Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control

Abstract

Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography–electrospray ionization–quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients). Long-term viral and immunological HIV-1 control was found to be strongly associated with elevated tricarboxylic acid (TCA) cycle function. Interestingly, of the nine metabolites identified in the TCA cycle, α-ketoglutaric acid (p = 0.004), a metabolite implicated in the activation of the mTOR complex, a modulator of HIV latency and regulator of several biological processes, was found to be a key metabolite in the persistent control. On the other hand, a lipidomics panel combining 45 lipid species showed an optimal percentage of separation and an ability to differentiate LTEC-extreme from LTEC-losing, revealing that an elevated lipidomics plasma profile could be a predictive factor for the reignition of viral replication in LTEC individuals.

Chewing the fat: How lipidomics is changing our understanding of human health and disease in 2022

“…Bibliometric analyses of clinical lipidomics publications in 2022 according to separation techniques, detectors, and RPLC columns used …”

“…Bibliometric analyses of clinical lipidomics publications in 2022 using Scopus search terms “lipidomics” AND “clinic*” on 15 th December 2022 …”

“…Bibliometric analyses of clinical lipidomics publications in 2022 using Scopus search terms "lipidomics" AND "clinic*" on 15 th December 2022. 51,60,61,68,77,[155][156][157]166,[212][213][214][215][310][311][312][313][314][322][323][324][325][326][327][328][329][330][331][332][333][334][335] . *Note: All biological sample types with more than 1.0% of total publications have been reported individually with all remainder combined under "Other".…”

“…306 These diseases have been subject to clinical lipidomics experiments to further disease understanding and manifestation. [310][311][312][313][314] Tuberculosis (TB) is a highly contagious airborne disease, dating back more than 9,000 years, 315 caused by the bacteria Mycobacterium tuberculosis. In 2020, the WHO reported an estimated 10 million new tuberculosis cases and 1.5 million TB-related deaths globally with twothirds of the cases spread across eight countries: India, China, Indonesia, Philippines, Pakistan, Nigeria, Bangladesh, and South Africa.…”

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“…reported among ECs with long-term viral and immunological HIV control vs no-long-term control to have elevated plasma levels of α-ketoglutaric acid. 5 This TCA cycle metabolite activates the mammalian target of rapamycin (mTOR) complex which is a regulator of cytotoxic function and glycolysis. Metformin, a pro-glycolytic anti-diabetic medication, acts by inhibiting mTOR by enhancing AMP-activated protein kinase.…”