PMID- 27057987
OWN - NLM
STAT- MEDLINE
DCOM- 20180412
LR  - 20181202
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Print)
IS  - 0168-8278 (Linking)
VI  - 65
IP  - 2
DP  - 2016 Aug
TI  - Sequence variations in HCV core-derived epitopes alter binding of KIR2DL3 to 
      HLA-C *03:04 and modulate NK cell function.
PG  - 252-8
LID - S0168-8278(16)30097-6 [pii]
LID - 10.1016/j.jhep.2016.03.016 [doi]
AB  - BACKGROUND & AIMS: Both natural killer (NK) cells and human leukocyte antigen 
      (HLA)/killer cell immunoglobulin like receptor (KIR) interactions have been shown 
      to play an important role in the control, clearance and progression of hepatitis 
      C virus (HCV) disease. Here we aimed at elucidating the effects of viral peptides 
      derived from HCV on HLA stabilization, changes in KIR binding and primary NK cell 
      function. METHODS: Transporter for antigen presentation-deficient 722.221 cells 
      stably transfected with HLA-C *03:04 were used to screen 200 overlapping peptides, 
      covering the non-structural protein 3 (NS3) and core protein of HCV genotype 1, 
      for their ability to bind and stabilize HLA-C *03:04. Binding of KIR2DL3 to the 
      HLA-peptide complex was assessed using a KIR2DL3-IgG fusion construct. Primary NK 
      cells were isolated from healthy donors to investigate the effects of identified 
      peptides on KIR2DL3(+) NK cell function. RESULTS: Thirty-one peptides able to 
      stabilize HLA-C *03:04 were identified. One 9mer peptide, YIPLVGAPL, resulted in 
      significantly higher KIR2DL3 binding to HLA-C *03:04(+) 722.221 cells and 
      suppression of primary KIR2DL3(+) NK cell function. Interestingly this sequence 
      exhibited a high frequency of mutations in different HCV genotypes. These 
      genotype-specific peptides showed lower HLA-C *03:04 stabilization, decreased 
      binding of the inhibitory KIR2DL3 and lower inhibition of NK cell function. 
      CONCLUSIONS: Taken together we show that a viral peptide derived from the core 
      protein of HCV genotype 1 binding to HLA-C *03:04 results in a sequence-dependent 
      engagement of the inhibitory NK cell receptor KIR2DL3, while the large majority 
      of the remaining 30 HLA-C *03:04 binding HCV core peptides did not. These data 
      show that sequence variations within HCV can modulate NK cell function, providing 
      potential pathways for viral escape. LAY SUMMARY: We identified a HCV peptide 
      that dampens NK cell responses, and thereby possibly prevents killing of infected 
      cells through this part of the innate immune system. This is facilitated via 
      presentation of the viral peptide on HLA *03:04 to the inhibitory KIR receptor 
      KIR2DL3 on NK cells. Naturally occurring sequence mutations in the peptide alter 
      these interactions making the inhibition less efficient.
CI  - Copyright (c) 2016 European Association for the Study of the Liver. All rights 
      reserved.
FAU - Lunemann, Sebastian
AU  - Lunemann S
AD  - Department for Viral Immunology, Heinrich-Pette-Institute, Hamburg, Germany.
FAU - Martrus, Gloria
AU  - Martrus G
AD  - Department for Viral Immunology, Heinrich-Pette-Institute, Hamburg, Germany.
FAU - Holzemer, Angelique
AU  - Holzemer A
AD  - Department of Internal Medicine, University Hospital Eppendorf, Hamburg, Germany.
FAU - Chapel, Anais
AU  - Chapel A
AD  - Department for Viral Immunology, Heinrich-Pette-Institute, Hamburg, Germany.
FAU - Ziegler, Maja
AU  - Ziegler M
AD  - Department for Viral Immunology, Heinrich-Pette-Institute, Hamburg, Germany.
FAU - Korner, Christian
AU  - Korner C
AD  - Department for Viral Immunology, Heinrich-Pette-Institute, Hamburg, Germany.
FAU - Garcia Beltran, Wilfredo
AU  - Garcia Beltran W
AD  - Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
FAU - Carrington, Mary
AU  - Carrington M
AD  - Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Cancer and 
      Inflammation Program, Leidos Biomedical Research, Inc., Frederick National 
      Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Wedemeyer, Heiner
AU  - Wedemeyer H
AD  - Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical 
      School, Hannover, Germany.
FAU - Altfeld, Marcus
AU  - Altfeld M
AD  - Department for Viral Immunology, Heinrich-Pette-Institute, Hamburg, Germany. 
      Electronic address: marcus.altfeld@hpi.uni-hamburg.de.
LA  - eng
GR  - R01 AI067031/AI/NIAID NIH HHS/United States
GR  - T32 GM007753/GM/NIGMS NIH HHS/United States
GR  - F31 AI116366/AI/NIAID NIH HHS/United States
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20160404
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Epitopes)
RN  - 0 (HLA-C Antigens)
RN  - 0 (Receptors, KIR2DL3)
SB  - IM
CIN - J Hepatol. 2016 Aug;65(2):237-9. PMID: 27212248
MH  - Epitopes
MH  - HLA-C Antigens
MH  - Hepatitis C
MH  - Humans
MH  - *Killer Cells, Natural
MH  - Receptors, KIR2DL3
PMC - PMC4955726
MID - NIHMS789807
OTO - NOTNLM
OT  - HCV
OT  - HLA
OT  - KIR
OT  - NK
EDAT- 2016/04/09 06:00
MHDA- 2018/04/13 06:00
PMCR- 2017/08/01
CRDT- 2016/04/09 06:00
PHST- 2015/05/27 00:00 [received]
PHST- 2016/03/23 00:00 [revised]
PHST- 2016/03/30 00:00 [accepted]
PHST- 2016/04/09 06:00 [entrez]
PHST- 2016/04/09 06:00 [pubmed]
PHST- 2018/04/13 06:00 [medline]
PHST- 2017/08/01 00:00 [pmc-release]
AID - S0168-8278(16)30097-6 [pii]
AID - 10.1016/j.jhep.2016.03.016 [doi]
PST - ppublish
SO  - J Hepatol. 2016 Aug;65(2):252-8. doi: 10.1016/j.jhep.2016.03.016. Epub 2016 Apr 
      4.