Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection

Flora Mikaeloff; Sara Svensson Akusjärvi; George Mondinde Ikomey; Shuba Krishnan; Maike Sperk; Soham Gupta; Gustavo Daniel Vega Magdaleno; Alejandra Escós; Emilia Lyonga; Marie Claire Okomo; Claude Tayou Tagne; Hemalatha Babu; Christian L. Lorson; Ákos Végvári; Akhil C. Banerjea; Julianna Kele; Luke Elizabeth Hanna; Kamal Singh; João Pedro De Magalhães; Rui Benfeitas; Ujjwal Neogi

doi:10.1038/s42003-021-02985-3

Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection

Flora Mikaeloff, Sara Svensson Akusjärvi, George Mondinde Ikomey, Shuba Krishnan, Maike Sperk, Soham Gupta, Gustavo Daniel Vega Magdaleno, Alejandra Escós, Emilia Lyonga, Marie Claire Okomo, Claude Tayou Tagne, Hemalatha Babu, Christian L. Lorson, Ákos Végvári, Akhil C. Banerjea, Julianna Kele, Luke Elizabeth Hanna, Kamal Singh, João Pedro De Magalhães, Rui BenfeitasUjjwal Neogi

Inflammation and Ageing

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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.

Original language	English
Article number	27
Number of pages	12
Journal	Communications Biology
Volume	5
Issue number	1
Early online date	11 Jan 2022
DOIs	https://doi.org/10.1038/s42003-021-02985-3
Publication status	Published - 1 Dec 2022

Bibliographical note

Funding 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.

Publisher Copyright:
© 2022, The Author(s).

Keywords

Adult
Anti-HIV Agents/therapeutic use
Cells, Cultured
Energy Metabolism/genetics
Female
Glutamine/metabolism
Glycolysis/genetics
HIV Infections/drug therapy
Humans
Male
Metabolome/genetics
Metabolomics
Middle Aged
Systems Biology

ASJC Scopus subject areas

General Agricultural and Biological Sciences
General Biochemistry,Genetics and Molecular Biology
Medicine (miscellaneous)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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MikaeloffF2022TransFinal published version, 4.81 MBLicence: Creative Commons: Attribution (CC BY)

https://www.nature.com/articles/s42003-021-02985-3Licence: Creative Commons: Attribution (CC BY)

Cite this

Mikaeloff, F., Svensson Akusjärvi, S., Ikomey, G. M., Krishnan, S., Sperk, M., Gupta, S., Magdaleno, G. D. V., Escós, A., Lyonga, E., Okomo, M. C., Tagne, C. T., Babu, H., Lorson, C. L., Végvári, Á., Banerjea, A. C., Kele, J., Hanna, L. E., Singh, K., De Magalhães, J. P., ... Neogi, U. (2022). Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection. Communications Biology, 5(1), Article 27. https://doi.org/10.1038/s42003-021-02985-3

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title = "Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection",

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.",

keywords = "Adult, Anti-HIV Agents/therapeutic use, Cells, Cultured, Energy Metabolism/genetics, Female, Glutamine/metabolism, Glycolysis/genetics, HIV Infections/drug therapy, Humans, Male, Metabolome/genetics, Metabolomics, Middle Aged, Systems Biology",

author = "Flora Mikaeloff and {Svensson Akusj{\"a}rvi}, Sara and Ikomey, {George Mondinde} and Shuba Krishnan and Maike Sperk and Soham Gupta and Magdaleno, {Gustavo Daniel Vega} and Alejandra Esc{\'o}s and Emilia Lyonga and Okomo, {Marie Claire} and Tagne, {Claude Tayou} and Hemalatha Babu and Lorson, {Christian L.} and {\'A}kos V{\'e}gv{\'a}ri and Banerjea, {Akhil C.} and Julianna Kele and Hanna, {Luke Elizabeth} and Kamal Singh and {De Magalh{\~a}es}, {Jo{\~a}o Pedro} and Rui Benfeitas and Ujjwal Neogi",

note = "Funding 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 {\AA}ke 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 {\AA}ke 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, Ume{\aa}, Sweden is acknowledged for targeted metabolic profiling. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s42003-021-02985-3",

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Mikaeloff, F, Svensson Akusjärvi, S, Ikomey, GM, Krishnan, S, Sperk, M, Gupta, S, Magdaleno, GDV, Escós, A, Lyonga, E, Okomo, MC, Tagne, CT, Babu, H, Lorson, CL, Végvári, Á, Banerjea, AC, Kele, J, Hanna, LE, Singh, K, De Magalhães, JP, Benfeitas, R & Neogi, U 2022, 'Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection', Communications Biology, vol. 5, no. 1, 27. https://doi.org/10.1038/s42003-021-02985-3

TY - JOUR

T1 - Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection

AU - Mikaeloff, Flora

AU - Svensson Akusjärvi, Sara

AU - Ikomey, George Mondinde

AU - Krishnan, Shuba

AU - Sperk, Maike

AU - Gupta, Soham

AU - Magdaleno, Gustavo Daniel Vega

AU - Escós, Alejandra

AU - Lyonga, Emilia

AU - Okomo, Marie Claire

AU - Tagne, Claude Tayou

AU - Babu, Hemalatha

AU - Lorson, Christian L.

AU - Végvári, Ákos

AU - Banerjea, Akhil C.

AU - Kele, Julianna

AU - Hanna, Luke Elizabeth

AU - Singh, Kamal

AU - De Magalhães, João Pedro

AU - Benfeitas, Rui

AU - Neogi, Ujjwal

N1 - Funding 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. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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.

AB - 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.

KW - Adult

KW - Anti-HIV Agents/therapeutic use

KW - Cells, Cultured

KW - Energy Metabolism/genetics

KW - Female

KW - Glutamine/metabolism

KW - Glycolysis/genetics

KW - HIV Infections/drug therapy

KW - Humans

KW - Male

KW - Metabolome/genetics

KW - Metabolomics

KW - Middle Aged

KW - Systems Biology

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U2 - 10.1038/s42003-021-02985-3

DO - 10.1038/s42003-021-02985-3

M3 - Article

C2 - 35017663

SN - 2399-3642

VL - 5

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 27

ER -

Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Cite this