PMID- 30769005
OWN - NLM
STAT- MEDLINE
DCOM- 20201201
LR  - 20201201
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Print)
IS  - 0168-8278 (Linking)
VI  - 70
IP  - 6
DP  - 2019 Jun
TI  - ERAP1 allotypes shape the epitope repertoire of virus-specific CD8(+) T cell 
      responses in acute hepatitis C virus infection.
PG  - 1072-1081
LID - S0168-8278(19)30111-4 [pii]
LID - 10.1016/j.jhep.2019.01.034 [doi]
AB  - BACKGROUND & AIMS: Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms 
      are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory 
      disorders, including ankylosing spondylitis and Behcet's disease. 
      Disease-associated ERAP1 allotypes exhibit distinct functional properties, but it 
      remains unclear how differential peptide trimming in vivo affects the repertoire 
      of epitopes presented to CD8(+) T cells. The aim of this study was to determine 
      the impact of ERAP1 allotypes on the virus-specific CD8(+) T cell epitope 
      repertoire in an HLA-B*27:05(+) individual with acute hepatitis C virus (HCV) 
      infection. METHODS: We performed genetic and functional analyses of ERAP1 
      allotypes and characterized the HCV-specific CD8(+) T cell repertoire at the 
      level of fine epitope specificity and HLA class I restriction, in a patient who 
      had acquired an HCV genotype 1a infection through a needle-stick injury. RESULTS: 
      Two hypoactive allotypic variants of ERAP1 were identified in an individual with 
      acute HCV infection. The associated repertoire of virus-derived epitopes 
      recognized by CD8(+) T cells was uncommon in a couple of respects. Firstly, 
      reactivity was directed away from classically immunodominant epitopes, 
      preferentially targeting either novel or subdominant epitopes. Secondly, 
      reactivity was biased towards longer epitopes (10-11-mers). Despite the patient 
      exhibiting favorable prognostic indicators, these atypical immune responses 
      failed to clear the virus and the patient developed persistent low-level 
      infection with HCV. CONCLUSIONS: ERAP1 allotypes modify the virus-specific CD8(+) 
      T cell epitope repertoire in vivo, leading to altered immunodominance patterns 
      that may contribute to the failure of antiviral immunity after infection with 
      HCV. LAY SUMMARY: Endoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role 
      in antigen presentation. Genetic variants of ERAP1 (leading to distinct 
      allotypes) are linked with specific autoinflammatory disorders, such as 
      ankylosing spondylitis and Behcet's disease. We found that ERAP1 allotypes 
      modified the repertoire of virus-specific CD8(+) T cell epitopes in a patient 
      with hepatitis C virus, leading to an altered pattern of immunodominance that may 
      have contributed to the failure of antiviral immunity in this patient.
CI  - Copyright (c) 2019 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Kemming, Janine
AU  - Kemming J
AD  - Department of Medicine II, University Medical Center Freiburg, Faculty of 
      Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, 
      University of Freiburg, Freiburg, Germany.
FAU - Reeves, Emma
AU  - Reeves E
AD  - Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, 
      University Hospital Southampton, Southampton, United Kingdom.
FAU - Nitschke, Katja
AU  - Nitschke K
AD  - Department of Medicine II, University Medical Center Freiburg, Faculty of 
      Medicine, University of Freiburg, Freiburg, Germany.
FAU - Widmeier, Vanessa
AU  - Widmeier V
AD  - Department of Medicine II, University Medical Center Freiburg, Faculty of 
      Medicine, University of Freiburg, Freiburg, Germany.
FAU - Emmerich, Florian
AU  - Emmerich F
AD  - Institute of Transfusion Medicine and Gene Therapy, University Hospital Freiburg, 
      Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Hermle, Tobias
AU  - Hermle T
AD  - Renal Division, University Medical Center Freiburg, Faculty of Medicine, 
      University of Freiburg, Freiburg, Germany.
FAU - Gostick, Emma
AU  - Gostick E
AD  - Division of Infection and Immunity, Cardiff University School of Medicine, 
      Cardiff, United Kingdom.
FAU - Walker, Andreas
AU  - Walker A
AD  - Institute for Virology, Heinrich Heine University, Dusseldorf, Germany.
FAU - Timm, Jorg
AU  - Timm J
AD  - Institute for Virology, Heinrich Heine University, Dusseldorf, Germany.
FAU - Price, David A
AU  - Price DA
AD  - Division of Infection and Immunity, Cardiff University School of Medicine, 
      Cardiff, United Kingdom.
FAU - Hofmann, Maike
AU  - Hofmann M
AD  - Department of Medicine II, University Medical Center Freiburg, Faculty of 
      Medicine, University of Freiburg, Freiburg, Germany.
FAU - Thimme, Robert
AU  - Thimme R
AD  - Department of Medicine II, University Medical Center Freiburg, Faculty of 
      Medicine, University of Freiburg, Freiburg, Germany.
FAU - James, Edward
AU  - James E
AD  - Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, 
      University Hospital Southampton, Southampton, United Kingdom.
FAU - Neumann-Haefelin, Christoph
AU  - Neumann-Haefelin C
AD  - Department of Medicine II, University Medical Center Freiburg, Faculty of 
      Medicine, University of Freiburg, Freiburg, Germany. Electronic address: 
      christoph.neumann-haefelin@uniklinik-freiburg.de.
LA  - eng
GR  - 100326/Z/12/Z/WT_/Wellcome Trust/United Kingdom
GR  - CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190213
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (Minor Histocompatibility Antigens)
RN  - EC 3.4.11.- (Aminopeptidases)
RN  - EC 3.4.11.- (ERAP1 protein, human)
SB  - IM
MH  - Acute Disease
MH  - Aminopeptidases/*genetics
MH  - CD8-Positive T-Lymphocytes/*immunology
MH  - Epitopes, T-Lymphocyte/*immunology
MH  - Hepacivirus/immunology
MH  - Hepatitis C/*immunology
MH  - Humans
MH  - Minor Histocompatibility Antigens/*genetics
PMC - PMC6527866
OTO - NOTNLM
OT  - ERAP1
OT  - Epitope repertoire
OT  - HLA-B*27
OT  - Hepatitis C virus
OT  - T cells
EDAT- 2019/02/16 06:00
MHDA- 2020/12/02 06:00
PMCR- 2019/06/01
CRDT- 2019/02/16 06:00
PHST- 2018/06/25 00:00 [received]
PHST- 2019/01/30 00:00 [revised]
PHST- 2019/01/31 00:00 [accepted]
PHST- 2019/02/16 06:00 [pubmed]
PHST- 2020/12/02 06:00 [medline]
PHST- 2019/02/16 06:00 [entrez]
PHST- 2019/06/01 00:00 [pmc-release]
AID - S0168-8278(19)30111-4 [pii]
AID - 10.1016/j.jhep.2019.01.034 [doi]
PST - ppublish
SO  - J Hepatol. 2019 Jun;70(6):1072-1081. doi: 10.1016/j.jhep.2019.01.034. Epub 2019 
      Feb 13.