Distinct Escape Pathway by Hepatitis C Virus Genotype 1a from a Dominant CD8+ T Cell Response by Selection of Altered Epitope Processing.

2.50
Hdl Handle:
http://hdl.handle.net/10033/606256
Title:
Distinct Escape Pathway by Hepatitis C Virus Genotype 1a from a Dominant CD8+ T Cell Response by Selection of Altered Epitope Processing.
Authors:
Walker, Andreas; Skibbe, Kathrin; Steinmann, Eike; Pfaender, Stephanie; Kuntzen, Thomas; Megger, Dominik A; Groten, Svenja; Sitek, Barbara; Lauer, Georg M; Kim, Arthur Y; Pietschmann, Thomas; Allen, Todd M; Timm, Joerg
Abstract:
Antiviral CD8(+) T cells are a key component of the adaptive immune response against HCV, but their impact on viral control is influenced by preexisting viral variants in important target epitopes and the development of viral escape mutations. Immunodominant epitopes highly conserved across genotypes therefore are attractive for T cell based prophylactic vaccines. Here, we characterized the CD8(+) T cell response against the highly conserved HLA-B*51-restricted epitope IPFYGKAI1373-1380 located in the helicase domain of NS3 in people who inject drugs (PWID) exposed predominantly to HCV genotypes 1a and 3a. Despite this epitope being conserved in both genotypes, the corresponding CD8(+) T cell response was detected only in PWID infected with genotype 3a and HCV-RNA negative PWID, but not in PWID infected with genotype 1a. In genotype 3a, the detection of strong CD8(+) T cell responses was associated with epitope variants in the autologous virus consistent with immune escape. Analysis of viral sequences from multiple cohorts confirmed HLA-B*51-associated escape mutations inside the epitope in genotype 3a, but not in genotype 1a. Here, a distinct substitution in the N-terminal flanking region located 5 residues upstream of the epitope (S1368P; P = 0.00002) was selected in HLA-B*51-positive individuals. Functional assays revealed that the S1368P substitution impaired recognition of target cells presenting the endogenously processed epitope. The results highlight that, despite an epitope being highly conserved between two genotypes, there are major differences in the selected viral escape pathways and the corresponding T cell responses.
Affiliation:
Twincore Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hanover and the Helmholtz Centre for Infection Research, Hanover, Germany.
Citation:
Distinct Escape Pathway by Hepatitis C Virus Genotype 1a from a Dominant CD8+ T Cell Response by Selection of Altered Epitope Processing. 2015, 90 (1):33-42 J. Virol.
Journal:
Journal of virology
Issue Date:
2015
URI:
http://hdl.handle.net/10033/606256
DOI:
10.1128/JVI.01993-15
PubMed ID:
26446603
Type:
Article
Language:
en
ISSN:
1098-5514
Appears in Collections:
publications of the department experimental Virology([TC]EVIR)

Full metadata record

DC FieldValue Language
dc.contributor.authorWalker, Andreasen
dc.contributor.authorSkibbe, Kathrinen
dc.contributor.authorSteinmann, Eikeen
dc.contributor.authorPfaender, Stephanieen
dc.contributor.authorKuntzen, Thomasen
dc.contributor.authorMegger, Dominik Aen
dc.contributor.authorGroten, Svenjaen
dc.contributor.authorSitek, Barbaraen
dc.contributor.authorLauer, Georg Men
dc.contributor.authorKim, Arthur Yen
dc.contributor.authorPietschmann, Thomasen
dc.contributor.authorAllen, Todd Men
dc.contributor.authorTimm, Joergen
dc.date.accessioned2016-04-21T08:58:39Zen
dc.date.available2016-04-21T08:58:39Zen
dc.date.issued2015en
dc.identifier.citationDistinct Escape Pathway by Hepatitis C Virus Genotype 1a from a Dominant CD8+ T Cell Response by Selection of Altered Epitope Processing. 2015, 90 (1):33-42 J. Virol.en
dc.identifier.issn1098-5514en
dc.identifier.pmid26446603en
dc.identifier.doi10.1128/JVI.01993-15en
dc.identifier.urihttp://hdl.handle.net/10033/606256en
dc.description.abstractAntiviral CD8(+) T cells are a key component of the adaptive immune response against HCV, but their impact on viral control is influenced by preexisting viral variants in important target epitopes and the development of viral escape mutations. Immunodominant epitopes highly conserved across genotypes therefore are attractive for T cell based prophylactic vaccines. Here, we characterized the CD8(+) T cell response against the highly conserved HLA-B*51-restricted epitope IPFYGKAI1373-1380 located in the helicase domain of NS3 in people who inject drugs (PWID) exposed predominantly to HCV genotypes 1a and 3a. Despite this epitope being conserved in both genotypes, the corresponding CD8(+) T cell response was detected only in PWID infected with genotype 3a and HCV-RNA negative PWID, but not in PWID infected with genotype 1a. In genotype 3a, the detection of strong CD8(+) T cell responses was associated with epitope variants in the autologous virus consistent with immune escape. Analysis of viral sequences from multiple cohorts confirmed HLA-B*51-associated escape mutations inside the epitope in genotype 3a, but not in genotype 1a. Here, a distinct substitution in the N-terminal flanking region located 5 residues upstream of the epitope (S1368P; P = 0.00002) was selected in HLA-B*51-positive individuals. Functional assays revealed that the S1368P substitution impaired recognition of target cells presenting the endogenously processed epitope. The results highlight that, despite an epitope being highly conserved between two genotypes, there are major differences in the selected viral escape pathways and the corresponding T cell responses.en
dc.language.isoenen
dc.titleDistinct Escape Pathway by Hepatitis C Virus Genotype 1a from a Dominant CD8+ T Cell Response by Selection of Altered Epitope Processing.en
dc.typeArticleen
dc.contributor.departmentTwincore Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hanover and the Helmholtz Centre for Infection Research, Hanover, Germany.en
dc.identifier.journalJournal of virologyen

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