Abstract
HIV associated neurocognitive disorders (HAND) are the spectrum of cognitive impairments present in patients infected with human immunodeficiency virus type 1 (HIV-1). The number of patients affected with HAND ranges from 30 to 50% of HIV infected individuals and although the development of combinational antiretroviral therapy (cART) has improved longevity, HAND continues to pose a significant clinical problem as the current standard of care does not alleviate or prevent HAND symptoms. At present, the pathological mechanisms contributing to HAND remain unclear, but evidence suggests that it stems from neuronal injury due to chronic release of neurotoxins, chemokines, viral proteins, and proinflammatory cytokines secreted by HIV-1 activated microglia, macrophages and astrocytes in the central nervous system (CNS). Furthermore, the blood–brain barrier (BBB) not only serves as a route for HIV-1 entry into the brain but also prevents cART therapy from reaching HIV-1 brain reservoirs, and therefore could play an important role in HAND. The goal of this review is to discuss the current data on the epidemiology, pathology and research models of HAND as well as address the potential pharmacological treatment approaches that are being investigated.
Highlights
Human immunodeficiency virus (HIV) associated neurocognitive disorders (HAND) are the spectrum of cognitive impairments present in patients infected with human immunodeficiency virus type 1 (HIV-1)
In a study using patients from the Multicentre Acquired immunodeficiency syndrome (AIDS) Cohort Study (MACS), Sacktor et al observed a frequency of HIV associated neurocognitive disorders (HAND) amongst 364 HIV+ gay/bisexual men within the 3 year period of 2007–2008 of 33% (14% classified as Asymptomatic Neurocognitive Impairment (ANI), 14% classified as Minor Neurocognitive Disorder (MND) and 5% as HIV-associated Dementia (HAD)) [5]
Available data generally proposes two main mechanisms of HIV-1-mediated central nervous system (CNS) pathology leading to the development of HAND: (1) viral proteins from the HIV genome directly causing neurotoxicity, and (2) activation of microglia, brain macrophages and astrocytes in response to HIV-1 and secretion of a range of proinflammatory cytokines and neurotoxins [tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), arachidonic and quinolinic acids, platelet-activating factor, neurotoxic amines, reactive oxygen species (ROS), nitric oxide (NO), glutamate, macrophage inflammatory protein 1α (MIP-1α), monocyte chemoattractant protein 1 (MCP-1) and growth-related oncogene α (GRO-α)], resulting in neuronal injury and death [95, 96]
Summary
Prevalence of HAND in the era of cARTHuman immunodeficiency virus type 1 (HIV-1) is the enveloped retrovirus responsible for the development of Acquired immunodeficiency syndrome (AIDS) in patients. Available data generally proposes two main mechanisms of HIV-1-mediated CNS pathology leading to the development of HAND: (1) viral proteins from the HIV genome directly causing neurotoxicity, and (2) activation of microglia, brain macrophages and astrocytes in response to HIV-1 and secretion of a range of proinflammatory cytokines and neurotoxins [tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), arachidonic and quinolinic acids, platelet-activating factor, neurotoxic amines, ROS, nitric oxide (NO), glutamate, macrophage inflammatory protein 1α (MIP-1α), monocyte chemoattractant protein 1 (MCP-1) and growth-related oncogene α (GRO-α)], resulting in neuronal injury and death [95, 96]. Tat released by infected astrocytes has been demonstrated to alter gap junction protein expression on the endothelial cells of the BBB leading to increased permeability [66] and Tat directly induces neuronal necrosis by disrupting mitochondrial function [104]. This is a very innovative approach deserving further investigation and that could potentially have clinical utility in the management of HIV infection of the brain [158]
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