Journal article
Conserved Motifs within Hepatitis C Virus Envelope (E2) RNA and Protein Independently Inhibit T Cell Activation
PLoS pathogens, Vol.11(9), pp.e1005183-e1005183
09/2015
DOI: 10.1371/journal.ppat.1005183
PMCID: PMC4589396
PMID: 26421924
Abstract
T cell receptor (TCR) signaling is required for T-cell activation, proliferation, differentiation, and effector function. Hepatitis C virus (HCV) infection is associated with impaired T-cell function leading to persistent viremia, delayed and inconsistent antibody responses, and mild immune dysfunction. Although multiple factors appear to contribute to T-cell dysfunction, a role for HCV particles in this process has not been identified. Here, we show that incubation of primary human CD4+ and CD8+ T-cells with HCV RNA-containing serum, HCV-RNA containing extracellular vesicles (EVs), cell culture derived HCV particles (HCVcc) and HCV envelope pseudotyped retrovirus particles (HCVpp) inhibited TCR-mediated signaling. Since HCVpp's contain only E1 and E2, we examined the effect of HCV E2 on TCR signaling pathways. HCV E2 expression recapitulated HCV particle-induced TCR inhibition. A highly conserved, 51 nucleotide (nt) RNA sequence was sufficient to inhibit TCR signaling. Cells expressing the HCV E2 coding RNA contained a short, virus-derived RNA predicted to be a Dicer substrate, which targeted a phosphatase involved in Src-kinase signaling (PTPRE). T-cells and hepatocytes containing HCV E2 RNA had reduced PTPRE protein levels. Mutation of 6 nts abolished the predicted Dicer interactions and restored PTPRE expression and proximal TCR signaling. HCV RNA did not inhibit distal TCR signaling induced by PMA and Ionomycin; however, HCV E2 protein inhibited distal TCR signaling. This inhibition required lymphocyte-specific tyrosine kinase (Lck). Lck phosphorylated HCV E2 at a conserved tyrosine (Y613), and phospho-E2 inhibited nuclear translocation of NFAT. Mutation of Y613 restored distal TCR signaling, even in the context of HCVpps. Thus, HCV particles delivered viral RNA and E2 protein to T-cells, and these inhibited proximal and distal TCR signaling respectively. These effects of HCV particles likely aid in establishing infection and contribute to viral persistence.
Details
- Title: Subtitle
- Conserved Motifs within Hepatitis C Virus Envelope (E2) RNA and Protein Independently Inhibit T Cell Activation
- Creators
- Nirjal Bhattarai - Research Service and, The Iowa City Veterans Affairs Medical Center, Iowa City, Iowa, United States of America; The Departments of Internal Medicine and Microbiology, University of Iowa, Iowa City, Iowa, United States of AmericaJames H McLinden - Research Service and, The Iowa City Veterans Affairs Medical Center, Iowa City, Iowa, United States of America; The Departments of Internal Medicine and Microbiology, University of Iowa, Iowa City, Iowa, United States of AmericaJinhua Xiang - Research Service and, The Iowa City Veterans Affairs Medical Center, Iowa City, Iowa, United States of America; The Departments of Internal Medicine and Microbiology, University of Iowa, Iowa City, Iowa, United States of AmericaThomas M Kaufman - Research Service and, The Iowa City Veterans Affairs Medical Center, Iowa City, Iowa, United States of America; The Departments of Internal Medicine and Microbiology, University of Iowa, Iowa City, Iowa, United States of AmericaJack T Stapleton - Research Service and, The Iowa City Veterans Affairs Medical Center, Iowa City, Iowa, United States of America; The Departments of Internal Medicine and Microbiology, University of Iowa, Iowa City, Iowa, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.11(9), pp.e1005183-e1005183
- DOI
- 10.1371/journal.ppat.1005183
- PMID
- 26421924
- PMCID
- PMC4589396
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Publisher
- Public Library of Science
- Grant note
- I01 CX000821 / CSRD VA I01 BX000207 / BLRD VA I01 BX001241 / BLRD VA
- Language
- English
- Date published
- 09/2015
- Academic Unit
- Microbiology and Immunology; Infectious Diseases; Internal Medicine
- Record Identifier
- 9984094336602771
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