Immunometabolic reprogramming during suppressive HIV-1 infection
Author: Svensson Akusjärvi, Sara
Date: 2022-06-01
Location: Lecture Hall 9Q “Månen”, Karolinska Institutet, Campus Flemingsberg
Time: 09.30
Department: Inst för laboratoriemedicin / Dept of Laboratory Medicine
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Thesis (5.953Mb)
Abstract
Since the implementation of antiretroviral therapy (ART), infection with human immunodeficiency virus type-1 (HIV-1) has been transformed into a chronic lifelong condition. The main obstacle for a HIV-1 cure is the persistence of latently infected cells in viral reservoirs. The viral endurance can instigate detrimental changes on the function and activity of immune cells, creating a chronic inflammatory environment in people living with HIV-1 (PLWH) on successful long-term suppressive antiretroviral therapy (PLWHART). The continuous activation of immune cells may lead to an earlier onset of age-related diseases. Immunometabolism is an emerging field that studies how metabolic reprogramming has an impact on the activation, differentiation, and function of immune cells. Given that these underlying processes are likely to contribute to chronic inflammation in PLWH, the overall aim of this thesis was to evaluate how immunometabolism is reprogrammed during “controlled” HIV-1 infection, either by ART in PLWHART or in PLWH with natural control of infection, elite controllers (PLWHEC).
In paper I, we integrated proteomic and transcriptomic data to investigate features distinct to the PLWHEC phenotype in a male cohort. We identified dysregulated hypoxia inducible factor (HIF) signalling and altered metabolism as unique characteristics of the male PLWHEC phenotype. As controlled HIV-1 infection still induce changes in the immune system we aimed to compare differences in the immune phenotype between PLWHEC and PLWHART and its relation to HIV-1 persistence in paper II. We identified a unique phenotype of decreased CCR6 expression on CD4+ and CD8+ T cells in PLWHEC compared to PLWHART and healthy controls (HC). Additionally, the CD4+CCR6+ cells exhibited a proteomic profile indicative of increased sensitivity towards cell death mechanisms in PLWHEC compared to PLWHART. A reduced proportion of integrated HIV-1 DNA in the reservoir of PLWHEC was found, although no difference in the amount of intact provirus. Continuing our evaluation of differences between PLWHEC and PLWHART we performed metabolo-transcriptomic analysis to understand and infer changes on a multisystem level in paper III. We detected a system level metabolic aberration mainly revolving around OXPHOS in PLWHART compared to PLWHEC. Using pharmacological modulation, we identified how this dysregulation of OXPHOS possibly affects HIV-1 reservoir dynamics and the immune senescence profile. Furthermore, to understand how HIV-1 chronicity affects long-lasting metabolic flexibility and adaptation we conducted plasma metabolomics to understand alterations during suppressive ART in a Swedish cohort in paper IV. We also aimed to characterize the cell populations that mainly contribute to changes in the metabolic environment. We detected aberrant energy metabolism in PLWHART, mainly revolving around the tricarboxylic acid cycle and amino acid synthesis. Cell-type specific evaluation showed that the main metabolic alterations occurred on monocytic cell populations, and that PLWHART exhibited dysregulated chemokine receptor expression of CCR2, CCR5, and CX3CR1 on myeloid cell lineages. In paper V, we wanted to evaluate if the altered metabolic environment was consistent on a global scale using two cohorts from low and middle-income countries (namely, Cameroon and India) using plasma metabolomics. We detected a dysregulation of amino acid metabolism and a switch towards glutaminolysis during long-term suppressive ART.
In summary, the research covered in this thesis illuminates the importance of metabolic reprogramming during HIV-1 persistence in PLWH with controlled infection.
In paper I, we integrated proteomic and transcriptomic data to investigate features distinct to the PLWHEC phenotype in a male cohort. We identified dysregulated hypoxia inducible factor (HIF) signalling and altered metabolism as unique characteristics of the male PLWHEC phenotype. As controlled HIV-1 infection still induce changes in the immune system we aimed to compare differences in the immune phenotype between PLWHEC and PLWHART and its relation to HIV-1 persistence in paper II. We identified a unique phenotype of decreased CCR6 expression on CD4+ and CD8+ T cells in PLWHEC compared to PLWHART and healthy controls (HC). Additionally, the CD4+CCR6+ cells exhibited a proteomic profile indicative of increased sensitivity towards cell death mechanisms in PLWHEC compared to PLWHART. A reduced proportion of integrated HIV-1 DNA in the reservoir of PLWHEC was found, although no difference in the amount of intact provirus. Continuing our evaluation of differences between PLWHEC and PLWHART we performed metabolo-transcriptomic analysis to understand and infer changes on a multisystem level in paper III. We detected a system level metabolic aberration mainly revolving around OXPHOS in PLWHART compared to PLWHEC. Using pharmacological modulation, we identified how this dysregulation of OXPHOS possibly affects HIV-1 reservoir dynamics and the immune senescence profile. Furthermore, to understand how HIV-1 chronicity affects long-lasting metabolic flexibility and adaptation we conducted plasma metabolomics to understand alterations during suppressive ART in a Swedish cohort in paper IV. We also aimed to characterize the cell populations that mainly contribute to changes in the metabolic environment. We detected aberrant energy metabolism in PLWHART, mainly revolving around the tricarboxylic acid cycle and amino acid synthesis. Cell-type specific evaluation showed that the main metabolic alterations occurred on monocytic cell populations, and that PLWHART exhibited dysregulated chemokine receptor expression of CCR2, CCR5, and CX3CR1 on myeloid cell lineages. In paper V, we wanted to evaluate if the altered metabolic environment was consistent on a global scale using two cohorts from low and middle-income countries (namely, Cameroon and India) using plasma metabolomics. We detected a dysregulation of amino acid metabolism and a switch towards glutaminolysis during long-term suppressive ART.
In summary, the research covered in this thesis illuminates the importance of metabolic reprogramming during HIV-1 persistence in PLWH with controlled infection.
List of papers:
I. Sara Svensson Akusjärvi*, Anoop T Ambikan*, Shuba Krishnan, Soham Gupta, Maike Sperk, Ákos Végvári, Flora Mikaeloff, Katie Healy, Jan Vesterbacka, Piotr Nowak, Anders Sönnerborg, and Ujjwal Neogi. Integrative proteo-transcriptomic and immunophenotyping signatures of HIV-1 elite control phenotype: A cross-talk between glycolysis and HIF signaling. iScience, 2022 Jan 21; 25(1):103607. *Equal contribution.
Fulltext (DOI)
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II. Sara Svensson Akusjärvi, Shuba Krishnan, Bianca B. Jütte, Anoop T Ambikan, Soham Gupta, Jimmy Esneider Rodriguez, Ákos Végvári, Maike Sperk, Piotr Nowak, Jan Vesterbacka, J. Peter Svensson, Anders Sönnerborg, and Ujjwal Neogi. Peripheral blood CD4+CCR6+ compartment differentiates HIV-1 infected or seropositive elite controllers from long-term successfully treated individual. Communications Biology, 2022 April 13; 5(1):357.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Anoop T Ambikan*, Sara Svensson Akusjärvi*, Shuba Krishnan, Maike Sperk, Piotr Nowak, Jan Vesterbacka, Anders Sönnerborg, Rui Benfeitas, and Ujjwal Neogi. Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV-infection. *Equal contribution. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Sara Svensson Akusjärvi, Shuba Krishnan, Anoop T Ambikan, Flora Mikaeloff, Sivasankaran Munusamy Ponnan, Jan Vesterbacka, Magda Lourda, Piotr Nowak, Anders Sönnerborg, and Ujjwal Neogi. Monocyte driven systemlevel inflammatory and immunometabolic dysregulation during prolonged successful HIV-1 treatment. [Manuscript]
V. 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, and Ujjwal Neogi. Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection. Communications Biology, 2022 Jan 11;5(1):27.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Sara Svensson Akusjärvi*, Anoop T Ambikan*, Shuba Krishnan, Soham Gupta, Maike Sperk, Ákos Végvári, Flora Mikaeloff, Katie Healy, Jan Vesterbacka, Piotr Nowak, Anders Sönnerborg, and Ujjwal Neogi. Integrative proteo-transcriptomic and immunophenotyping signatures of HIV-1 elite control phenotype: A cross-talk between glycolysis and HIF signaling. iScience, 2022 Jan 21; 25(1):103607. *Equal contribution.
Fulltext (DOI)
Pubmed
II. Sara Svensson Akusjärvi, Shuba Krishnan, Bianca B. Jütte, Anoop T Ambikan, Soham Gupta, Jimmy Esneider Rodriguez, Ákos Végvári, Maike Sperk, Piotr Nowak, Jan Vesterbacka, J. Peter Svensson, Anders Sönnerborg, and Ujjwal Neogi. Peripheral blood CD4+CCR6+ compartment differentiates HIV-1 infected or seropositive elite controllers from long-term successfully treated individual. Communications Biology, 2022 April 13; 5(1):357.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Anoop T Ambikan*, Sara Svensson Akusjärvi*, Shuba Krishnan, Maike Sperk, Piotr Nowak, Jan Vesterbacka, Anders Sönnerborg, Rui Benfeitas, and Ujjwal Neogi. Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV-infection. *Equal contribution. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Sara Svensson Akusjärvi, Shuba Krishnan, Anoop T Ambikan, Flora Mikaeloff, Sivasankaran Munusamy Ponnan, Jan Vesterbacka, Magda Lourda, Piotr Nowak, Anders Sönnerborg, and Ujjwal Neogi. Monocyte driven systemlevel inflammatory and immunometabolic dysregulation during prolonged successful HIV-1 treatment. [Manuscript]
V. 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, and Ujjwal Neogi. Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection. Communications Biology, 2022 Jan 11;5(1):27.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Sönnerborg, Anders
Co-supervisor: Neogi, Ujjwal; Gupta, Soham
Issue date: 2022-05-10
Rights:
Publication year: 2022
ISBN: 978-91-8016-577-8
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