Emerging Role of Nef in the Development of HIV Associated Neurological Disorders
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INVITED REVIEW
Emerging Role of Nef in the Development of HIV Associated Neurological Disorders Shadan S. Yarandi 1 & Michael R. Duggan 1 & Ilker K. Sariyer 1 Received: 24 April 2020 / Accepted: 8 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords HAND . HIV-1 Nef . Autophagy . Exosome
Introduction Human immunodeficiency virus (HIV) infection and its associated neurological consequences remain a consistent public health concern. Recent reports suggested that an additional 1.7 million people were infected with the virus in 2018, bringing the total number of people living with HIV to 37.9 million worldwide (UN AIDS 2019). Despite improved patient outcomes due to enhanced diagnostic testing and targeted therapies, there remains no effective vaccine for HIV, or a permanent cure for HIV-infected individuals (Davenport et al. 2019). Moreover, HIV continues to be a leading cause of morbidity across the globe (World Health Organization 2018). However, the implementation of combined antiretroviral therapy (cART) has transformed this once fatal disease into a chronic, manageable condition (Deeks et al. 2013; Saylor et al. 2016). Following its introduction in the mid-
* Ilker K. Sariyer [email protected] 1
Department of Neuroscience and Center for Neurovirology, Temple University Lewis Katz School of Medicine, 3500 North Broad Street, Medical Education and Research Building Room 753, 7th Floor, Philadelphia, PA 19140, USA
1990s, cART has substantially increased the life expectancy of the HIV population, which is now approaching that of the general population (Fauci and Marston 2015; Trickey et al. 2017). Although current treatments can control HIV infection, infected individuals maintain increased risks for numerous chronic comorbidities, including HIV-Associated Neurological Disorder (HAND) (Sengupta and Siliciano 2018). Amongst HIV infected individuals, HAND is estimated to afflict up to half of patients, even if cognitive deficits
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