Human immunodeficiency virus‐1/simian immunodeficiency virus infection induces opening of pannexin‐1 channels resulting in neuronal synaptic compromise: A novel therapeutic opportunity to prevent NeuroHIV

Górska, Anna; Donoso, Maribel; Valdebenito, Silvana; Prideaux, Brendan; Queen, Suzanne E.; Scemes, Eliana; Clements, Janice E.; Eugenin, Eliseo A.

doi:10.1111/jnc.15374

Cited by 14 publications

(21 citation statements)

References 114 publications

(198 reference statements)

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“…ATP released through these open Panx1 channels in the extracellular environment binds to purinergic P2 receptors, which drive the activation of NLRP3 inflammasomes [ 44 , 45 , 46 , 47 ]. Furthermore, Panx1-mediated ATP release has been associated with viral infections, replication, and pathogeneses [ 20 , 21 , 48 , 49 ]. It was previously shown that anti-inflammatory drugs [ 50 , 51 ] and antiviral drugs [ 52 ] are able to alter Panx1 channel activity.…”

Section: Resultsmentioning

confidence: 99%

Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels

Caufriez

Tabernilla

Campenhout

et al. 2022

IJMS

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Although many efforts have been made to elucidate the pathogenesis of COVID-19, the underlying mechanisms are yet to be fully uncovered. However, it is known that a dysfunctional immune response and the accompanying uncontrollable inflammation lead to troublesome outcomes in COVID-19 patients. Pannexin1 channels are put forward as interesting drug targets for the treatment of COVID-19 due to their key role in inflammation and their link to other viral infections. In the present study, we selected a panel of drugs previously tested in clinical trials as potential candidates for the treatment of COVID-19 early on in the pandemic, including hydroxychloroquine, chloroquine, azithromycin, dexamethasone, ribavirin, remdesivir, favipiravir, lopinavir, and ritonavir. The effect of the drugs on pannexin1 channels was assessed at a functional level by means of measurement of extracellular ATP release. Immunoblot analysis and real-time quantitative reversetranscription polymerase chain reaction analysis were used to study the potential of the drugs to alter pannexin1 protein and mRNA expression levels, respectively. Favipiravir, hydroxychloroquine, lopinavir, and the combination of lopinavir with ritonavir were found to inhibit pannexin1 channel activity without affecting pannexin1 protein or mRNA levels. Thusthree new inhibitors of pannexin1 channels were identified that, though currently not being used anymore for the treatment of COVID-19 patients, could be potential drug candidates for other pannexin1-related diseases.

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Section: Resultsmentioning

confidence: 99%

Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels

Caufriez

Tabernilla

Campenhout

et al. 2022

IJMS

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“…However, only ATP was predictive of the early stages of cognitive decline in the HIV-infected population [ 110 ]. We identified that viral reservoirs, myeloid and astrocytic, can release ATP, contributing to the purinergic dysfunction [ 33 , 111 , 112 ]. We also identified that residual expression of gp120 and virus could activate Panx-1 and Connexin-43 hemichannels in several cell types, further increasing ATP release during chronic HIV infection.…”

Section: Crusade To Find Reliable Biomarkers To Identify Chronic and ...mentioning

confidence: 99%

“…Our data in simian immunodeficiency virus (SIV)-infected macaques indicate that blocking Panx-1 channel opening after SIV infection prevents immune compromise, leukocyte differentiation induced by the virus, transmigration into the CNS, and loss of complex synapses [ 33 , 110 ]. These data indicate that despite the complex animal model, mimetic peptides to Panx-1 can be used to prevent CNS damage and improve immune response.…”

Section: Panx-1 and Purinergic Signaling Axis In Hiv Infectionmentioning

confidence: 99%

“…Additionally, in the context of HIV, these reservoirs are known to have dysregulation of hemichannels and gap junction proteins, such as Pannexin-1 (Panx-1) and Connexin 43, which promote the local secretion of inflammatory molecules such as ATP (adenosine-5’-triphosphate) and lipids [ 32 , 33 ]. The secretion or propagation of these inflammatory molecules through these hemichannels or gap junctions can lead to bystander apoptosis [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

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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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“…Neuropilin-1 (NRP-1) and Cluster of Differentiation 147 (CD147) can interact with furin cleaved SARS-CoV-2 spike protein since furin preactivation of the S protein increases the binding affinity to its receptor and cofactors, resulting in a widespread infectious cycle introducing differences in comparison to SARS-CoV despite both viruses targeting ACE2 (84). With reference to other RNA viruses, HIV-1 infection was found to induce the opening of ubiquitously expressed Pannexin-1 (Panx-1) channels on the surface of peripheral blood mononuclear cells, leading to a release of ATP that could stimulate purinergic signaling pathways that enhanced viral binding, accelerating HIV infectious entry and contributed to the compromised synaptic function found in cases of HIV-associated neurocognitive disorder (85). It was proposed SARS-CoV-2 may also induce opening of the large ionic Panx-1 channels, allowing passive outflux of ATP, metabolites and other small anions likely to have a role in exacerbating the inflammatory response (86).…”

Section: Sars-cov-2 Interactions With the Purinomementioning

confidence: 99%

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

2022

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A long-shared evolutionary history is congruent with the multiple roles played by purinergic signaling in viral infection, replication and host responses that can assist or hinder viral functions. An overview of the involvement of purinergic signaling among a range of viruses is compared and contrasted with what is currently understood for SARS-CoV-2. In particular, we focus on the inflammatory and antiviral responses of infected cells mediated by purinergic receptor activation. Although there is considerable variation in a patient’s response to SARS-CoV-2 infection, a principle immediate concern in Coronavirus disease (COVID-19) is the possibility of an aberrant inflammatory activation causing diffuse lung oedema and respiratory failure. We discuss the most promising potential interventions modulating purinergic signaling that may attenuate the more serious repercussions of SARS-CoV-2 infection and aspects of their implementation.

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Human immunodeficiency virus‐1/simian immunodeficiency virus infection induces opening of pannexin‐1 channels resulting in neuronal synaptic compromise: A novel therapeutic opportunity to prevent NeuroHIV

Abstract: Despite the successful introduction of antiretroviral therapy (ART), at least half of the human immunodeficiency virus-1 (HIV)-positive population develop some degree of HIV-associated neurocognitive disorder, but the mechanisms are still under active investigation

Cited by 14 publications

References 114 publications

Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels

Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels

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

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

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