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

Gonzalez, Hemil; Podany, Anthony T.; Al‐Harthi, Lena; Wallace, Jennillee

doi:10.1007/s11481-020-09907-w

Cited by 23 publications

(21 citation statements)

References 174 publications

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“…Some ART medications may also disrupt astrocyte clearance of glutamate at therapeutic concentrations, as studies show that the protease inhibitors amprenavir and lopinavir reduce EAAT2 levels and function in primary human astrocytes [ 177 ]. Thus, the loss of neuronal support described above may be compounded by ART [ 178 ] as well as changes in glial cell metabolism [ 179 ]. Astrocytes exposed to HIV tat and cocaine shift their metabolic status from glucose oxidation to fatty acid oxidation, which is associated with a reduced production of lactate [ 180 , 181 ].…”

Section: Mechanisms That Affect Synaptodendritic Damage and Network Dysfunction In Handmentioning

confidence: 99%

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Irollo

Luchetta

et al. 2021

Cell. Mol. Life Sci.

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HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient’s quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment.

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Section: Mechanisms That Affect Synaptodendritic Damage and Network Dysfunction In Handmentioning

confidence: 99%

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Irollo

Luchetta

et al. 2021

Cell. Mol. Life Sci.

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“…The TSPO labeling pattern that we observe in the cerebellum of HIV-OPNmice could be related to alterations in both Bergmann glia and Purkinje cell number, integrity, and/or activation state. The elevation of astrocyte GFAP expression as a measure of the glia inflammation in response to viral infection using different experimental models has been well-documented [57][58][59], although it was not detected at a significant level in a macaque model of HIV infection that found elevated TSPO binding [49]. Seminal studies revealed that astrocytes can respond in ways that exacerbate or help the brain return to homeostasis after an inflammatory process [60].…”

Section: Discussionmentioning

confidence: 99%

Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection

Mahmud

Greif

et al. 2020

J Neuroinflammation

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Background Osteopontin (OPN) as a secreted signaling protein is dramatically induced in response to cellular injury and neurodegeneration. Microglial inflammatory responses in the brain are tightly associated with the neuropathologic hallmarks of neurodegenerative disease, but understanding of the molecular mechanisms remains in several contexts poorly understood. Methods Micro-positron emission tomography (PET) neuroimaging using radioligands to detect increased expression of the translocator protein (TSPO) receptor in the brain is a non-invasive tool used to track neuroinflammation in living mammals. Results In humanized, chronically HIV-infected female mice in which OPN expression was knocked down with functional aptamers, uptake of TSPO radioligand DPA-713 was markedly upregulated in the cortex, olfactory bulb, basal forebrain, hypothalamus, and central grey matter compared to controls. Microglia immunoreactive for Iba-1 were more abundant in some HIV-infected mice, but overall, the differences were not significant between groups. TSPO+ microglia were readily detected by immunolabeling of post-mortem brain tissue and unexpectedly, two types of neurons also selectively stained positive for TSPO. The reactive cells were the specialized neurons of the cerebellum, Purkinje cells, and a subset of tyrosine hydroxylase-positive neurons of the substantia nigra. Conclusions In female mice with wild-type levels of osteopontin, increased levels of TSPO ligand uptake in the brain was seen in animals with the highest levels of persistent HIV replication. In contrast, in mice with lower levels of osteopontin, the highest levels of TSPO uptake was seen, in mice with relatively low levels of persistent infection. These findings suggest that osteopontin may act as a molecular brake regulating in the brain, the inflammatory response to HIV infection.

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“…It is also reported that human fetal astrocytes infected with HIV-1 demonstrated astrocyte senescence, and this was further validated in ex vivo astrocytes isolated from HIV-1-infected humanized mice as well as in the brains of HIV-1 transgenic rats [ 178 ]. The precise mechanisms underlying astrocyte senescence, however, remains unclear [ 186 ].…”

Section: Role Of Astrocytes—inflammasomes and Agingmentioning

confidence: 99%

Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging

Sil

Niu

Chivero

et al. 2020

Cells

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Despite the effectiveness of combined antiretroviral therapy (cART) in suppressing virus replication, chronic inflammation remains one of the cardinal features intersecting HIV-1, cART, drug abuse, and likely contributes to the accelerated neurocognitive decline and aging in people living with HIV-1 (PLWH) that abuse drugs. It is also estimated that ~30–60% of PLWH on cART develop cognitive deficits associated with HIV-1-associated neurocognitive disorders (HAND), with symptomatology ranging from asymptomatic to mild, neurocognitive impairments. Adding further complexity to HAND is the comorbidity of drug abuse in PLWH involving activated immune responses and the release of neurotoxins, which, in turn, mediate neuroinflammation. Premature or accelerated aging is another feature of drug abusing PLWH on cART regimes. Emerging studies implicate the role of HIV-1/HIV-1 proteins, cART, and abused drugs in altering the inflammasome signaling in the central nervous system (CNS) cells. It is thus likely that exposure of these cells to HIV-1/HIV-1 proteins, cART, and/or abused drugs could have synergistic/additive effects on the activation of inflammasomes, in turn, leading to exacerbated neuroinflammation, ultimately resulting in premature aging referred to as “inflammaging” In this review, we summarize the current knowledge of inflammasome activation, neuroinflammation, and aging in central nervous system (CNS) cells such as microglia, astrocytes, and neurons in the context of HIV-1 and drug abuse.

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

Cited by 23 publications

References 174 publications

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection

Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging

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