Sugar or Fat?—Metabolic Requirements for Immunity to Viral Infections

Shehata, Hesham M.; Murphy, Andrew; Lee, Man Kit Sam; Gardiner, Clair M.; Crowe, Suzanne; Sanjabi, Shomyseh; Finlay, David K.; Palmer, Clovis S.

doi:10.3389/fimmu.2017.01311

Cited by 38 publications

(65 citation statements)

References 108 publications

(175 reference statements)

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“…Finally, pathways involved in glycolysis and oxidative phosphorylation were altered in the NK cells of HIV patients only compared to NK cells from healthy controls. These altered metabolic pathways may affect NK cell functionality and may be linked to dysfunctional NK cell responses in HIV patients, as has been observed for CD8 ϩ T cells (30). However, little is known regarding how metabolic processes impact NK cell activity during chronic viral infections (31).…”

Section: Resultsmentioning

confidence: 99%

Persistent Replication of HIV, Hepatitis C Virus (HCV), and HBV Results in Distinct Gene Expression Profiles by Human NK Cells

Boeijen

Hou

Groen

et al. 2019

J Virol

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NK cells during chronic viral infection have been well studied in the past. We performed an unbiased next-generation RNA-sequencing approach to identify commonalities or differences of the effect of HIV, HCV and HBV viremia on NK cell transcriptomes. Using cell sorting, we obtained CD3-CD56+ NK cells from blood of 6 HIV, 8 HCV, and 32 HBV infected patients without treatment. After library preparation and sequencing, we used an in-house analytic pipeline to compare expression levels with matched healthy controls. In NK cells from HIV, HCV and HBV patients, transcriptome analysis identified 272, 53, and 56 differentially expressed genes, respectively (fold change >1.5, q-value 0.2). Interferon stimulated genes were induced in NK cells from HIV/HCV patients, but not during HBV infection. HIV viremia downregulated ribosome assembly genes in NK cells. In HBV, viral load and ALT variation had little effect on genes related to NK effector function. In conclusion, we compare, for the first time, NK cell transcripts of viremic HIV, HCV and HBV patients. We clearly demonstrate distinctive NK cell gene signatures in 3 different populations, suggestive for a different degree of functional alterations of the NK cell compartment as compared to healthy individuals. Three viruses exist that can result in persistently high viral loads in immune competent humans: HIV, hepatitis C and hepatitis B. In the last decades, using flow cytometry and in vitro assays on NK cells from patients with these diseases, several impairments have been established, particularly during and possibly contributing to HIV viremia. However, the background of NK cell impairments in viremic patients is not well understood. In this study we describe the NK cell transcriptome of patients with high viral loads of different etiologies. We clearly demonstrate distinctive NK cell gene signatures, with regard to ISG induction, expression of genes coding for activation markers or proteins involved in cytotoxic action, as well immunological genes. This study provides important details necessary to uncover the origin of functional and phenotypical differences between viremic patients and healthy subjects, and provides many leads that can be confirmed using future in vitro manipulation experiments.

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Section: Resultsmentioning

confidence: 99%

Persistent Replication of HIV, Hepatitis C Virus (HCV), and HBV Results in Distinct Gene Expression Profiles by Human NK Cells

Boeijen

Hou

Groen

et al. 2019

J Virol

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“…There are many potential approaches to leverage metabolic pathways for the development of memory T cell‐targeted therapeutics . Metabolic parameters can be manipulated to enhance or attenuate the magnitude and function of memory T‐cell responses depending on the specific disease.…”

Section: Therapeutic Opportunities For Targeting Memory T‐cell Metabomentioning

confidence: 99%

“…There are many potential approaches to leverage metabolic pathways for the development of memory T cell-targeted therapeutics. 76,77 Metabolic parameters can be manipulated to enhance or attenuate the magnitude and function of memory T-cell responses depending on the specific disease. For example favoring memory cell development during CAR T cell and adoptive cellular immune therapy for cancer, 78 or reducing the negative impact memory T cells can have in conditions such as psoriasis, systemic sclerosis and multiple sclerosis.…”

Section: Therapeutic Opportunities For Targeting Memory T-cell Metabomentioning

confidence: 99%

The metabolic spectrum of memory T cells

O’Sullivan

2019

Immunol Cell Biol

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The development and persistence of memory T cells are integral to effective host defenses. Cell metabolism has a central role in the maintenance of these populations and engagement of specific metabolic pathways can influence T‐cell fate. Nuances in memory T‐cell metabolism are both context dependent, and exist, on a spectrum that complements and supports the activity of specific memory T‐cell subsets. This review explores how metabolic pathways and substrate choice can influence the phenotype and function of memory T cells.

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“…Generally, immunometabolism and metabolic reprogramming refer to the regulation of immune cell development, differentiation, and function by systemic metabolism and intracellular metabolic pathways - more specifically, major bioenergetic pathways including glycolysis, oxidative phosphorylation, and fatty acid oxidation and lipid metabolism [106–113]. These topics have been extensively reviewed and studied mostly in the context of cancer immunology, but recent studies have begun to demonstrate their importance for HIV replication and pathogenesis.…”

Section: Immunometabolism Metabolic Reprogramming and Relevance For mentioning

confidence: 99%

HIV Persistence in Adipose Tissue Reservoirs

Couturier

Lewis

2018

Curr HIV/AIDS Rep

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Memory CD4 T cells and macrophages, the major host cells for HIV, accumulate in adipose tissue during HIV/SIV infection of humans and rhesus macaques. Whereas HIV and SIV proviral DNA is detectable in CD4 T cells of multiple fat depots in virtually all infected humans and monkeys examined, viral RNA is less frequently detected, and infected macrophages may be less prevalent in adipose tissue. However, based on viral outgrowth assays, adipose-resident CD4 T cells are latently infected with virus that is replication-competent and infectious. Additionally, adipocytes interact with CD4 T cells and macrophages to promote immune cell activation and inflammation which may be supportive for HIV persistence. Antiviral effector cells, such as CD8 T cells and NK/NKT cells, are abundant in adipose tissue during HIV/SIV infection and typically exceed CD4 T cells, whereas B cells are largely absent from adipose tissue of humans and monkeys. Additionally, CD8 T cells in adipose tissue of HIV patients are activated and have a late differentiated phenotype, with unique TCR clonotypes of less diversity relative to blood CD8 T cells. With respect to the distribution of antiretroviral drugs in adipose tissue, data is limited, but there may be class-specific penetration of fat depots. The trafficking of infected immune cells within adipose tissues is a common event during HIV/SIV infection of humans and monkeys, but the virus may be mostly transcriptionally dormant. Viral replication may occur less in adipose tissue compared to other major reservoirs, such as lymphoid tissue, but replication competence and infectiousness of adipose latent virus are comparable to other tissues. Due to the ubiquitous nature of adipose tissue, inflammatory interactions among adipocytes and CD4 T cells and macrophages, and selective distribution of antiretroviral drugs, the sequestration of infected immune cells within fat depots likely represents a major challenge for cure efforts.

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Sugar or Fat?—Metabolic Requirements for Immunity to Viral Infections

Cited by 38 publications

References 108 publications

Persistent Replication of HIV, Hepatitis C Virus (HCV), and HBV Results in Distinct Gene Expression Profiles by Human NK Cells

Persistent Replication of HIV, Hepatitis C Virus (HCV), and HBV Results in Distinct Gene Expression Profiles by Human NK Cells

The metabolic spectrum of memory T cells

HIV Persistence in Adipose Tissue Reservoirs

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