Multifaceted Role of Nef in HIV-Associated Neurocognitive Disorder: Histopathological Alterations and Underlying Mechanisms

: Although antiretroviral regimens achieve durable suppression of human immunodeficiency virus (HIV) replication, individuals living with HIV remain at an increased risk of developing chronic comorbidities, such as HIV-associated neurocognitive disorder (HAND). In the absence of definitive biomarkers or curative treatments, HAND impacts the survival and quality of life in up to 50% of individuals with HIV. Therefore, novel strategies are highly warranted to improve the diagnosis, monitoring, and treatment of individuals with HAND and a deeper characterization of the still poorly understood pathogenesis of HAND is fundamental to this aim. The pathogenesis, progression, and clinical outcomes of HAND are influenced by different factors, including viral proteins like negative factor (Nef). Among HIV proteins, Nef emerges as a potential key contributor to HAND pathogenesis. Nef could drive specific histopathological alterations in the brain and could be involved in HAND through different interconnected pathogenetic mechanisms. These include: immune dysregulation, oxidative stress, mitochondrial dysfunction, disruption of autophagy, myelin damage and oligodendrocytes dysfunction, blood-brain barrier disruption, alterations of cholesterol homeostasis, and certain potential converging mechanisms with Alzheimer's disease. Both extracellular and intracellular Nef can contribute to the development of HAND. Interestingly, it has been proposed that Nef may participate in HAND through its incorporation into extracellular vesicles. This review explores the multifaceted role of Nef in HAND, highlighting the histopathological alterations and the pathogenetic mechanisms potentially involved and the potential emerging relevance of Nef as a diagnostic and therapeutic target in HAND.