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Persistent hepatitis C viral replication despite priming of functional CD8+ T cells by combined therapy with a vaccine and a directâacting antiviral
- Source :
- Hepatology. 63:1442-1454
- Publication Year :
- 2015
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2015.
-
Abstract
- Exhaustion of antiviral CD8(+) T cells contributes to persistence of hepatitis C viral (HCV) infection. This immune response has proved difficult to restore by therapeutic vaccination, even when HCV replication is suppressed using antiviral regimens containing type I interferon. Because immunomodulatory effects of type I interferon may be a factor in poor T-cell priming, we undertook therapeutic vaccination in two chronically infected chimpanzees during treatment with a direct-acting antiviral (DAA) targeting the HCV NS5b polymerase protein. Immunization with genetic vaccines encoding the HCV NS3-NS5b nonstructural proteins during DAA treatment resulted in a multifunctional CD8(+) T-cell response. However, these antiviral CD8(+) T cells did not prevent persistent replication of DAA-resistant HCV variants that emerged during treatment. Most vaccine-induced CD8(+) T cells targeted class I epitopes that were not conserved in the circulating virus. Exhausted intrahepatic CD8(+) T-cell targeting-conserved epitopes did not expand after vaccination, with a notable exception. A sustained, multifunctional CD8(+) T-cell response against at least one intact class I epitope was detected in blood after vaccination. Persistence of HCV was not due to mutational escape of this epitope. Instead, failure to control HCV replication was likely caused by localized exhaustion in the liver, where CD8(+) T-cell expression of the inhibitory receptor programmed cell death 1 increased 25-fold compared with those in circulation. CONCLUSION: Treatment with a DAA during therapeutic vaccination provided transient control of HCV replication and a multifunctional T-cell response, primarily against nonconserved class I epitopes; exhaustion of liver-infiltrating CD8(+) T cells that target conserved epitopes may not be averted when DAA therapy fails prematurely due to emergence of resistant HCV variants.
- Subjects :
- Viral Hepatitis Vaccines
0301 basic medicine
Pan troglodytes
Hepacivirus
CD8-Positive T-Lymphocytes
Viral Nonstructural Proteins
Biology
Virus Replication
Antiviral Agents
Epitope
Virus
03 medical and health sciences
Immune system
Interferon
medicine
Animals
Cytotoxic T cell
Hepatology
Vaccination
virus diseases
Hepatitis C, Chronic
Virology
030104 developmental biology
Viral replication
Immunology
CD8
medicine.drug
Subjects
Details
- ISSN :
- 15273350 and 02709139
- Volume :
- 63
- Database :
- OpenAIRE
- Journal :
- Hepatology
- Accession number :
- edsair.doi.dedup.....ef4c4fee6ea2ceb6c42b3e8257263f32