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The far-reaching HAND of cART: cART effects on astrocytes
Hemil Gonzalez1,2, Anthony Podany3, Lena Al-Harthi2
1Department of Internal Medicine, Division of Infectious Disease, Rush University Medical Center, Chicago, IL, USA.
Insights
Combination antiretroviral therapy (cART) manages human immunodeficiency virus (HIV) but may activate astrocytes, contributing to neuroinflammation and HIV-Associated Neurocognitive Disorders (HAND) in the central nervous system (CNS).
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Human immunodeficiency virus (HIV) infection is now a manageable chronic condition due to combination antiretroviral therapy (cART).
- Persons living with HIV (PLWH) experience aging-related co-morbidities, including HIV-Associated Neurocognitive Disorders (HAND), characterized by persistent CNS inflammation despite cART.
- While cART suppresses HIV, emerging evidence suggests antiretroviral drugs (ARVs) may independently contribute to neuroinflammation by affecting central nervous system (CNS) cells.
Purpose of the Study:
- To review current knowledge on the impact of ARVs on astrocytes, the most abundant glial cells in the CNS.
- To elucidate the physiological consequences of ARV-induced astrocyte dysfunction in the CNS.
- To provide a framework for understanding the role of cART-mediated astrocyte dysregulation in HAND pathogenesis and developing neuro-friendly therapeutic strategies.
Main Methods:
- Literature review focusing on the effects of ARVs on astrocyte function and CNS physiology.
- Analysis of emerging data on ARV-induced cellular changes in the CNS.
- Synthesis of current knowledge to identify gaps in understanding neuroHIV pathogenesis.
Main Results:
- Astrocytes play critical roles in CNS homeostasis, including neuronal support, neurotransmitter clearance, and blood-brain barrier (BBB) integrity.
- cART, particularly CNS-penetrating ARVs, may activate astrocytes into a neurotoxic phenotype (A1).
- Activated astrocytes can secrete inflammatory cytokines and neurotoxic factors, impacting neurons and microglia/macrophages, and may disrupt BBB permeability and metabolic homeostasis.
Conclusions:
- Dysregulation of astrocyte function by cART may be a significant contributor to persistent neuroinflammation and HAND in PLWH.
- Further research is needed to understand the precise mechanisms by which ARVs affect astrocytes and to develop targeted, neuroprotective therapeutic strategies for HIV management.
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.
