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

Abstract

The discovery of the glial-lymphatic or glymphatic fluid clearance pathway in the rodent brain led researchers to search for a parallel system in humans and to question the implications of this pathway in neurodegenerative diseases. Magnetic resonance imaging studies revealed that several features of the glymphatic system may be present in humans. In both rodents and humans, this pathway promotes the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF) through the arterial perivascular spaces into the brain parenchyma. This process is facilitated in part by aquaporin-4 (AQP4) water channels located primarily on astrocytic end feet that abut cerebral endothelial cells of the blood brain barrier. Decreased expression or mislocalization of AQP4 from astrocytic end feet results in decreased interstitial flow, thereby, promoting accumulation of extracellular waste products like hyperphosphorylated Tau (pTau). Accumulation of pTau is a neuropathological hallmark in Alzheimer's disease (AD) and is accompanied by mislocalization of APQ4 from astrocyte end feet to the cell body. HIV infection shares many neuropathological characteristics with AD. Similar to AD, HIV infection of the CNS contributes to abnormal aging with altered AQP4 localization, accumulation of pTau and chronic neuroinflammation. Up to 30% of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND), and changes in AQP4 may be clinically important as a contributor to cognitive disturbances. In this review, we provide an overview and discussion of the potential contributions of NeuroHIV to glymphatic system functions by focusing on astrocytes and AQP4. Although HAND encompasses a wide range of neurocognitive impairments and levels of neuroinflammation vary among and within PWH, the potential contribution of disruption in AQP4 may be clinically important in some cases. In this review we discuss implications for possible AQP4 disruption on NeuroHIV disease trajectory and how HIV may influence AQP4 function.

The Glymphatic System (En)during Inflammation

“…Depending on the nature of the inflammatory insult, stagnating fluid drainage will then contribute to edema formation, cytokine accumulation, and reactive responses of microglia, astrocytes, and/or neurons. Astrocytic AQP4 water channels are upregulated during this process, but their mislocation away from the vascular endfeet during inflammatory suppresses, rather than facilitates, polarized glymphatic flow [ 27 , 60 , 172 , 173 , 174 , 175 ].…”

Immune Functions of Astrocytes in Viral Neuroinfections

“…Viral infection of astrocytes may play an important role in the functioning of the glymphatic system. The glymphatic system comprises perivascular tunnels, shaped by astrocytes, which function as a waste clearance system for the elimination of soluble proteins and metabolites from the CNS and facilitate the distribution of glucose, lipids, amino acids, growth factors, and neuromodulators in the brain [ 160 , 161 ]. Proper functioning of the glymphatic system is supported by astrocytic endfeet that surround cerebral endothelial cells in the BBB [ 160 ].…”

“…The glymphatic system comprises perivascular tunnels, shaped by astrocytes, which function as a waste clearance system for the elimination of soluble proteins and metabolites from the CNS and facilitate the distribution of glucose, lipids, amino acids, growth factors, and neuromodulators in the brain [ 160 , 161 ]. Proper functioning of the glymphatic system is supported by astrocytic endfeet that surround cerebral endothelial cells in the BBB [ 160 ]. One of the hallmarks of astrocyte endfeet is condensed localization of aquaporin-4 (AQP4) water channels that promote the exchange of interstitial and cerebrospinal fluid [ 160 , 162 , 163 ].…”

“…Proper functioning of the glymphatic system is supported by astrocytic endfeet that surround cerebral endothelial cells in the BBB [ 160 ]. One of the hallmarks of astrocyte endfeet is condensed localization of aquaporin-4 (AQP4) water channels that promote the exchange of interstitial and cerebrospinal fluid [ 160 , 162 , 163 ]. Interestingly, HIV-1 infection instigates a decrease in the expression of AQP4 and its mislocalization, which results in decreased interstitial flow and accumulation of extracellular waste products [ 160 ].…”

PTSD as an Endothelial Disease: Insights From COVID-19

“…Several viruses, including HIV and SARS-CoV-2, were associated with AQP-4 autoantibodies, suggesting that disabling the water channels to upregulate lactate may be a strategy adopted by select pathogens (Lundgaard et al, 2017;Rahimy et al, 2017;Mariajoseph-Antony et al, 2020;Tice et al, 2020;Erickson et al, 2021). Indeed, AQP-4 autoantibodies were found in a subset of COVID-19 patients with neurological symptoms, linking defective water channels to COVID-19 critical illness (Corrêa et al, 2021).…”