Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
FASEB J. 2023 Dec;37(12):e23301. doi: 10.1096/fj.202301239RR.
HIV-associated neurocognitive disorders (HAND) is a term describing a complex set of cognitive impairments accompanying HIV infection. Successful antiretroviral therapy (ART) reduces the most severe forms of HAND, but milder forms affect over 50% of people living with HIV (PLWH). Pathogenesis of HAND in the ART era remains unknown. A variety of pathogenic factors, such as persistent HIV replication in the brain reservoir, HIV proteins released from infected brain cells, HIV-induced neuroinflammation, and some components of ART, have been implicated in driving HAND pathogenesis in ART-treated individuals. Here, we propose another factor-impairment of cholesterol homeostasis and lipid rafts by HIV-1 protein Nef-as a possible contributor to HAND pathogenesis. These effects of Nef on cholesterol may also underlie the effects of other pathogenic factors that constitute the multifactorial nature of HAND pathogenesis. The proposed Nef- and cholesterol-focused mechanism may provide a long-sought unified explanation of HAND pathogenesis that takes into account all contributing factors. Evidence for the impairment by Nef of cellular cholesterol balance, potential effects of this impairment on brain cells, and opportunities to therapeutically target this element of HAND pathogenesis are discussed.
HIV 相关神经认知障碍（HAND）是指伴随 HIV 感染出现的一系列复杂认知障碍。成功的抗逆转录病毒疗法（ART）可降低最严重形式的 HAND，但仍有超过 50%的 HIV 感染者（PLWH）存在较轻形式的 HAND。ART 时代 HAND 的发病机制尚不清楚。多种致病因素，如大脑储库中持续的 HIV 复制、感染脑细胞释放的 HIV 蛋白、HIV 诱导的神经炎症，以及 ART 的某些成分，都可能导致接受 ART 治疗的个体 HAND 发病机制。在这里，我们提出另一个因素 - HIV-1 蛋白 Nef 破坏胆固醇稳态和脂筏 - 可能是 HAND 发病机制的一个促成因素。Nef 对胆固醇的这些影响也可能是构成 HAND 发病机制多因素性质的其他致病因素的基础。拟议的以 Nef 和胆固醇为重点的机制可能为 HAND 发病机制提供一个长期以来被寻求的综合解释，该机制考虑了所有致病因素。本文讨论了 Nef 破坏细胞胆固醇平衡的证据、这种破坏对脑细胞的潜在影响，以及靶向 HAND 发病机制这一元素的治疗机会。
