essential component of sensory pathways, but spinal cord sampling and evaluation in people with HIV has been very limited, especially in those on ART. The SIV/macaque model allows for assessment of the spinal cord at key time points throughout infection with and without ART. In this study, RNA was isolated from the spinal cord of uninfected, SIV+, and SIV + ART animals to track alterations in gene expression using global RNA-seq. Next, the SeqSeek platform was used to map changes in gene expression to specific cell types. Pathway analysis of differentially expressed genes demonstrated that highly upregulated genes in SIV-infected spinal cord aligned with interferon and viral response pathways. Additionally, this upregulated gene set significantly overlapped with those expressed in myeloid-derived cells including microglia. Downregulated genes were involved in cholesterol and collagen biosynthesis, and TGF-b regulation of extracellular matrix. In contrast, enriched pathways identified in SIV + ART animals included neurotransmitter receptors and post synaptic signaling regulators, and transmission across chemical synapses. SeqSeek analysis showed that upregulated genes were primarily expressed by neurons rather than glia. These findings indicate that pathways activated in the spinal cord of SIV + ART macaques are predominantly involved in neuronal signaling rather than proinflammatory pathways. This study provides the basis for further evaluation of mechanisms of SIV infection + ART within the spinal cord with a focus on therapeutic interventions to maintain synaptodendritic homeostasis.
摘要：
尽管抗逆转录病毒治疗（ART），HIV相关的周围神经病变仍然是HIV感染最普遍的神经系统表现之一。脊髓是感觉通路的重要组成部分,但是对HIV感染者的脊髓采样和评估非常有限，尤其是在艺术上。SIV/猕猴模型允许在使用和不使用ART的整个感染的关键时间点评估脊髓。在这项研究中,从未感染的脊髓中分离出RNA，SIV+,和SIV+ART动物使用全局RNA-seq跟踪基因表达的变化。接下来,SeqSeek平台用于将基因表达的变化映射到特定细胞类型。差异表达基因的通路分析表明，SIV感染的脊髓中高度上调的基因与干扰素和病毒反应通路一致。此外,这种上调的基因与包括小胶质细胞在内的骨髓来源细胞中表达的基因显著重叠.下调的基因参与胆固醇和胶原蛋白的生物合成，和TGF-b调节细胞外基质。相比之下,在SIV+ART动物中确定的富集途径包括神经递质受体和突触后信号调节因子，以及化学突触间的传递.SeqSeek分析表明，上调的基因主要由神经元而不是神经胶质表达。这些发现表明在SIV+ART猕猴的脊髓中激活的通路主要涉及神经元信号传导而不是促炎通路。这项研究为进一步评估脊髓内SIV感染+ART的机制提供了基础，重点是维持突触树突稳态的治疗干预措施。
