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.
Bibliographical noteFunding Information:
The study is supported by the Swedish Research Council (2017-01330, 2018-06156 and 2021-01756), Karolinska Institutet Stiftelser och Fonder (2020-01554), and Åke Wiberg Stiftelse grant (M18-0021). Swedish Physicians Against AIDS Foundation (FOb20170004) and Jeanssons Stiftelser (JS2016–0185) to UN. MS acknowledges the support received from the Swedish Physicians Against AIDS Foundation (FOa2019-0020). SG acknowledges support from the Swedish Research Council Establishment grant (2021-03035), the Center for Medical Innovation grant (CIMED-FoUI-093304), Kar-olinska Institutet Stiftelser och Fonder (2020-02153), and Åke Wiberg Stiftelse grant (M20-0220). We thank all the study subjects for their participation. Authors acknowledge support from the Proteomics Biomedicum; Karolinska Institute, Solna, for LC-MS/ MS analysis. Swedish Metabolomics Centre, Umeå, Sweden is acknowledged for targeted metabolic profiling.
© 2022, The Author(s).
- Anti-HIV Agents/therapeutic use
- Cells, Cultured
- Energy Metabolism/genetics
- HIV Infections/drug therapy
- Middle Aged
- Systems Biology
ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine (miscellaneous)