ApoA-I mimetics attenuate macrophage activation in chronic treated HIV.

OBJECTIVE(S) Despite antiretroviral therapy (ART), there is an unmet need for therapies to mitigate immune activation in HIV infection. The goal of this study is to determine whether the apoA-I mimetics 6F and 4F attenuate macrophage activation in chronic HIV. DESIGN Preclinical assessment of the in vivo impact of Tg6F and the ex vivo impact of apoA-I mimetics on biomarkers of immune activation and gut barrier dysfunction in treated HIV. METHODS We used two humanized murine models of HIV infection to determine the impact of oral Tg6F with ART (HIVARTTg6F) on innate immune activation (plasma human sCD14, sCD163) and gut barrier dysfunction [murine I-FABP, endotoxin (LPS), LPS binding protein (LBP), murine sCD14]. We also used gut explants from 10 uninfected and 10 HIV infected men on potent ART and no morbidity, to determine the impact of ex vivo treatment with 4F for 72 hours on secretion of sCD14, sCD163 and I-FABP from gut explants. RESULTS When compared to mice treated with ART alone (HIVART), HIVARTTg6F mice attenuated (i) macrophage activation (h-sCD14, h-sCD163), (ii) gut barrier dysfunction (m-IFABP, LPS, LBP and m-sCD14), iii) plasma and gut tissue oxidized lipoproteins. The results were consistent with independent mouse models and ART regimens. Both 4F and 6F attenuated shedding of I-FABP and sCD14 from gut explants from HIV infected and uninfected participants. CONCLUSIONS Given that gut barrier dysfunction and macrophage activation are contributors to comorbidities like cardiovascular disease in HIV, apoA-I mimetics should be tested as therapy for morbidity in chronic treated HIV.