Distinct lipid profile, low-level inflammation and increased antioxidant defense as a signature in HIV-1 elite control status

Abstract

<jats:title>Abstract</jats:title><jats:p>HIV-1 elite controllers (EC) are a rare but heterogeneous group of HIV-1-infected individuals who are able to suppress viral replication in the absence of antiretroviral therapy. The mechanisms of how EC achieve undetectable viral loads remain unclear. This study aimed to investigate host plasma metabolomics and targeted plasma proteomics in a Swedish HIV-1 cohort including EC and treatment-naïve viremic progressors (VP) as well as HIV-negative individuals (HC) to get insights into mechanisms governing EC status. Metabolites belonging to antioxidant defense had higher levels in EC relative to VP while inflammation markers were increased in VP compared to EC. Only four plasma proteins (CCL4, CCL7, CCL20, and NOS3) were increased in EC compared to HC and CCL20/CCR6 axis can play important role. Our study suggests that low-level inflammation and oxidative stress at physiological levels could be important factors contributing to control of viral replication.</jats:p><jats:sec><jats:title>One Sentence Summary</jats:title><jats:p>HIV-1 elite controllers had a distinct lipid profile, reduced inflammation, and increased antioxidant defense that might contribute to elite control status.</jats:p></jats:sec>

Novel mechanism of HIV elite control by enriching gut dipeptides as HIV-1 antagonist but Prevotella agonist

“…Amino acids (essential and non-essential) as a class were signi cantly decreased in feces of EC and increased in feces of VP relative to HC, further supporting enhanced intestinal absorption/uptake in ECs and impaired absorption in VP. Moreover, our recent study on plasma metabolites in the same cohort identi ed that many amino acids were signi cantly elevated in EC plasma samples relative to VP, which further supports the assumption of impaired amino acid absorption/uptake in VP 15 . Differences can in uence these changes in the dietary intake but since the present cohort lacked extensive dietary data, the study groups were instead matched by several parameters including BMI, sexual practice and general food habit.…”

“…AhR acts hereby as a transcription factor regulating antimicrobial defense and intestinal immune homeostasis as well as inducing anti-in ammatory responses 32,33 . Interestingly, in our recent study on plasma metabolomics, we also observed an enhancement in antioxidant defense pathways, together with low in ammation levels in EC as compared to VP 15 . Hence, indole and skatol produced by the gut microbiota might support and contribute to EC status by providing an unfavorable intestinal environment for HIV-1 replication in EC.…”

“…However, due to overall enhanced intestinal absorption/uptake of metabolites and presence of dipeptide transporters in the human gut that most likely facilitates the e ciency of dipeptides transport into the circulation, impaired protein absorption in EC seems less reasonable 29,30 . Furthermore, dipeptides were also observed in plasma of EC arguing against impaired peptide absorption from the gut 15 . As all EC in our cohort has elevated levels of dipeptides this metabolic signature could also serve as a potential biomarker of EC status.…”

“…In a recent study, the loss of virologic control in EC was characterized by immune-metabolic deregulation 14 . Our recent study indicated a unique plasma metabolic signature in EC attributing to the elite control status 15 .…”

“…Cross-sectional fecal samples were collected between 2010 and 2016 from three groups of individuals; i) an unbiased cohort of untreated HIV-1-infected EC (n=14), as well as age-, gender-and body mass index-(BMI) matched ii) treatment-naïve HIV-1-infected patients with viremia (VP, n=16), and iii) HIV-1-negative controls (HC, n = 12). The de nitions of EC 5 and clinical characteristics of the study participants 15 are presented elsewhere. Study subjects are part of InfCareHIV cohort and samples were collected at Karolinska University Hospital, Huddinge, Sweden.…”