Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics

Abstract

Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our current understanding is that HIV enters the central nervous system (CNS) during infection, persisting and replicating in resident immune and supporting cells, with the subsequent host immune response and inflammation likely adding to the development of HAND. Differences in host (human) genetics determine, in part, the effectiveness of the immune response and other factors that increase the vulnerability to HAND. This review describes findings from studies investigating the role of human host genetics in the pathogenesis of HAND, including potential risk factors for developing HAND. The similarities and differences between HAND and Alzheimer’s disease are also discussed. While some specific variations in host genes regulating immune responses and neurotransmission have been associated with protection or risk of HAND development, the effects are generally small and findings poorly replicated. Nevertheless, a few specific gene variants appear to affect the risk for developing HAND and aid our understanding of HAND pathogenesis.

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

“…This recommendation draws from the knowledge that the HIV-1 sub-type C virus predominates in this region and variation in the neurovirulence and synaptodendritic alteration effect of HIV-1 subtypes have been established. 111,112 In addition, the association of low cognitive reserve with neurocognitive impairment in HIV, 113 makes it imperative to study the impact of confounding risk factors which are abundant in sub-Saharan Africa and their impact on BDNF and neurocognition. These factors include low literacy levels, limited access to healthcare, chronic exposure to trauma, poor dietary diversity, higher rates of treatment failure and late-onset of treatment.…”

7,8-dihydroxyflavone Improves Neuropathological Changes in the Brain of Tg26 Mice, A Model for HIV-associated Neurocognitive Disorder

“…Viral proteins such as gp120, Tat, and Vpr are indirectly neurotoxic by binding to CXCR4 and CCR5 and activating macrophages, microglia, and astrocytes [64]. This indirect neurotoxicity fosters an environment of chronic in ammation that is characteristic of HAND [65]. HAND is characterized by glial activation, cytokine/chemokine dysregulation, and neuronal damage and loss [9,66].…”

Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

“…HIV infection of the CNS occurs early after infection and macrophages and microglia are responsible in large part for productive infection within the CNS. HIV has been shown to infect astrocytes to a lesser degree, and productive infection and release of infectious virions by astrocytes has not been observed consistently (Brack-Werner et al, 1992 ; Conant et al, 1994 ; Brack-Werner, 1999 ; Canki et al, 2001 ; Olivier et al, 2018 ). Astrocytes are not infected with HIV through classical gp120 and CD4 binding, but possibly through cell-to cell contact or receptor mediated endocytosis (Chauhan et al, 2014 ; Do et al, 2014 ; Luo and He, 2015 ; Russell et al, 2017 ), allowing for reverse transcription and incorporation of viral DNA into the host genome (Narasipura et al, 2012 ).…”

“…While cART has dramatically increased the life expectancy of PWH, it has also brought attention to an array of neurocognitive issues, collectively known as HAND. HAND has been described as a spectrum disorder that is typically diagnosed by neurocognitive testing to assess attention, information processing, language, executive functioning, sensory-perceptual skills, simple motor skills, complex perceptual-motor skills and memory (Olivier et al, 2018 ; Robinson-Papp et al, 2019 ; Saloner et al, 2019 ). In earlier efforts, the National Institute of Mental Health and National Institute of Neurological Diseases and Stroke charged a working group to assess HAND criteria and develop an updated consensus for the definition (Antinori et al, 2007 ).…”