Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction

Younes, Souheil-Antoine; Talla, Aarthi; Ribeiro, Susan Pereira; Сайдакова, Е. В.; Korolevskaya, L. B.; Shmagel, K. V.; Shive, Carey L.; Freeman, Michael L.; Panigrahi, Soumya; Zweig, Sophia Alison; Balderas, Robert; Margolis, Leonid; Douek, Daniel C.; Anthony, Donald D.; Pandiyan, Pushpa; Cameron, Mark J.; Sieg, Scott F.; Calabrese, Leonard H.; Rodrı́guez, Benigno; Lederman, Michael M.

doi:10.1172/jci120245

Cited by 77 publications

(77 citation statements)

References 60 publications

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“…These effects were each dependent on the STAT5 signal transduction pathway, consistent with mechanistic studies in mice that demonstrated that antigen-independent inflammatory IL-15 stimulation of CD8 + Tmem enhances cycling via STAT5 and mTORC1 (38) and survival via Bcl-2 (45). We found that IL-15 stimulates cell growth, mitochondrial biogenesis, and OXPHOS in CX3CR1 + CD57 + CD28 -CD8 + Tmem, consistent with previous reports in CD8 + and CD4 + T cells (30,35). IL-15 likely elicits these effects, at least in part, through its upregulation of c-myc, since c-myc activity is strongly linked to cell proliferation (46), mitochondrial biogenesis (47), and cell metabolism (48), and c-myc has been shown to be important for IL-15-mediated homeostatic proliferation of CD8 + Tmem (31).…”

Section: Discussionsupporting

confidence: 91%

“…IL-15 promotes CX3CR1 + CD57 + CD8 + Tmem viability via STAT5 and Bcl-2 activity. IL-15 has been shown to induce mitochondrial biogenesis and promote oxidative phosphorylation (OXPHOS) in T cells (30,35). Therefore, we next measured forward scatter (i.e., cell size), mitochondrial mass, OXPHOS, and c-myc expression in stimulated CX3CR1 + CD57 + CD8 + Tmem (Figure 3, C-F).…”

Section: Resultsmentioning

confidence: 99%

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"Inflammescent" CX3CR1+CD57+ CD8 T cells are generated and expanded by IL-15

Morris¹,

Chen²,

Mudd³

et al. 2020

JCI Insight

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

"Inflammescent" CX3CR1+CD57+ CD8 T cells are generated and expanded by IL-15

Morris¹,

Chen²,

Mudd³

et al. 2020

JCI Insight

Self Cite

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“…For instance, IL-15 regenerates mitochondrial fitness by facilitating cell division via restoration of the expression of PGC1α. 32 Decreased mitochondrial function and increased ROS are associated with the downregulation of PGC1A in Fibulin-4 mutant mice with aneurysmal aortas. 33 Melatonin attenuates the development of diabetes-induced cardiac dysfunction by preventing mitochondrial fission via the SIRT1-PGC1α pathway.…”

Section: Discussionmentioning

confidence: 99%

Protection of hepatocyte mitochondrial function by blueberry juice and probiotics via SIRT1 regulation in non-alcoholic fatty liver disease

et al. 2019

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“…When energy levels are reduced, glutamate can be converted into α-ketoglutarate and can enter the Krebs cycle for energy production, trying to fully compensate for the lack of oxidative Krebs cycle activity. Moreover, another indicator of defective mitochondrial function was the significant decrease in succinate levels in TCs [[49], [50], [51]], reinforcing the key role of mitochondria in the progression of HIV infection [52,53].…”

Section: Discussionmentioning

confidence: 99%

Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infection

et al. 2019

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Background Approximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control. Methods Plasma samples from EC who spontaneously lost virological control (Transient Controllers, TC, n = 8), at two and one year before the loss of control, were compared with a control group of EC who persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n = 8). The determination of metabolites and plasma lipids was performed by GC-qTOF and LC-qTOF using targeted and untargeted approaches. Metabolite levels were associated with the polyfunctionality of HIV-specific CD8 + T-cell response. Findings Our data suggest that, before the loss of control, TCs showed a specific circulating metabolomic profile characterized by aerobic glycolytic metabolism, deregulated mitochondrial function, oxidative stress and increased immunological activation. In addition, CD8 + T-cell polyfunctionality was strongly associated with metabolite levels. Finally, valine was the main differentiating factor between TCs and PCs. Interpretation All these metabolomic differences should be considered not only as potential biomarkers but also as therapeutic targets in HIV infection. Fund This work was supported by grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos FEDER; Red de Investigación en Sida, Gilead Fellowship program, Spanish Ministry of Education and Spanish Ministry of Economy and Competitiveness.

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Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction

Cited by 77 publications

References 60 publications

"Inflammescent" CX3CR1+CD57+ CD8 T cells are generated and expanded by IL-15

"Inflammescent" CX3CR1+CD57+ CD8 T cells are generated and expanded by IL-15

Protection of hepatocyte mitochondrial function by blueberry juice and probiotics via SIRT1 regulation in non-alcoholic fatty liver disease

Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infection

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