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

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

Abstract

The NOD-like receptor protein family pyrin domain containing 3 (NLRP3) inflammasome, activated in the setting of HIV, contributes to pro-atherogenic inflammation. Among antriretroviral therapy-naïve people with HIV (vs controls), levels of caspase-1-a key component of the NLRP3 inflammasome-were significantly increased. Six months of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate significantly decreased caspase-1 levels in association with CD4+/CD8+ ratio recovery.

Trial registration. ClinicalTrials.gov NCT01766726.

Keywords: HIV; NLRP3 inflammasome; atherosclerosis; cardiovascular disease; caspase-1; pyroptosis.

© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Role of NLRP3 inflammasome activation in atherogenesis. NLRP3 inflammasome activation within macrophages requires 2 distinct signals. In vitro studies have demonstrated that HIV infection can serve as the first signal for inflammasome activation by stimulating NF-ĸB intracellular signaling within monocytes. NF-ĸB intracellular signaling, in turn, promotes the expression of the protein NLRP3 and the formation of the NLRP3 inflammasome. A distinct secondary signal, such as cholesterol crystals, is then required for inflammasome activation. After inflammasome activation, pro-caspase-1 is cleaved to generate caspase-1, which in turn mediates the generation of pro-inflammatory and pro-atherogenic cytokines, such as IL-18 and IL-1β. Abbreviations: ATP, adenosine triphosphate; IL-18, interleukin-18; IL-1β, interleukin-1 beta; LDL, low-density lipoprotein; LPS, lipopolysaccharide; NLRP3, NOD-like receptor protein family pyrin domain containing 3; NF-kB, nuclear factor–kB; TLR4-MD2, Toll-like receptor 4–myeloid differentiation factor 2.
Figure 2.
Figure 2.
Plasma caspase-1 levels among ART-naïve PWH, PWH treated with INSTI-based ART, and matched control participants. Box plots are used to demonstrate non–normally distributed data. Whiskers represent minimum and maximum data values. Newly diagnosed ART-naïve PWH demonstrated significantly higher plasma caspase-1 levels at baseline as compared with matched participants without HIV. Among PWH, 6 months of treatment with INSTI-based ART (E/C/F/TDF) resulted in a significant reduction in plasma caspase-1 levels. However, among PWH, post-treatment plasma caspase-1 levels tended to remain higher than levels observed among matched participants without HIV. Abbreviations: ART, antiretroviral therapy; E/C/F/TDF, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate; INSTI, integrase strand transfer inhibitor; PWH, people with HIV.

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