Effects of Integrase Inhibitor–Based ART on the NLRP3 Inflammasome Among ART-Naïve People With HIV

Toribio, Mabel; Burdo, Tricia H.; Fulda, Evelynne S; Cetlin, Madeline; Chu, Sarah M; Feldpausch, Meghan N.; Robbins, Gregory K.; Neilan, Tomas G.; Melbourne, Kathleen; Grinspoon, Steven; Zanni, Markella V.

doi:10.1093/ofid/ofaa459

Cited by 8 publications

(7 citation statements)

References 21 publications

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“…Tan et al [ 25 ] showed that increased inflammatory vesicle activation and upregulation of caspase-1, IL-1 β , and NLRP3 levels in up to 25% of HIV/tuberculosis-coinfected patients triggered an excessive inflammatory response after antiretroviral therapy (ART) initiation. Toribio et al [ 26 ] similarly demonstrated that caspase-1 levels were significantly elevated in ART-treated HIV patients compared to controls, which in turn promoted an increase in NLRP3 inflammatory vesicles. CD4+ T cells in pyroptosis releasing proinflammatory cellular inclusions including ATP may provide a second inflammatory stimulus.…”

Section: Introductionmentioning

confidence: 99%

“…Six months of treatment with an INSTI-based ART regimen can significantly reduce plasma caspase-1 levels in ART-naïve PLHIV [ 26 ], and newly initiated ART reduces the percentage of circulating CD4+ T cells expressing caspase-1 [ 40 ]. Such studies assess the importance of the specific effects of different treatment regimens on chronic inflammation and IA.…”

Section: Introductionmentioning

confidence: 99%

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Research Progress on the Relationship between the NLRP3 Inflammasome and Immune Reconstitution in HIV-Infected Patients Receiving Antiretroviral Therapy

Shi

Zhang

2022

Computational and Mathematical Methods in Medicine

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Human immunodeficiency virus (HIV) infection is characterized not only by severe immunodeficiency but also by persistent inflammation and immune activation. These characteristics persist in people living with HIV (PLHIV) receiving effective antiretroviral therapy (ART) and are associated with morbidity and mortality in nonacquired immunodeficiency syndrome (AIDS) events. ART can inhibit HIV replication and promote immune reconstitution, which is currently the most effective way to control AIDS. However, despite effective long-term ART and overall suppression of plasma HIV RNA level, PLHIV still shows chronic low-level inflammation. The exact mechanisms that trigger chronic inflammation are unknown. Activation of the inflammasome is essential for the host response to pathogens, and some recent studies have confirmed the role of the inflammasome in the pathogenesis of inflammatory diseases. The NLRP3 inflammasome has been widely studied, which is a pyrin domain-containing protein 3 belonging to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs). Recent studies suggest that inflammasome-mediated pyroptosis is associated with CD4+ T cell loss in the absence of persistent infectious HIV replication. This article reviews the mechanism of the NLRP3 inflammasome and its correlation with immune reconstitution in PLHIV treated with ART.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Research Progress on the Relationship between the NLRP3 Inflammasome and Immune Reconstitution in HIV-Infected Patients Receiving Antiretroviral Therapy

Shi

Zhang

2022

Computational and Mathematical Methods in Medicine

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“…PWH before ART show a higher level of caspase-1 compared to people without HIV. ART decreases caspase-1 levels but they still tend to be higher than people without HIV, indicating that there is still inflammation and activation of NLRP3 inflammasome [14]. Combination ART use is associated with a 26% relative increase in the rate of myocardial infarction (MI) per year of exposure to ART [25].…”

Section: Discussionmentioning

confidence: 99%

“…The same study found a correlation between the NLRP3 inflammasome and coronary artery plaque composition and severity in PWH on ART. In a collaborative study [14], we showed that PWH who have not received ART compared to uninfected controls have higher levels of plasma caspase-1, a component of the NLRP3 inflammasome.…”

Section: Introductionmentioning

confidence: 96%

HIV Infection Drives Foam Cell Formation via NLRP3 Inflammasome Activation

Caocci,

Niu,

Fox

et al. 2024

IJMS

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Persistent immune activation is linked to an increased risk of cardiovascular disease (CVD) in people with HIV (PWH) on antiretroviral therapy (ART). The NLRP3 inflammasome may contribute to elevated CVD risk in PWH. This study utilized peripheral blood mononuclear cells (PBMCs) from 25 PWH and 25 HIV-negative controls, as well as HIV in vitro infections. Transcriptional changes were analyzed using RNAseq and pathway analysis. Our results showed that in vitro HIV infection of macrophages and PBMCs from PWH had increased foam cell formation and expression of the NLRP3 inflammasome components and downstream cytokines (caspase-1, IL-1β, and IL-18), which was reduced with inhibition of NLRP3 activity using MCC950. Transcriptomic analysis revealed an increased expression of multiple genes involved in lipid metabolism, cholesterol storage, coronary microcirculation disorders, ischemic events, and monocyte/macrophage differentiation and function with HIV infection and oxLDL treatment. HIV infection and NLRP3 activation increased foam cell formation and expression of proinflammatory cytokines, providing insights into the mechanisms underlying HIV-associated atherogenesis. This study suggests that HIV itself may contribute to increased CVD risk in PWH. Understanding the involvement of the inflammasome pathway in HIV atherosclerosis can help identify potential therapeutic targets to mitigate cardiovascular risks in PWH.

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“…These drugs, together with the new analogues of hydroxychloroquine, can form an interesting set of compounds for further investigations [ 92 ]. Due to similar links to inflammation, NLRP3 inflammasome activation, and Panx1-related infectious diseases, the proposed group of drugs could hold great potential to uncover additional Panx1 channel inhibitors [ 93 , 94 , 95 , 96 , 97 , 98 ]. To conclude, three new Panx1 channel inhibitors were identified from a panel of drugs formerly repurposed for the treatment of COVID-19 patients.…”

Section: Discussionmentioning

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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Effects of Integrase Inhibitor–Based ART on the NLRP3 Inflammasome Among ART-Naïve People With HIV

Cited by 8 publications

References 21 publications

Research Progress on the Relationship between the NLRP3 Inflammasome and Immune Reconstitution in HIV-Infected Patients Receiving Antiretroviral Therapy

Research Progress on the Relationship between the NLRP3 Inflammasome and Immune Reconstitution in HIV-Infected Patients Receiving Antiretroviral Therapy

HIV Infection Drives Foam Cell Formation via NLRP3 Inflammasome Activation

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

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