Microglia: The Real Foe in HIV-1-Associated Neurocognitive Disorders?

López, Ana Borrajo; Penedo, Maria Aránzazu; Rivera-Baltanás, Tania; Pérez-Rodríguez, Daniel; Alonso-Crespo, David; Fernández‐Pereira, Carlos; Olivares, J.M.; Agís‐Balboa, Roberto Carlos

doi:10.3390/biomedicines9080925

Cited by 13 publications

(10 citation statements)

References 172 publications

(308 reference statements)

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“…; Hornik et al., 2014 ; Gillispie et al., 2021 ). Indeed, several neurotropic viruses, including HIV-1 and HSV-1 were demonstrated to fuse microglia, connecting them to neurodegeneration ( Borrajo López et al., 2021 ). In addition, fused microglia were shown to comprise major HIV reservoirs, suggesting that SARS-CoV-2 may also avoid elimination by dwelling in these cells ( Wallet et al., 2019 ).…”

Section: Cell-cell Fusion the Molecular Actorsmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a “decentralized” information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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Section: Cell-cell Fusion the Molecular Actorsmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Although modern therapies like cART have transformed HIV from a lethal disease to a manageable condition, associated neurocognitive consequences remain a concern 51 . Paradoxically, microglia and macrophages, which comprise the innate defense system in the brain and are crucial for CNS homeostasis, are targets for HIV and key players in its neuropathogenesis 52,53 . In addition, these infected cells can serve as viral reservoirs even with effective treatment 54 .…”

Section: Discussionmentioning

confidence: 99%

“… 51 Paradoxically, microglia and macrophages, which comprise the innate defense system in the brain and are crucial for CNS homeostasis, are targets for HIV and key players in its neuropathogenesis. 52 , 53 In addition, these infected cells can serve as viral reservoirs even with effective treatment. 54 Here, using an scRNA‐seq approach in the SIV‐NHP model, we demonstrate differential transcriptional programs in brain myeloid cells from monkeys under 4 conditions: uninfected, SIV‐infected without treatment (SIV untreated), SIV infected, cART treated to suppress viremia (SIV treated), and SIV infected with SIVE.…”

Section: Discussionmentioning

confidence: 99%

Antiretroviral therapy restores the homeostatic state of microglia in SIV-infected rhesus macaques

Trease

Niu

Morsey

et al. 2022

Journal of Leukocyte Biology

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Microglia and macrophages are essential for homeostatic maintenance and innate immune response in the brain. They are the first line of defense against infections such as HIV/SIV in the brain. However, they are susceptible to infection and function as viral reservoirs even under effective viral suppression. While current antiretroviral regimens successfully suppress viremia and improve quality of life and lifespan, neurologic complications persist and are in part attributed to activated microglia. We sought to test the hypothesis that brain microglia return to a more homeostatic‐like state when viremia is suppressed by combination antiretroviral therapy. Using the SIV‐rhesus macaque model, we combined single‐cell RNA sequencing, bioinformatics, and pathway analysis to compare gene expression profiles of brain myeloid cells under 4 conditions: uninfected, SIV infected, SIV infected with cART suppression, and SIV encephalitis (SIVE). Our study reveals greater myeloid diversity and an elevated proinflammatory state are associated with untreated SIV infection compared with uninfected animals. The development of encephalitis and suppression of viremia both reduced myeloid diversity. However, they had converse effects on the activation state of microglia and inflammation. Notably, suggestive of a restoration of a homeostatic state in microglia, gene expression and activation of pathways related to inflammation and immune response in cART‐suppressed monkeys were most similar to that in uninfected monkeys. Untreated SIV infection shared characteristics, especially in brain macrophages to SIVE, with SIVE showing dramatic inflammation. In support of our hypothesis, our study demonstrates that cART indeed restores this key component of the brain's homeostatic state. Summary: ScRNA‐seq of rhesus monkey microglia reveals clusters of cells in activated states in the setting of SIV infection, which is primarily reversed by suppressing viremia with combination antiretroviral therapy.

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“…However, the brain is susceptible to several neurotropic viruses, including polyomavirus JC, Zika virus, dengue, Japanese encephalitis virus, West Nile, and HIV [ 40 , 41 , 42 , 43 , 44 , 45 ]. In the brain, the main infected cells correspond to microglia/macrophages and a small population of astrocytes [ 31 , 46 ]. However, the role of myeloid and glial cells has only recently been examined.…”

Section: Viral Reservoirs In the Brainmentioning

confidence: 99%

The Role of Pannexin-1 Channels in HIV and NeuroHIV Pathogenesis

Hernandez

Eugenin

2022

Cells

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The human immunodeficiency virus-1 (HIV) enters the brain shortly after infection, leading to long-term neurological complications in half of the HIV-infected population, even in the current anti-retroviral therapy (ART) era. Despite decades of research, no biomarkers can objectively measure and, more importantly, predict the onset of HIV-associated neurocognitive disorders. Several biomarkers have been proposed; however, most of them only reflect late events of neuronal damage. Our laboratory recently identified that ATP and PGE2, inflammatory molecules released through Pannexin-1 channels, are elevated in the serum of HIV-infected individuals compared to uninfected individuals and other inflammatory diseases. More importantly, high circulating ATP levels, but not PGE2, can predict a decline in cognition, suggesting that HIV-infected individuals have impaired ATP metabolism and associated signaling. We identified that Pannexin-1 channel opening contributes to the high serological ATP levels, and ATP in the circulation could be used as a biomarker of HIV-associated cognitive impairment. In addition, we believe that ATP is a major contributor to chronic inflammation in the HIV-infected population, even in the anti-retroviral era. Here, we discuss the mechanisms associated with Pannexin-1 channel opening within the circulation, as well as within the resident viral reservoirs, ATP dysregulation, and cognitive disease observed in the HIV-infected population.

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Microglia: The Real Foe in HIV-1-Associated Neurocognitive Disorders?

Cited by 13 publications

References 172 publications

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Antiretroviral therapy restores the homeostatic state of microglia in SIV-infected rhesus macaques

The Role of Pannexin-1 Channels in HIV and NeuroHIV Pathogenesis

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