Dataset Information

Extracellular HCV-core protein induces an immature regulatory phenotype in NK cells: implications for outcome of acute infection.

ABSTRACT:

Background

Hepatitis C viral (HCV) proteins, including core, demonstrate immuno-modulatory properties; however, the effect of extracellular core on natural killer (NK) cells has not previously been investigated.

Aims

To characterise NKs in acute HCV infection over time, and, to examine the effect of exogenous HCV-core protein on NK cell phenotype and function.

Methods

Acute HCV patients (n?=?22), including 10 subjects who spontaneously recovered, were prospectively studied. Flow-cytometry was used to measure natural cytotoxicity and to phenotype NKs directly ex vivo and after culture with HCV-core protein. Microarray analysis was used to identify pathways involved in the NK cell response to exogenous HCV-core.

Results

Direct ex vivo analysis demonstrated an increased frequency of immature/regulatory CD56bright NKs early in acute HCV infection per se which normalized with viral clearance. Natural cytotoxicity was reduced and did not recover after viral clearance. There was a statistically significant correlation between the frequency of CD56bright NKs and circulating serum levels of HCV core protein. In vitro culture of purified CD56bright NK cells with HCV-core protein in the presence of IL-15 maintained a significant proportion of NKs in the CD56bright state. The in vitro effect of core closely correlates with NK characteristics measured directly ex vivo in acute HCV infection. Pathway analysis suggests that HCV-core protein attenuates NK interferon type I responses.

Conclusions

Our data suggest that HCV-core protein alters NK cell maturation and may influence the outcome of acute infection.

SUBMITTER: Golden-Mason L

PROVIDER: S-EPMC4116173 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Extracellular HCV-core protein induces an immature regulatory phenotype in NK cells: implications for outcome of acute infection.

Golden-Mason Lucy L Golden-Mason Lucy L Hahn Young S YS Strong Michael M Cheng Linling L Rosen Hugo R HR

PloS one 20140730 7

<h4>Background</h4>Hepatitis C viral (HCV) proteins, including core, demonstrate immuno-modulatory properties; however, the effect of extracellular core on natural killer (NK) cells has not previously been investigated.<h4>Aims</h4>To characterise NKs in acute HCV infection over time, and, to examine the effect of exogenous HCV-core protein on NK cell phenotype and function.<h4>Methods</h4>Acute HCV patients (n = 22), including 10 subjects who spontaneously recovered, were prospectively studied. ...[more]

PMID: 25076408

Similar Datasets

Project description: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.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.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.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.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.

Dataset Information

Extracellular HCV-core protein induces an immature regulatory phenotype in NK cells: implications for outcome of acute infection.

Background

Aims

Methods

Results

Conclusions

Publications

Extracellular HCV-core protein induces an immature regulatory phenotype in NK cells: implications for outcome of acute infection.

Similar Datasets

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