Despite adherence to treatment, individuals living with HIV have an increased risk for developing cognitive impairments, referred to as HIV-associated neurological disorders (HAND). Due to continued growth in the HIV population, particularly amongst the aging cohort, the neurobiological mechanisms of HAND are increasingly relevant. Similar to other viral proteins (e.g. Tat, Gp120, Vpr), the Negative Factor (Nef) is associated with numerous adverse effects in the CNS as well as cognitive impairments. In particular, emerging data indicate the consequences of Nef may be facilitated by the modulation of cellular autophagy as well as its inclusion into extracellular vesicles (EVs). The present review examines evidence for the molecular mechanisms by which Nef might contribute to neuronal dysfunction underlying HAND, with a specific focus on autophagy and EVs. Based on the these data, we propose an integrated model by which Nef may contribute to underlying neuronal dysfunction in HAND and highlight potentially novel therapeutic targets for HAND.

尽管坚持治疗，艾滋病毒感染者出现认知障碍的风险仍然增加，称为艾滋病毒相关神经障碍（HAND）。由于艾滋病毒人群的持续增长，特别是在老龄化群体中，HAND 的神经生物学机制变得越来越重要。与其他病毒蛋白（例如 Tat、Gp120、Vpr）类似，负因子 (Nef) 与中枢神经系统的许多不良影响以及认知障碍有关。特别是，新出现的数据表明，细胞自噬的调节及其纳入细胞外囊泡 (EV) 可能会促进 Nef 的后果。本综述研究了 Nef 可能导致 HAND 神经元功能障碍的分子机制的证据，特别关注自噬和 EV。基于这些数据，我们提出了一个综合模型，通过该模型，Nef 可能会导致 HAND 的潜在神经元功能障碍，并强调 HAND 的潜在新治疗靶点。