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Executable models of immune signaling pathways in HIV-associated atherosclerosis

Atherosclerosis (AS)-associated cardiovascular disease is an important cause of mortality in an aging population of people living with HIV (PLWH). This elevated risk has been attributed to viral infection, anti-retroviral therapy, chronic inflammation, and lifestyle factors. However, the rates at wh...

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Autores principales: Palshikar, Mukta G., Palli, Rohith, Tyrell, Alicia, Maggirwar, Sanjay, Schifitto, Giovanni, Singh, Meera V., Thakar, Juilee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9492768/
https://www.ncbi.nlm.nih.gov/pubmed/36131068
http://dx.doi.org/10.1038/s41540-022-00246-5
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author Palshikar, Mukta G.
Palli, Rohith
Tyrell, Alicia
Maggirwar, Sanjay
Schifitto, Giovanni
Singh, Meera V.
Thakar, Juilee
author_facet Palshikar, Mukta G.
Palli, Rohith
Tyrell, Alicia
Maggirwar, Sanjay
Schifitto, Giovanni
Singh, Meera V.
Thakar, Juilee
author_sort Palshikar, Mukta G.
collection PubMed
description Atherosclerosis (AS)-associated cardiovascular disease is an important cause of mortality in an aging population of people living with HIV (PLWH). This elevated risk has been attributed to viral infection, anti-retroviral therapy, chronic inflammation, and lifestyle factors. However, the rates at which PLWH develop AS vary even after controlling for length of infection, treatment duration, and for lifestyle factors. To investigate the molecular signaling underlying this variation, we sequenced 9368 peripheral blood mononuclear cells (PBMCs) from eight PLWH, four of whom have atherosclerosis (AS+). Additionally, a publicly available dataset of PBMCs from persons before and after HIV infection was used to investigate the effect of acute HIV infection. To characterize dysregulation of pathways rather than just measuring enrichment, we developed the single-cell Boolean Omics Network Invariant Time Analysis (scBONITA) algorithm. scBONITA infers executable dynamic pathway models and performs a perturbation analysis to identify high impact genes. These dynamic models are used for pathway analysis and to map sequenced cells to characteristic signaling states (attractor analysis). scBONITA revealed that lipid signaling regulates cell migration into the vascular endothelium in AS+ PLWH. Pathways implicated included AGE-RAGE and PI3K-AKT signaling in CD8+ T cells, and glucagon and cAMP signaling pathways in monocytes. Attractor analysis with scBONITA facilitated the pathway-based characterization of cellular states in CD8+ T cells and monocytes. In this manner, we identify critical cell-type specific molecular mechanisms underlying HIV-associated atherosclerosis using a novel computational method.
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spelling pubmed-94927682022-09-23 Executable models of immune signaling pathways in HIV-associated atherosclerosis Palshikar, Mukta G. Palli, Rohith Tyrell, Alicia Maggirwar, Sanjay Schifitto, Giovanni Singh, Meera V. Thakar, Juilee NPJ Syst Biol Appl Article Atherosclerosis (AS)-associated cardiovascular disease is an important cause of mortality in an aging population of people living with HIV (PLWH). This elevated risk has been attributed to viral infection, anti-retroviral therapy, chronic inflammation, and lifestyle factors. However, the rates at which PLWH develop AS vary even after controlling for length of infection, treatment duration, and for lifestyle factors. To investigate the molecular signaling underlying this variation, we sequenced 9368 peripheral blood mononuclear cells (PBMCs) from eight PLWH, four of whom have atherosclerosis (AS+). Additionally, a publicly available dataset of PBMCs from persons before and after HIV infection was used to investigate the effect of acute HIV infection. To characterize dysregulation of pathways rather than just measuring enrichment, we developed the single-cell Boolean Omics Network Invariant Time Analysis (scBONITA) algorithm. scBONITA infers executable dynamic pathway models and performs a perturbation analysis to identify high impact genes. These dynamic models are used for pathway analysis and to map sequenced cells to characteristic signaling states (attractor analysis). scBONITA revealed that lipid signaling regulates cell migration into the vascular endothelium in AS+ PLWH. Pathways implicated included AGE-RAGE and PI3K-AKT signaling in CD8+ T cells, and glucagon and cAMP signaling pathways in monocytes. Attractor analysis with scBONITA facilitated the pathway-based characterization of cellular states in CD8+ T cells and monocytes. In this manner, we identify critical cell-type specific molecular mechanisms underlying HIV-associated atherosclerosis using a novel computational method. Nature Publishing Group UK 2022-09-21 /pmc/articles/PMC9492768/ /pubmed/36131068 http://dx.doi.org/10.1038/s41540-022-00246-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Palshikar, Mukta G.
Palli, Rohith
Tyrell, Alicia
Maggirwar, Sanjay
Schifitto, Giovanni
Singh, Meera V.
Thakar, Juilee
Executable models of immune signaling pathways in HIV-associated atherosclerosis
title Executable models of immune signaling pathways in HIV-associated atherosclerosis
title_full Executable models of immune signaling pathways in HIV-associated atherosclerosis
title_fullStr Executable models of immune signaling pathways in HIV-associated atherosclerosis
title_full_unstemmed Executable models of immune signaling pathways in HIV-associated atherosclerosis
title_short Executable models of immune signaling pathways in HIV-associated atherosclerosis
title_sort executable models of immune signaling pathways in hiv-associated atherosclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9492768/
https://www.ncbi.nlm.nih.gov/pubmed/36131068
http://dx.doi.org/10.1038/s41540-022-00246-5
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