Executable models of immune signaling pathways in HIV-associated atherosclerosis

Authors

Mukta G. Palshikar, Biophysics, Structural, and Computational Biology Program, University of Rochester School of Medicine and Dentistry, Rochester, USA.
Rohith Palli, Medical Scientist Training Program, University of Rochester School of Medicine and Dentistry, Rochester, USA.
Alicia Tyrell, University of Rochester Clinical & Translational Science Institute, Rochester, USA.
Sanjay Maggirwar, Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Giovanni Schifitto, Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, USA.
Meera V. Singh, Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, USA.
Juilee Thakar, Biophysics, Structural, and Computational Biology Program, University of Rochester School of Medicine and Dentistry, Rochester, USA. Juilee_Thakar@URMC.Rochester.edu.

Document Type

Journal Article

Publication Date

9-21-2022

Journal

NPJ systems biology and applications

Volume

8

Issue

1

DOI

10.1038/s41540-022-00246-5

Abstract

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.

APA Citation

Palshikar, Mukta G.; Palli, Rohith; Tyrell, Alicia; Maggirwar, Sanjay; Schifitto, Giovanni; Singh, Meera V.; and Thakar, Juilee, "Executable models of immune signaling pathways in HIV-associated atherosclerosis" (2022). GW Authored Works. Paper 1601.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/1601

Department

Microbiology, Immunology, and Tropical Medicine