Duggan Michael R, Mohseni Ahooyi Taha, Parikh Vinay, Khalili Kamel
Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, 7th Floor, Philadelphia, PA, 19140, USA.
Department of Psychology, College of Liberal Arts at Temple University, 1701 N 13th Street, 9th Floor, Philadelphia, PA, 19122, USA.
Cell Death Discov. 2021 Mar 26;7(1):60. doi: 10.1038/s41420-021-00424-0.
Despite increasing numbers of aged individuals living with HIV, the mechanisms underlying HIV-associated neurological disorders (HANDs) remain elusive. As HIV-1 pathogenesis and aging are characterized by oxidative stress as well as altered protein quality control (PQC), reactive oxygen species (ROS) themselves might constitute a molecular mediator of neuronal PQC by modulating BCL-2 associated athanogene (BAG) family members. Present results reveal HO replicated and exacerbated a reduction in neuronal BAG3 induced by the expression of HIV-1 viral proteins (i.e., Tat and Nef), while also causing an upregulation of BAG1. Such a reciprocal regulation of BAG3 and BAG1 levels was also indicated in two animal models of HIV, the doxycycline-inducible Tat (iTat) and the Tg26 mouse. Inhibiting oxidative stress via antioxidants in primary culture was capable of partially preserving neuronal BAG3 levels as well as electrophysiological functioning otherwise altered by HIV-1 viral proteins. Current findings indicate HIV-1 viral proteins and HO may mediate neuronal PQC by exerting synergistic effects on complementary BAG family members, and suggest novel therapeutic targets for the aging HIV-1 population.
尽管感染艾滋病毒的老年人数量不断增加，但艾滋病毒相关神经障碍（HANDs）的潜在机制仍不清楚。由于HIV-1发病机制和衰老的特征是氧化应激以及蛋白质质量控制（PQC）改变，活性氧（ROS）本身可能通过调节BCL-2相关抗凋亡基因（BAG）家族成员而构成神经元PQC的分子介质。目前的结果显示，HO复制并加剧了由HIV-1病毒蛋白（即Tat和Nef）表达所诱导的神经元BAG3的减少，同时还导致BAG1的上调。在两种HIV动物模型，即强力霉素诱导的Tat（iTat）和Tg26小鼠中，也表明了BAG3和BAG1水平的这种相互调节。在原代培养中通过抗氧化剂抑制氧化应激能够部分维持神经元BAG3水平以及否则会被HIV-1病毒蛋白改变的电生理功能。目前的研究结果表明，HIV-1病毒蛋白和HO可能通过对互补的BAG家族成员发挥协同作用来介导神经元PQC，并为老年HIV-1人群提出了新的治疗靶点。
