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Review
. 2021 Mar;16(1):144-158.
doi: 10.1007/s11481-020-09907-w. Epub 2020 Mar 9.

The far-reaching HAND of cART: cART effects on astrocytes

Hemil Gonzalez  1   2 , Anthony Podany  3 , Lena Al-Harthi  2 , Jennillee Wallace  4
Affiliations
Review

The far-reaching HAND of cART: cART effects on astrocytes

Hemil Gonzalez et al. J Neuroimmune Pharmacol. 2021 Mar.

Abstract

Following the introduction of combination antiretroviral therapy (cART), the morbidity and mortality from human immunodeficiency virus (HIV) infection has been drastically curtailed and HIV has now become a chronic manageable disease. Persons living with HIV (PLWH) are living longer and experiencing significant co-morbidities and conditions of aging. NeuroHIV, clinically defined as HIV-Associated Neurocognitive Disorders (HAND) and pathologically manifested by persistent inflammation in the CNS despite cART, is a significant co-morbid condition for PLWH. In the pre-cART era, HIV mediated much of the pathogenesis in the Central Nervous System (CNS); in the cART era, with low to undetectable viremia, other mechanisms may be contributing to persistent neuroinflammation. Emerging data point to the adverse effects at the cellular level of cART, independent of HIV. Astrocytes are the most abundant cells in the CNS, playing vital roles in maintaining CNS homeostasis (e.g. metabolic support to neurons, clearance of neurotransmitters, ion balance, modulation of synaptic functions and maintaining the structural integrity of the blood brain barrier (BBB). Therefore, any disruption of their function will have wide repercussions in the CNS. In this review, we will address current knowledge and gaps on the impact of antiretrovirals (ARVs) on astrocytes and physiologic consequences in the CNS. Understanding the status of this field, will provide a practical framework to elucidate the potential role of cART-mediated dysregulation of astrocytes in neuroHIV pathogenesis and inform therapeutic strategies that are "neuro-friendly". Graphical abstract CNS-penetrating cART have the potential to cause resting astrocytes to become activated into an A1 or neurotoxic phenotype. These cells can in turn secrete inflammatory cytokines that affect surrounding microglia macrophages, as well as neurotoxic factors that impact nearby neurons. In addition, impairment in the physiologic functions of astrocytes will result in altered BBB permeability and disrupted metabolic homeostasis. CNS=Central Nervous System; cART=combined antiretroviral therapy; BBB=blood brain barrier.

Keywords: ARVs; Astrocytes; HAND; Neurotoxicity; cART.

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Figures

Fig 1
Fig 1. Shift in epidemiological distribution of HAND in the pre- and post-cART eras.
A significant decrease in the prevalence of HAD has been observed following implementation of cART, however, the increased prevalence of milder forms of HAND remains a pressing issue. Neuronal and glial cART-induced toxicity plays a significant role in this phenomenon HAD = HIV-associated dementia; HAND = HIV-associated neurocognitive disorders Data sources: Saylor D et al. (2016) HIV-associated neurocognitive disorder - pathogenesis and prospects for treatment Nature reviews Neurology 12:309 Heaton RK et al. (2015) Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Fig 1
Fig 1. Shift in epidemiological distribution of HAND in the pre- and post-cART eras.
A significant decrease in the prevalence of HAD has been observed following implementation of cART, however, the increased prevalence of milder forms of HAND remains a pressing issue. Neuronal and glial cART-induced toxicity plays a significant role in this phenomenon HAD = HIV-associated dementia; HAND = HIV-associated neurocognitive disorders Data sources: Saylor D et al. (2016) HIV-associated neurocognitive disorder - pathogenesis and prospects for treatment Nature reviews Neurology 12:309 Heaton RK et al. (2015) Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Fig 2
Fig 2. Normal functions of human astrocytes and proposed model of cART effects on astrocytes.
Agents that can cross the BBB affect astrocyte structure and functionality thus causing increased BBB permeability, decreased glutamate uptake and release of inflammatory cytokines. The end result of these changes is dendritic pruning and neuronal loss from excitotoxicity BBB=blood brain barrier; cART = combination antiretroviral therapy; CNS = central nervous system; GSH = Glutathione; PBMCs = peripheral blood mononuclear cells Data sources: Stobart JL, Anderson CM (2013) Multifunctional role of astrocytes as gatekeepers of neuronal energy supply Frontiers in cellular neuroscience 7:38
Fig 3
Fig 3. Astrocytes in Neuroprotection and Neurodegeneration.
Resting astrocytes can be skewed into one of two phenotypes when subjected to specific stimuli. Inflammatory cytokines will generate an A1 or pro-inflammatory profile whereas an A2 or repair phenotype can be induced by ischemia Data sources: Baldwin, K. T., & Eroglu, C. (2017) Molecular mechanisms of astrocyte-induced synaptogenesis Current opinion in neurobiology, 45, 113–120
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