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Plasma Proteome Analysis Reveals Overlapping, yet Distinct Mechanisms of Immune Activation in Chronic HCV and HIV Infections

Schlatzer, Daniela M. BS*; Sugalski, Julia M. MS; Chen, Yanwen MS, PhD; Barnholtz-Sloan, Jill PhD; Davitkov, Perica MD; Hazlett, Fred E. MS*; Funderburg, Nicholas PhD; Rodriguez, Benigno MD; Lederman, Michael M. MD; Sieg, Scott F. PhD; Chance, Mark R. PhD*; Anthony, Donald D. MD, PhD†,§

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 15th, 2013 - Volume 63 - Issue 5 - p 563–571
doi: 10.1097/QAI.0b013e3182909847
Basic and Translational Science

Background: HIV infection contributes to accelerated rates of progression of liver fibrosis during hepatitis C virus (HCV) infection, and HCV liver disease contributes to mortality during HIV infection. Although mechanisms underlying these interactions are not well known, soluble and cellular markers of immune activation associate with disease progression during both infections.

Methods: We identified proteins varying in expression across the plasma proteomes of subjects with untreated HIV infection, untreated HCV infection with low aspartate transaminase/platelet ratio index, untreated HCV infection with high aspartate transaminase/platelet ratio index, HIV–HCV coinfection, and controls. We examined correlations between dysregulated proteins and markers of immune activation to uncover biomarkers specific to disease states.

Results: We observed the anticipated higher frequencies of HLA-DR+CD38+CD4 and CD8 T cells, higher serum soluble CD14 levels, and higher serum interleukin-6 levels for HCV- and HIV-infected groups compared with controls. Plasma proteome analysis identified 2297 peptides mapping to 227 proteins, and quantitative analysis of peptide intensity identified significant changes in 85 proteins across the 5 groups. Abundance for 7 of these proteins was validated by enzyme-linked immunosorbent assay. Forty-three of these proteins correlated with markers of immune activation, including at least 2 proteins that may directly drive T-cell activation. As a functional validation, we tested the enzymatic pathway product (lysophosphatidic acid, LPA) of one such protein, ecotonucleotide pyrophosphatase/phosphodiesterase-2, for ability to activate T cells in vitro. LPA activated T cells to express CD38 and HLA-DR.

Conclusions: These data indicate that elevated levels of ecotonucleotide pyrophosphatase/phosphodiesterase-2 and LPA during advanced HCV disease may play a role in exacerbating immune activation during HCV–HIV coinfection.

Supplemental Digital Content is Available in the Text.

*Center for Proteomics and Bioinformatics;

Divisions of Infectious and Rheumatic Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH;

Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH; and

§Veterans Administration Medical Center, Center for AIDS Research, University Hospitals of Cleveland, Cleveland, OH.

Correspondence to: Donald D. Anthony, MD, PhD, Department of Medicine and Pathology, Biomedical Research Building 1028, Case Western Reserve University, 2109 Adelbert Road, Cleveland, OH 44106 (e-mail:

Supported by National Institutes of Health grant P20-DA-026133, NIH R01 DK068361, VA Merit, the Case Western Reserve University Center for AIDS Research Core facilities (AI 36219), and the Clinical and Translational Science Collaborative of Cleveland, UL1TR000439, from the National Center for Advancing Translational Sciences component of the National Institutes of Health and National Institutes of Health roadmap for Medical Research.

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Presented as an oral poster at HIV and Liver Disease meeting, September 6–8, 2012, Jackson, Wyoming.

Received November 21, 2012

Accepted March 04, 2013

© 2013 by Lippincott Williams & Wilkins