ApoA-I mimetics reduce systemic and gut inflammation in chronic treated HIV

Abstract

Novel therapeutic strategies are needed to attenuate increased systemic and gut inflammation that contribute to morbidity and mortality in chronic HIV infection despite potent antiretroviral therapy (ART). The goal of this study is to use preclinical models of chronic treated HIV to determine whether the antioxidant and anti-inflammatory apoA-I mimetic peptides 6F and 4F attenuate systemic and gut inflammation in chronic HIV. We used two humanized murine models of HIV infection and gut explants from 10 uninfected and 10 HIV infected persons on potent ART, to determine the in vivo and ex vivo impact of apoA-I mimetics on systemic and intestinal inflammation in HIV. When compared to HIV infected humanized mice treated with ART alone, mice on oral apoA-I mimetic peptide 6F with ART had consistently reduced plasma and gut tissue cytokines (TNF-α, IL-6) and chemokines (CX3CL1) that are products of ADAM17 sheddase activity. Oral 6F attenuated gut protein levels of ADAM17 that were increased in HIV-1 infected mice on potent ART compared to uninfected mice. Adding oxidized lipoproteins and endotoxin (LPS) ex vivo to gut explants from HIV infected persons increased levels of ADAM17 in myeloid and intestinal cells, which increased TNF-α and CX3CL1. Both 4F and 6F attenuated these changes. Our preclinical data suggest that apoA-I mimetic peptides provide a novel therapeutic strategy that can target increased protein levels of ADAM17 and its sheddase activity that contribute to intestinal and systemic inflammation in treated HIV. The large repertoire of inflammatory mediators involved in ADAM17 sheddase activity places it as a pivotal orchestrator of several inflammatory pathways associated with morbidity in chronic treated HIV that make it an attractive therapeutic target.

Mitoquinone mesylate attenuates brain inflammation in humanized mouse model of chronic HIV infection

“…1a). Similar to our prior data that potent ART effectively suppressed HIV-1 replication in NSG BLT mice [6], all HIV + ART + NSG BLT mice had suppressed plasma viremia after 4 weeks of potent ART (data not shown). NSG BLT HIV + ART + mice had increased levels of the cytokines human (h) IL-1β (Fig.…”

“…Three groups were used: uninfected (group A: HIV − , n = 5), infected and on ART (group B: HIV + ART + , n = 12), and infected on ART and MitoQ (group C: HIV + ART + MitoQ + , n = 10). Brain human and murine cytokines and chemokines were determined using Luminex immunoassays according to the manufacturer's instructions (R&D Systems, Minneapolis, MN, USA) and as described previously [6]. The Kruskal–Wallis test or the Mann–Whitney compared different groups.…”

The role of gut-derived oxidized lipids and bacterial lipopolysaccharide in systemic inflammation and atherosclerosis

“…Kelesidis and colleagues [ 49 ■ , 50 ■ , 51 ■ ] used two humanized mouse models of HIV infection, as well as gut explants from ten uninfected and ten HIV-infected men without evident morbidity to study the chronic inflammatory response in mice and humans on ART with no detectable HIV in blood. The mice were either infected with HIV or not, either treated with ART to reduce viral load to undetectable levels in blood or the mice did not receive ART, and either received a concentrate of transgenic tomatoes expressing the 6F peptide (Tg6F) that was added to their chow or they received a control transgenic tomato concentrate without the 6F peptide.…”

“…Daskou et al . [ 51 ■ ] also found that HIV infected humanized mice on ART and the control transgenic tomato concentrate had higher gut tissue cytokine levels (TNF-α and IL-6) and chemokines (CX3CL1) that are products of a disintegrin metalloprotease 17 (ADAM17) sheddase activity compared to HIV infected humanized mice on ART and Tg6F. ADAM17 is an inflammation-inducible enzyme that is responsible for the protease-driven shedding of TNF-α, CX3CL1 and plasma soluble CD163 (sCD163).…”

“…The latter, sCD163, is one the most robust biomarkers of innate immune activation that is associated with mortality in chronic treated HIV [ 52 ]. Adding oxidized lipoproteins and LPS ex vivo to gut explants from the HIV infected men on ART increased levels of ADAM17 in myeloid and intestinal cells, which increased TNF-α, CX3CL1; the apoA-I mimetic peptides 4F and 6F attenuated these changes [ 51 ■ ].…”