Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV

Hileman, Corrilynn Olesky; Kalayjian, Robert C.; Azzam, Sausan; Schlatzer, Daniela; Wu, Kun; Tassiopoulos, Katherine; Bedimo, Roger; Ellis, Ronald J.; Erlandson, Kristine M.; Kallianpur, Asha R.; Koletar, Susan L.; Landay, Alan; Palella, Frank J.; Taiwo, Babafemi; Pallaki, Muralidhar; Hoppel, Charles L.

doi:10.1093/cid/ciab107

Cited by 13 publications

(9 citation statements)

References 37 publications

(47 reference statements)

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“…In a metabolomic study of the cerebrospinal fluid (CSF) from people with HIV with neurocognitive impairment (NCI), there were higher levels of citrate and succinate than in the CSF from people without HIV [ 154 ]. Interestingly, in patients with HIV, the increase in plasma citrate and succinate correlates with the degree of NCI observed, hinting at the importance of these metabolites, and metabolic reprogramming in a broader sense, in NCI [ 155 ]. In CSF from HIV patients on cART, there is still an increase in malate and succinate compared to CSF of uninfected patients, suggesting traditional antivirals may not be targeted enough to restore the TCA rewiring that has occurred [ 156 ].…”

Section: Viruses and Mitochondrial Changes And Tca Cycle Rewiringmentioning

confidence: 99%

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

Allen

Arjona

Santerre

et al. 2022

Viruses

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Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.

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Section: Viruses and Mitochondrial Changes And Tca Cycle Rewiringmentioning

confidence: 99%

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

Allen

Arjona

Santerre

et al. 2022

Viruses

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“…The role of the NLRP3 in ammasome in HIV-1 pathogenesis has been described in multiple cell types, including macrophages and lymphocytes, as a mediator of proin ammatory signaling and pyroptotic programmed cell death (14-34, 36, 37, 76-106). The role of oxidative phosphorylation has been described in clinical settings as related to mitochondrial dysfunction (107)(108)(109)(110). HIV-1 can increase metabolism and immune cell oxidative stress in (111).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 activates oxidative phosphorylation in infected CD4 T cells and the NLRP3 inflammasome in bystander macrophages

Freeman

Zhao

Schrode

et al. 2023

Preprint

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Human immunodeficiency virus type 1 (HIV-1) leads to a chronic, incurable infection that causes immune activation, resulting in chronic inflammation in people with HIV-1 (PWH) despite virologic suppression on antiretroviral therapy (ART). The mechanisms underlying this chronic inflammation are multifactorial; literature supports the role of lymphoid structures as reservoirs for viral latency and immune activation. The cell type-specific transcriptomic changes induced by HIV-1 infection in lymphoid tissue have not been analyzed. Human tonsil explants from four donors were infected with HIV-1 ex vivo. Single-cell RNA sequencing (scRNA Seq) was performed to evaluate the represented cell types and the impact of infection, differential gene expression, and inflammatory signaling pathways. Infected CD4+ T cells exhibited increased respiratory electron transport pathway genes. Macrophages exposed to the virus but uninfected demonstrated increased NLRP3 inflammasome pathway genes, suggesting that these cells may play a bystander role in HIV-associated inflammatory pathogenesis. We show that HIV-1-infected CD4+ T cells activate oxidative phosphorylation. Bystander macrophages activate the NLRP3 inflammasome, activating proinflammatory signaling pathways and pyroptotic cell death. These observations support important mechanistic understanding to drive the development of therapeutic strategies to eradicate disease in PWH.

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“…The role of the NLRP3 in ammasome in HIV-1 pathogenesis has been described in multiple cell types, including myeloid cells and lymphocytes, as a mediator of proin ammatory signaling and pyroptotic programmed cell death (14-34, 36, 37, 70-100). The role of oxidative phosphorylation has been described in clinical settings as related to mitochondrial dysfunction (101)(102)(103)(104). HIV-1 can increase metabolism and immune cell oxidative stress in (105).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 infection of human tonsils activates CD4+ T cell oxidative phosphorylation and myeloid NLRP3 inflammasome activation

Swartz

Freeman

Zhao

et al. 2022

Preprint

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Human immunodeficiency virus type 1 (HIV-1) leads to a chronic, incurable infection that causes immune activation, resulting in chronic inflammation in people with HIV-1 (PWH) despite virologic suppression on antiretroviral therapy (ART). The mechanisms underlying this chronic inflammation are multifactorial, but significant literature supports the role of lymphoid structures as reservoirs for viral latency and centers of immune activation. A systematic analysis of the cell type-specific transcriptomic changes induced by HIV-1 infection in lymphoid tissue has not been conducted. Human tonsil explants from four distinct donors were infected with HIV-1 ex vivo. Single-cell RNA sequencing (scRNA Seq) was performed to evaluate the represented cell types and the impact of infection, including differential gene expression, and associated inflammatory signaling pathways. Most of the cells (80%) are lymphocytes with nearly equivalent representation from T (38%) and B (42%) lymphocytes. We also identify smaller populations of NK, epithelial, and myeloid cells. CD4+ T cells demonstrated the highest levels of HIV-1 transcript expression. Highly infected CD4+ T cells also exhibited increased expression of genes involved in the respiratory electron transport pathway. Cells in the myeloid compartment that expressed low levels of HIV-1 transcript demonstrated increased expression of genes involved in the NLRP3 inflammasome pathway, suggesting that these cells may play a “bystander” role in HIV-associated inflammatory pathogenesis. We propose a model in which HIV-1-infected CD4+ T cells activate oxidative phosphorylation pathways, resulting in excess ATP efflux. Bystander myeloid cells may sense the resulting extracellular ATP, thereby triggering NLRP3 inflammasome activation, proinflammatory signaling pathways, and pyroptotic cell death. These observations support important mechanistic understanding to drive the development of therapeutic and care strategies to eradicate disease in PWH.

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Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV

Cited by 13 publications

References 37 publications

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

HIV-1 activates oxidative phosphorylation in infected CD4 T cells and the NLRP3 inflammasome in bystander macrophages

HIV-1 infection of human tonsils activates CD4+ T cell oxidative phosphorylation and myeloid NLRP3 inflammasome activation

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