Abstract
ObjectiveWe investigated whether apolipoprotein A-I (apoA-I) mimetic peptides 4F and 6F can be a novel therapeutic strategy to reduce blood and gut bioactive lipids, proinflammatory effects of endotoxin (LPS) and aberrant activation of cyclooxygenase 2 (COX-2) as instigators of increased risk for cardiometabolic disease in chronic treated HIV. MethodsWe used two humanized murine models of chronic treated HIV infection (n = 109 mice) and gut explants from HIV infected (n = 10) persons to determine whether Tg6F and 4F attenuate in vivo and ex vivo increased blood and gut bioactive lipids (measured by mass spectrometry) and intestinal protein levels of COX-2 (measured by immunoassays) in chronic treated HIV. ResultsIn these models of HIV, when compared to HIV-1 infected mice on antiretroviral therapy (ART) alone, oral Tg6F in combination with ART attenuated increases in plasma and gut bioactive lipids (and particularly COX lipids) and intestinal COX-2. 4F and Tg6F also reduced ex vivo production of COX-2 protein and associated secretion of bioactive lipids in gut explants from HIV-1 infected persons treated with LPS. ConclusionApoA-I mimetics favorably impact the proinflammatory effects of LPS, COX-2 and production of bioactive lipids that collectively drive gut and systemic inflammation in chronic treated HIV. Given prior experimental evidence that the proinflammatory effects of LPS, COX-2 and gut dysfunction contribute to cardiometabolic syndrome in chronic HIV, apoA-I mimetic peptides may be a novel therapy to treat cardiometabolic syndrome in chronic HIV.
Highlights
Chronic treated HIV is a state of gut barrier dysfunction in which HIV, antiretroviral therapy (ART), gut cells, microbial products such as Abbreviations: ART, antiretroviral therapy (ART); Bone Marrow Liver Thymic mice (BLT), Bone Marrow/Liver/Thymus mouse; C57BL/6, C57 black 6; EV, a concentrate of transgenic control tomatoes, FTC, Emtricitabine; Graft versus host disease (GVHD), graft versus host disease; HIV, Human Immunodeficiency Virus; HDL, High Density Lipoprotein; LC-MS-MS, Liquid Chromatography with tandem mass spectrometry; LPS, lipopolysaccharide or endotoxin; MFI, mean fluorescence intensity; NSG, NOD.CgPrkdcscidIl2rgtm1Wjl/SZJ or NOD/SCID/IL2Rγ−/−; PBS, phosphate buffered saline; Tg6F, a concentrate of transgenic tomatoes that express the apoA-1 mimetic peptide 6F; TKO, recombination activating gene 2 (Rag2)γcCD47 triple knockout or Rag2−/−γc−/−CD47−/−
We hypothesized that plasma and gut bioactive lipids of the proinflammatory Arachidonic acid (AA) pathways and other major pathways of eicosanoids would be increased in chronic treated HIV and could be targeted therapeutically with apolipoprotein A-I (apoA-I) mimetic peptides
Our results suggest that apoA-I mimetic peptides attenuate the crosstalk between increased gut barrier dysfunction, LPS, cyclooxygenase 2 (COX-2) and associated production of COX-2 lipids in gut tissue that contribute to gut and systemic inflammation and cardiometabolic risk in chronic treated HIV (Fig. 8)
Summary
Lipopolysaccharides (LPS) and bioactive lipids interact to drive increased systemic and intestinal inflammation, immune dysfunction and metabolic syndrome [1]. The exact mechanisms of increased risk for cardiometabolic disease in chronic treated HIV are unclear. Pending results from clinical trials, it is unclear whether statins can prevent metabolic syndrome and morbidity in chronic treated HIV [2]. There is a tremendous unmet need for novel therapies to reduce metabolic abnormalities and morbidity in chronic treated HIV. Identifying the mechanisms that drive intestinal inflammation, LPS, bioactive lipids and gut barrier dysfunction may lead to novel therapies for chronic treated HIV-related metabolic comorbidities
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