title: HCV-specific T-cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance.
abstract: In order to understand the parameters associated with resolved hepatitis C virus (HCV)-infection, we analysed the HCV-specific T-cell responses longitudinally in 13 injecting drug-users (IDUs) with a prospectively identified acute HCV infection. Seven IDUs cleared HCV and six IDUs remained chronically infected. T-cell responses were followed in the period needed to resolve and a comparable time span in chronic carriers. Ex vivo T-cell responses were measured using interferon-gamma Elispot assays after stimulation with overlapping peptide pools spanning the complete HCV genome. CD4+ memory-T-cell responses were determined after 12-day stimulation with HCV proteins. The maximum response was compared between individuals. The T-cell responses measured directly ex vivo were weak but significantly higher in resolvers compared to chronic carriers, whereas the CD4+ memory-T-cell response was not different between resolvers and chronic carriers. However, HCV Core protein was targeted more often in chronic carriers compared to individuals resolving HCV infection. CD4+ T-cell responses predominantly targeting nonstructural proteins were associated with resolved HCV infection. Interestingly, observation of memory-T-cell responses present before the documented HCV-seroconversion suggests that reinfections in IDUs occur often. The presence of these responses however, were not predictive for the outcome of infection. However, a transition of the HCV-specific CD4+ memory-T-cell response from targeting Core to targeting nonstructural proteins during onset of infection was associated with a favourable outcome. Therefore, the specificity of the CD4+ memory-T-cell responses measured after 12-day expansion seems most predictive of resolved infection.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, International Antiviral Therapy and Evaluation Center (IATEC) and Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: T A
authors.initials: TA
authors.lastname: Ruys
authors.forename: N M
authors.initials: NM
authors.lastname: Nanlohy
authors.forename: C H S B
authors.initials: CH
authors.lastname: van den Berg
authors.forename: E
authors.initials: E
authors.lastname: Hassink
authors.forename: M
authors.initials: M
authors.lastname: Beld
authors.forename: T
authors.initials: T
authors.lastname: van de Laar
authors.forename: S
authors.initials: S
authors.lastname: Bruisten
authors.forename: F
authors.initials: F
authors.lastname: Wit
authors.forename: A
authors.initials: A
authors.lastname: Krol
authors.forename: M
authors.initials: M
authors.lastname: Prins
authors.forename: J
authors.initials: J
authors.lastname: Lange
authors.forename: D
authors.initials: D
authors.lastname: van Baarle
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D016174:Hepacivirus / Q000276:immunology*; D018936:Hepatitis C Antigens / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation; D015819:Substance Abuse, Intravenous / Q000276:immunology*; D014758:Viral Core Proteins / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology*
chemical_list: D018936:Hepatitis C Antigens; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; D007371:Interferon-gamma