Abstract
Despite successful combination antiretroviral therapy (cART), persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic flexibility and adaptation in people living with HIV (PLWH). Our study investigated alterations in the plasma metabolic profiles by comparing PLWH on long-term cART(>5 years) and matched HIV-negative controls (HC) in two cohorts from low- and middle-income countries (LMIC), Cameroon, and India, respectively, to understand the system-level dysregulation in HIV-infection. Using untargeted and targeted LC-MS/MS-based metabolic profiling and applying advanced system biology methods, an altered amino acid metabolism, more specifically to glutaminolysis in PLWH than HC were reported. A significantly lower level of neurosteroids was observed in both cohorts and could potentiate neurological impairments in PLWH. Further, modulation of cellular glutaminolysis promoted increased cell death and latency reversal in pre-monocytic HIV-1 latent cell model U1, which may be essential for the clearance of the inducible reservoir in HIV-integrated cells.
Highlights
Despite successful combination antiretroviral therapy, persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic flexibility and adaptation in people living with human immunodeficiency virus type1 (HIV) (PLWH)
To identify mechanisms associated with HIV and combination antiretroviral therapy (cART), the differentially abundant metabolites having a Human Metabolome Database (HMDB) annotation ( Mann–Whitney U-test, p < 0.05) were submitted to metabolite set enrichment analysis (MSEA) using Ingenuity Pathway Analysis (IPA)
The common factor in this trans-cohort study was the lower level of essential amino acid (AA) methionine, phenylalanine, threonine, valine, and tryptophan and elevated glutamate in people living with HIV (PLWH) on cART compared to HIV-negative controls (HC)
Summary
Despite successful combination antiretroviral therapy (cART), persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic flexibility and adaptation in people living with HIV (PLWH). Our study investigated alterations in the plasma metabolic profiles by comparing PLWH on long-term cART(>5 years) and matched HIV-negative controls (HC) in two cohorts from low- and middle-income countries (LMIC), Cameroon, and India, respectively, to understand the system-level dysregulation in HIV-infection. In our recent untargeted metabolomics study on the COCOMO cohort from Denmark, we reported alterations in the amino acid (AA) metabolism as a central characteristic of PLWH with a median of 13 years of therapy. This study investigates alterations in plasma metabolic profiles by comparing PLWH on long-term cART and matched HIVnegative controls (HC) in two cohorts from low- and middleincome countries (LMIC), Cameroon and India, respectively, using untargeted metabolomics to understand the system-level alterations during prolonged therapy in HIV-infection. Our study provides a comprehensive metabolic profile of PLWH on cART, while HIV latency in cellular models can shed light on the metabolic reprogramming in long-term successfully treated HIV infection and its potential role in accelerated aging in PLWH
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