Consistent Beneficial Effects of Killer Cell Immunoglobulin-Like Receptor 2DL3 and Group 1 Human Leukocyte Antigen-C Following Exposure to Hepatitis C Virus

Article (PDF Available)inHepatology 51(4):1168-75 · April 2010with23 Reads
DOI: 10.1002/hep.23477 · Source: PubMed
Abstract
Unlabelled: Natural killer cells are a key component in the immune control of viral infections. Their functions are controlled by inhibitory receptors for major histocompatability complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIR). KIR2DL3 in combination with its cognate human leukocyte antigen (HLA)-C ligand has been shown to be associated with spontaneous resolution of viremia following hepatitis C virus (HCV) infection. In order to determine if this gene combination is advantageous across all potential outcomes following HCV exposure, we studied individuals with apparent resistance to HCV infection who remain seronegative and aviremic despite long-term injection drug use and also individuals chronically infected with HCV who successfully clear HCV with treatment. Homozygosity for KIR2DL3 in combination with group 1 HLA-C allotypes was more frequent in exposed seronegative aviremic individuals as compared to those with chronic HCV (25.0% versus 9.7%, P = 0.003, odds ratio [OR] = 3.1, 95% confidence interval [CI] = 1.3-7.1) in a model similar to that found for those spontaneously resolving HCV. In individuals undergoing treatment for HCV, those with KIR2DL3 and group 1 HLA-C were more likely to make a sustained virological response (SVR) (P = 0.013, OR = 2.3, 95% CI = 1.1-4.5). KIR and HLA-C protection in both treatment response and spontaneously resolving HCV was validated at the allelic level, in which KIR2DL3-HLA-Cw*03 was associated with SVR (P = 0.004, OR = 3.4, 95% CI = 1.5-8.7) and KIR2DL3/KIR2DL3-HLA-Cw*03 was associated with spontaneous resolution of HCV infection (P = 0.01, OR = 2.3, 95% CI = 1.2-4.4). Conclusion: KIR and HLA-C genes are consistently beneficial determinants in the outcome of HCV infection. This advantage extends to the allelic level for both gene families.

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Available from: Ann-Margaret Little, Oct 16, 2014
Consistent Beneficial Effects of Killer Cell
Immunoglobulin-Like Receptor 2DL3 and Group 1
Human Leukocyte Antigen-C Following Exposure to
Hepatitis C Virus
Susanne Knapp,1Usama Warshow,2Doha Hegazy,2Louise Brackenbury,1I. Neil Guha,3Andrew Fowell,3
Ann-Margaret Little,4Graeme J. Alexander,5William M.C. Rosenberg,6Matthew E. Cramp,2and Salim I. Khakoo1
Natural killer cells are a key component in the immune control of viral infections. Their
functions are controlled by inhibitory receptors for major histocompatability complex
(MHC) class I, including the killer cell immunoglobulin-like receptors (KIR). KIR2DL3 in
combination with its cognate human leukocyte antigen (HLA)-C ligand has been shown to
be associated with spontaneous resolution of viremia following hepatitis C virus (HCV)
infection. In order to determine if this gene combination is advantageous across all potential
outcomes following HCV exposure, we studied individuals with apparent resistance to HCV
infection who remain seronegative and aviremic despite long-term injection drug use and
also individuals chronically infected with HCV who successfully clear HCV with treatment.
Homozygosity for KIR2DL3 in combination with group 1 HLA-C allotypes was more
frequent in exposed seronegative aviremic individuals as compared to those with chronic
HCV (25.0% versus 9.7%, P0.003, odds ratio [OR] 3.1, 95% confidence interval [CI]
1.3-7.1) in a model similar to that found for those spontaneously resolving HCV. In
individuals undergoing treatment for HCV, those with KIR2DL3 and group 1 HLA-C were
more likely to make a sustained virological response (SVR) (P0.013, OR 2.3, 95% CI
1.1-4.5). KIR and HLA-C protection in both treatment response and spontaneously resolv-
ing HCV was validated at the allelic level, in which KIR2DL3-HLA-Cw*03 was associated
with SVR (P0.004, OR 3.4, 95% CI 1.5-8.7) and KIR2DL3/KIR2DL3-HLA-Cw*03
was associated with spontaneous resolution of HCV infection (P0.01, OR 2.3, 95%
CI 1.2-4.4). Conclusion: KIR and HLA-C genes are consistently beneficial determinants in
the outcome of HCV infection. This advantage extends to the allelic level for both gene
families. (HEPATOLOGY 2010;51:1168-1175.)
Hepatitis C virus (HCV) is a common chronic viral
infection. The virus poses a significant challenge
to the immune system as the majority of individ-
uals exposed to HCV fail to spontaneously clear the virus,
develop a chronic infection, and are predisposed to cirrhosis
and hepatocellular carcinoma. This failure to mount a suc-
cessful immune response is multifactorial in nature and in-
cludes abnormalities in T, B, and dendritic cell responses.
Abbreviations: HCV, hepatitis C virus; HLA, human leukocyte antigen; HLA-C1, group 1 HLA-C allotype; IFN, interferon; KIR, killer cell immunoglobulin-like
receptor; MHC, major histocompatability complex; PEG-IFN: pegylated-interferon; SVR, sustained virological response.
From the 1Department of Hepatology, Division of Medicine, Imperial College London, UK; 2Hepatology Research Group, Peninsula Medical School and Hepatology
Department Derriford Hospital, Plymouth, UK; 3Department of Hepatology, University of Southampton, Southampton, UK; 4Anthony Nolan Research Institute, Royal
Free Hospital, London, UK; 5Department of Medicine, University of Cambridge, Cambridge, UK; 6Institute of Liver Studies, University College, London, UK.
Received July 27, 2009; accepted November 22, 2009.
Supported by a Wellcome Trust Senior Clinical fellowship (to S.I.K.) and a grant from the DANA foundation.
Address reprint request to: Salim I. Khakoo, Department of Hepatology, Division of Medicine, Imperial College London, St Mary’s Hospital Campus, South Wharf Road,
London W2 1PG, UK. E-mail: skhakoo@imperial.ac.uk; fax: 44 207 724 9369.
Copyright © 2009 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.23477
Potential conflict of interest: Nothing to report.
1168
Natural killer (NK) cells are a subset of lymphocytes
that interact directly with virus-infected cells, but can also
activate dendritic cells and secrete Th1-type cytokines to
augment antiviral cytotoxic T-cell responses. Their re-
sponses are controlled by multiple activating and inhibi-
tory receptors and it is thought that the net inhibitory or
activating signal derived from these receptors determines
whether or not they become activated. NK cells are en-
riched in the liver in comparison to peripheral blood.
1
However, their role in the outcome of HCV infection
remains controversial. Initial work demonstrated that NK
cell killing was depressed in chronic HCV, that this could
be restored with interferon treatment,
2,3
and that they had
low levels of perforin.
4
Conversely, more recent work has
suggested that NK cell cytotoxicity in chronic HCV may
not be impaired,
5
and may even be augmented, with an
impairment of Th1 type cytokine secretion, and aug-
mented interleukin 10 (IL-10) secretion.
6-8
Phenotypic
studies have also given conflicting results in terms of ex-
pression of natural cytotoxicity receptors.
7,9
Alterations of
NK cell function have been related to the binding of the
HCV envelope proteins to CD81. Cross-linking of this
molecule can impair NK cell function in vitro.
10,11
How-
ever, this effect cannot be demonstrated for infectious
HCV particles and so is thought unlikely to occur in
vivo.
12
More recently, the changes in NK cell phenotype
and function have been associated with chronic exposure
to interferon-alpha (IFN-
).
8
One family of receptors that make a substantial contribu-
tion to the NK cell receptor repertoire are the killer-cell im-
munoglobulin-like receptors (KIR). The ligands for these
receptors are human leukocyte antigen (HLA) class I. Nearly
all NK cells express an inhibitory receptor for self-HLA class
I, which are important for both NK cell development and
function.
13,14
The KIRs are expressed exclusively on the
CD56dim subset of NK cells,
22
and this perforin and gran-
zyme-rich subset is reduced in individuals with chronic
HCV infection.
15
One feature of KIR, in comparison to
other NK cell receptors, is their substantial genetic diversi-
ty.
16
The KIR locus is rapidly evolving and exhibits signifi-
cant population diversity.
17
Thus, different individuals can
have different numbers of KIR genes. Furthermore, the li-
gand for the inhibitory KIR are subsets of the polymorphic
HLA class I molecules, HLA-A,-B, and -C, and this gener-
ates a further level of diversity.
18
Exposure to HCV leads to a number of clinical profiles
that may be determined by the host immune response.
Individuals may remain HCV Ab-negative and HCV
RNA-negative (seronegative, aviremic), HCV Ab-posi-
tive HCV RNA-negative (spontaneous resolver), and
HCV Ab-positive HCV RNA-positive (chronically in-
fected). This latter group may be further subdivided into
those who clear HCV RNA following therapy (sustained
virological responders) and those who do not. KIR2DL3
binds a subset of HLA-C allotypes that include HLA-
Cw*01, -Cw*03, -Cw*07, -Cw*08 and Cw*12, Cw*14
and Cw*16. Collectively, these are called the group 1
HLA-C (HLA-C1) allotypes. HLA-Cw*01 was shown to
be protective against HCV infection, and it was subse-
quently shown in two independent studies that individu-
als who spontaneously resolve infection are more likely to
have the gene KIR2DL3 in combination with its cognate
HLA-C1 ligands than those who remain chronically in-
fected.
19,20
This receptor:ligand combination is thought
to provide weaker inhibitory signals than other inhibitory
KIR:HLA-C receptor:ligand pairings and thus permit a
more responsive NK cell phenotype.
21,22
Furthermore,
although KIR3DS1 is protective against HCV-associated
hepatocellular carcinoma, it is not known if the HLA-C-
specific KIR influences the course of the other stages of
infection.
23
Seronegative aviremic individuals with a long history
of likely HCV exposure through high-risk injection drug
use have detectable HCV-specific T-cell responses in up
to 60% of cases, despite the absence of these conventional
markers of infection.
24,25
These individuals have been
previously termed “exposed uninfected”
31
with “unin-
fected” indicating the absence of demonstrable infection,
as defined by conventional antibody or RNA testing, at
the time of recruitment. The presence of T-cell responses
to nonstructural antigens may indicate that at some stage
they have had a replicative infection the magnitude of
which is not clear.
25
Nevertheless, they appear to have a
favorable immune response to HCV infection and, con-
sistent with an augmented T-cell response being impor-
tant to the HCV status of these individuals, they also have
an increased frequency of a high IL-12-producing allele.
26
It is noteworthy that IL-12 is also an NK cell activating
cytokine.
Another potent NK cell activating cytokine is interfer-
on-alpha (IFN-
). It increases both NK cell cytotoxicity
and IFN-
production. IFN-
in combination with riba-
virin forms the cornerstone of current anti-HCV thera-
pies. Treatment with IFN-
and ribavirin is effective in
over 50% of treated individuals, with the most important
determinant of outcome being viral genotype. However,
there is a considerable heterogeneity in response to IFN-
and host genetic factors also play a role.
27-29
Moreover, it
has also been shown that treatment-induced or enhanced
cellular immune responses are important in the outcome
of the treatment of HCV infection.
30-32
Successful treat-
ment with IFN-
has been associated with augmented
cytotoxicity and up-regulation of activating receptors, im-
plying a normalization of NK cell function.
3,9
These find-
HEPATOLOGY, Vol. 51, No. 4, 2010 KNAPP ET AL. 1169
ings are controversial because of recent work showing that
cytotoxicity and activating receptor expression are already
up-regulated in chronic HCV infection.
6-8
However,
IFN-
stimulated expression of MIC-A and -B, the ligand
for the activating NK cell receptor NKGD, is impaired on
monocyte-derived dendritic cells from HCV-infected in-
dividuals.
33
Therefore, the balance of activating and in-
hibitory interactions may be important in determining
the outcome of IFN-
treatment in HCV infection, and
this may be related to effects on target cells, in addition to
the NK cells themselves. The role of NK cell receptors in
HCV infection is thus complex. The aim of this study was
to study one aspect of this complexity, namely, to deter-
mine whether the gene combination of KIR2LD3 and
group 1 HLA-C is beneficial across the spectrum of po-
tential clinical outcomes following HCV exposure.
Patients and Methods
Seronegative Aviremic Cohort. Forty-eight HCV
exposed but seronegative aviremic cases were recruited
from Dartmoor prison (n 19) and from various needle
exchange and community drug services in Plymouth (n
29), between 2001 to 2007, with Ethical Committee ap-
proval. Individuals with a substantial history of past or
present intravenous drug use, sharing of needles or other
drug injection equipment, and who tested negative for
both HCV antibody and HCV RNA were included. No
other selection criteria were applied. The absence of HCV
antibodies was determined by third-generation enzyme-
linked immunosorbent assay (ELISA; Abbott IMx, Ab-
bott Diagnostics, Maidenhead, UK), and HCV RNA by
commercially available qualitative polymerase chain reac-
tion (PCR; Amplicor, Roche, Basel, Switzerland). All
were HIV-and hepatitis B surface antigen (HBsAg)-neg-
ative. Detailed information about drug-injecting behav-
ior was ascertained by means of a structured questionnaire
(Table 1). Mean duration of drug use was 8.4 years with
an estimated median number of injection episodes of over
4,000.
Intravenous Drug Use (IDU) Cohort. A total of 257
Caucasian individuals were recruited from the hepatology
clinics at Southampton General Hospital from 2003 to
2007, with Ethical Committee approval. These individu-
als were selected on the basis of race and having intrave-
nous drug usage as their only parenteral risk factor for
acquiring HCV (Table 1). HBsAg-and HIV-positive in-
dividuals were excluded. All individuals were positive by
second-generation ELISA and confirmed viremic using
the HCV COBAS Amplicor system (Roche). The mean
age was 43.9 years, 187 (72.8%) were male, and seven had
biopsy-proven cirrhosis.
Interferon-Treated Cohort. In all, 208 individuals
with chronic HCV underwent treatment for chronic
HCV infection. These individuals were selected on the
basis of having completed 80% of a course of IFN-
-
based treatment, and of these 32, individuals had dosage
modifications to their treatment regimen. A total of 165
were from the IDU cohort and the remainder denied IDU
as a risk factor for HCV infection. Of these, 18 had re-
ceived blood products, 20 had an unknown route of in-
fection, and five had potential exposure by needlestick
injury or tattooing. Individuals coinfected with HBV or
HIV were excluded. These individuals were also recruited
from the hepatology clinics at Southampton General
Hospital, with Ethical Committee approval between
2003 and 2007. All had viremia confirmed by the CO-
BAS Amplicor system. HCV genotyping was performed
using quantitative PCR (iQur, Southampton, UK). De-
tails of this cohort are given in Table 2. Individuals were
determined to have a sustained response to therapy if they
had a negative HCV-RNA test at the end of treatment
and a second negative test at least 6 months after cessation
of treatment using the same assays.
Retrospective Analysis. For the retrospective analysis
of resolved against chronically infected individuals the
Table 1. Demographics and Drug-Injecting Behavior of
Exposed Seronegative Aviremic and Chronically Infected IDU
Cohorts
Exposed Seronegative
Aviremic n (%)
Chronic IDU
n (%)
P
Value
Number of patients 48 257
Sex (male) 39 (81%) 187 (72.8%) 0.22
Age (years) 28.8 5.2 43.9 9.8 0.001
Caucasian 48 (100) 243 (94.6%) 0.14
Age at first injection drug use
(years) 19 5—
Duration of injection drug use
(years) 8.4 7.5 (0.5-24)
Lifetime injection episodes
(median n) 4380 (36-17,520)
Frequency of injection drug
use(n)
4-6 times a day 2 (4%)
2-3 times a day 33 (69%)
Daily 8 (17%)
Every few days/weekly 3 (6%)
Monthly or less 2 (4%)
Currently using (n) 13 (27%)
Sharing behavior (n)
Any sharing 48 (100%)
Shared needles 44 (91.7%)
Shared syringes 42 (87.5%)
Shared other drug injecting
paraphernalia 46 (95.8%)
Shared with someone
known to have HCV
infection 19 (39.5%)
1170 KNAPP ET AL. HEPATOLOGY, April 2010
previously described UK cohort of HCV exposed individ-
uals was used.
19
This group consisted of 341 individuals
(122 HCV Ab-positive, RNA-negative, and 219 HCV
Ab-positive, RNA-positive). The mean age was 41.9
years, 339 (99%) were Caucasian, and 227 (66.5%) were
male. There was no significance in these parameters be-
tween the Ab-positive, RNA-negative, and Ab-positive,
RNA-positive groups.
19
These individuals were recruited
between 1999 to 2003.
KIR and HLA Genotyping. Genomic DNA was ex-
tracted from peripheral blood lymphocytes convention-
ally using a salt precipitation method or the QIAamp
blood kit (Qiagen, Crawley, UK). KIR genotyping was
performed using the Lifematch kit (Tepnel, Stamford,
CT) and by PCR using sequence specific primers as de-
scribed.
19
HLA typing was performed by direct sequenc-
ing of PCR products.
34
HLA types that were not resolved
by sequencing or which gave unusual results were also
tested by sequence specific oligonucleotide probe typing
(PCR-SSOP), using commercial kits (Dynal, RELI SSO,
Wirral, UK).
Statistical Analysis. Statistical analysis was per-
formed using SPSS v. 17. The data presented were ana-
lyzed by chi-squared analysis unless otherwise stated. The
Bonferroni correction was applied where relevant. Bino-
mial logistic regression was performed using SPSS version
17 using the ENTER method.
Results
Group 1 HLA-C and KIR2DL3 Is Overrepresented
in Exposed Seronegative Aviremic Individuals. Forty-
eight individuals with apparent resistance to HCV infec-
tion from injection drug use were typed for HLA-C and
for KIR2DL2 and KIR2DL3. Twenty-four of these had
been tested for T-cell responses by ELISPOT assay,
24
of
whom 15 had a positive response to at least one of the
HCV antigens studied. The KIR genotypes in these 48
cases were compared to the 257 individuals with chronic
HCV acquired from IDU. Both groups had similar fre-
quencies of KIR2DL2 and KIR2DL3 alleles, and group 1
and 2 HLA-C alleles (Table 3). Furthermore, there was no
difference in the frequency of KIR2DL3 or KIR2DL2 in
combination with one group 1 HLA-C allele. However,
the combination of homozygosity for KIR2DL3 and 2
group 1 HLA-C alleles was found at a significantly greater
frequency in the exposed seronegative aviremic individu-
als as compared to chronically infected individuals
(25.0% versus 9.7%, P0.003, odds ratio [OR] 3.1,
95% confidence interval [CI] 1.3-7.1). This recessive
model of protection from HCV infection is similar to
that observed for antibody-positive HCV-exposed in-
dividuals.
19,20
Group 1 HLA-C in Combination with KIR2DL3 Is
Beneficial in Chronic HCV Infection. In all, 165 of the
IDU with chronic HCV infection and 43 additional in-
Table 2. Demographics of the Interferon-Treated Cohort
SVR n (%) No SVR n (%) PValue
Number of patients 107 101
Mean age 43.6 9.2 48.0 8.2 0.001
Male sex 74 (69.2) 71 (70.3) 0.88
Caucasian 99 (92.5) 96 (95.0) 0.45
Mean ALT 69.8 60.0 79 54.8 0.36
Dose reduction 14 (13.1) 17 (16.8) 0.34
Genotype
1 30 (28.0) 56 (55.4) 0.001
2/3 68 (63.6) 29 (28.7)
Other 1 (0.9) 1 (1.0)
Not available 8 (7.5) 15 (14.9)
Cirrhosis 9 (8.4) 4 (4.0) 0.25
Treatment:
IFN 3 (2.8) 29 (28.7) 0.001
IFNRib 7 (6.5) 6 (5.9)
PEG-IFN 1 (0.9) 4 (4.0)
PEG-IFNRib 96 (89.7) 62 (61.4)
Table 3. KIR and HLA-C Associations in the Exposed Seronegative Aviremic Individuals
Characteristic
Seronegative Aviremic
n (%)
Chronic
n (%) PValue (Pc) OR (95% CI)
Number of patients 48 257
KIR2DL2 22 (45.8) 136 (52.9) 036
KIR2DL3 43 (89.6) 223 (86.8) 0.59
Group 1 HLA-C 40 (83.3) 214 (83.3) 0.99
Group 2 HLA-C 28 (58.3) 181 (70.4) 0.10 0.59 (0.30-1.16)
KIR2DL2-C1 18 (37.5) 114 (44.4) 0.38
KIR2DL3-C1 36 (77.0) 187 (72.8) 0.75
KIR2DL3-C1 homozygous 12 (25.0) 25 (9.7) 0.003 (0.02) 3.1 (1.3-7.1)
KIR2DL3-C1 heterozygous 24 (50.0) 162 (63.0) 0.09 0.59 (0.30-1.14)
HEPATOLOGY, Vol. 51, No. 4, 2010 KNAPP ET AL. 1171
dividuals with chronic HCV infection had been treated
with IFN-
-based therapy in our outpatient clinics. The
frequencies of KIR2DL2 and KIR2DL3 were similar be-
tween those with and those without a sustained virologi-
cal response (SVR). Individuals who had an SVR to
IFN-
therapy were more likely to have at least one group
1 HLA-C allotype than those without SVR (87.9% versus
75.2%, P0.02, OR 2.4, 95% CI 1.1-5.3) (Table
4). Consideration of HLA-C with their cognate KIR re-
ceptors demonstrated that the beneficial effect of group 1
HLA-C was mediated in combination with KIR2DL3
(82.2% versus 67.3%, P0.01, OR 2.3, 95% CI
1.2-4.3), but not KIR2DL2 (43% versus 39.6%, P
0.1). Furthermore, binomial logistic regression in a model
considering group 1 HLA-C in the presence or the ab-
sence of KIR2DL3 demonstrated that SVR was associated
with group 1 HLA-C only in combination with
KIR2DL3 (P0.016, OR 2.49, 95% CI 1.19-
5.22). In contrast to our findings for the exposed seroneg-
ative aviremic individuals, we observed no statistically
significant association with homozygosity of KIR2DL3:
HLA-C group 1 being protective (P0.1). Logistic re-
gression analysis demonstrated that the effect of
KIR2DL3:HLA-C group 1 was independent of genotype,
age, ALT, dose modifications, duration, cirrhosis, and
gender within our cohort (Table 5). It was also indepen-
dent of whether the individual had received the current
gold standard of therapy (pegylated interferon and riba-
virin versus other protocols, P0.028, OR 2.34, 95%
CI 1.01-5.00), the use of pegylated versus standard
interferon (P0.033, OR 2.27, 95% CI 1.07-
4.82), and more weakly independent of the use of ribavi-
rin (P0.057, OR 2.13, 95% CI 0.98-4.66).
Standardized viral load data on the cohort was not avail-
able and therefore could not be included in this analysis.
Allelic Specificity of Protection by HLA-C and KIR.
Although the specificity of KIR2DL3 for HLA-C is de-
termined by residue 80 of the MHC class I heavy chain,
the binding of KIR to HLA-C is determined by several
additional residues. Recent work has shown that HLA-C
allelic diversity can affect binding of KIR to HLA-C, and
hence different HLA-C alleles within the C1 grouping
may have different protective effects in HCV infection.
22
To test this model we determined the frequency with
which specific group 1 HLA-C alleles were beneficial in
combination with KIR2DL3 in the IFN-treated popula-
tion. HLA-Cw*03 alleles were found more frequently in
combination with KIR2DL3 in individuals with SVR
than in those without SVR (22.4% versus 7.9%, P
0.004, OR 3.4, 95% CI 1.5-8.7) (Table 6). This
trend was observed in individuals treated with pegylated
IFN-
and ribavirin (21.8% with SVR versus 11.3%
without SVR, P0.06), and also in those with other
regimens (3 out 11 with SVR versus 1 out of 39 without
SVR P0.03, Fisher’s exact test). By logistic regression
analysis the beneficial effect of KIR2DL3-Cw*03 was also
independent of genotype, age, ALT, dose modifications,
duration, cirrhosis, and gender and the following treat-
ment regimens: pegylated interferon and ribavirin versus
Table 4. KIR and HLA-C Associations in the Interferon-Treated Individuals
SVR
n (%)
No SVR
n (%)
PValue
(Pc) OR (95% CI)
Number of patients 107 101
KIR2DL2 54 (50.5) 60 (59.4) 0.20
KIR2DL3 98 (91.6) 90 (89.1) 0.54
Group 1 HLA-C 94 (87.9) 76 (75.2) 0.02 (0.1) 2.4 (1.1-5.3)
Group 2 HLA-C 63 (58.9) 67 (66.3) 0.27
KIR2DL2-C1 46 (43.0) 40 (39.6) 0.62
KIR2DL3-C1 88 (82.2) 68 (67.3) 0.01 (0.1) 2.3 (1.2-4.3)
KIR2DL3-C1 homozygous 18 (16.8) 13 (12.9) 0.64
KIR2DL3-C1 heterozygous 70 (65.4) 55 (54.4) 0.11
Table 5. Logistic Regression Analysis of the Association of
KIR2DL3-C1 with the Outcome of Interferon Treatment
95% CI
POR Lower Upper
Age 40 .001 4.44 1.85 10.64
Pegylated IFN Ribavirin .003 7.66 1.98 29.67
Genotype 1 .021 0.18 0.04 0.77
KIR2DL3-C1 .028 2.34 1.01 5.00
Normal ALT .063 1.95 0.97 3.93
Race .218 0.38 0.08 1.76
Dose reduction .323 0.64 0.26 1.56
Cirrhosis .514 0.64 0.17 2.46
Duration 24 versus 48 .663 0.99 0.92 1.05
Sex .935 1.03 0.50 2.13
1172 KNAPP ET AL. HEPATOLOGY, April 2010
other protocols (P0.028, OR 3.06, 95% CI
1.13-8.31), the use of pegylated versus standard inter-
feron (P0.032, OR 2.94, 95% CI 1.10-7.84),
and the use of ribavirin (P0.019, OR 3.41, 95%
CI 1.23-9.49). Overall, HLA-Cw*12 in combination
with KIR2DL3 was also more common in those with
SVR (12.1% versus 4.0%, P0.03, OR 3.4, 95%
CI 1.0-14.6). The most frequent group 1 HLA-C al-
lele, HLA-Cw*07 (27% of all HLA-C alleles in this pop-
ulation), was not associated with SVR, indicating that the
described associations are not related purely to an effect of
study power.
As both treatment-induced and spontaneously resolv-
ing HCV infection are associated with KIR2DL3 and
group 1 HLA-C alleles, we determined if the same
HLA-C alleles were associated with spontaneously resolv-
ing HCV infection in our previously described UK co-
hort.
19
Data were available on 341 individuals (122 with
resolved infection and 219 persistently infected). Individ-
uals with spontaneous resolution of HCV, as compared to
those remaining persistently infected, were more likely to
have the combination of HLA-Cw*03 and KIR2DL3
(31.2% versus 19.2%, P0.01 OR 1.9, 95% CI
1.1-3.2) (Table 7). Furthermore, this was only beneficial
in individuals homozygous for KIR2DL3 (18.9% versus
9.1%, P0.01, OR 2.3, 95% CI 1.2-4.4), indicat-
ing that this is not purely an effect of HLA and so unlikely
to be due to linkage disequilibrium with another gene at
the MHC. HLA-Cw*12 in combination with KIR2DL3
was also found more frequently in those with resolved
HCV infection, but this did not reach statistical signifi-
cance. No specific effects of HLA-C allelism were noted in
the exposed seronegative aviremic cohort, with the fre-
quency of HLA-Cw*03 in combination with KIR2DL3
being 16.7% in the exposed seronegative aviremic indi-
viduals as compared to 18.3% in the chronically infected
IDU. The increase in group 1 HLA-C allotypes as com-
pared to the chronically infected individuals is thus re-
lated to small changes across the range of group 1 HLA-C
alleles.
Discussion
This work shows that KIR2LD3 and its group 1
HLA-C ligand are associated with favorable outcomes
across a spectrum of clinical profiles following HCV ex-
posure. These data, combined with our previous work
and that of Romero et al.,
20
show a beneficial influence of
these genes in HCV infection for the following subgroups
of individuals: those having an apparent degree of resis-
tance to HCV infection becoming established; those with
spontaneous resolution of established infection; and those
who resolve chronic infection with IFN-
-based treat-
ment.
The exposed seronegative aviremic individuals have no
detectable anti-HCV Ab or RNA, but up to 60% of these
individuals will have detectable T-cell responses to HCV
antigens, implying anti-HCV immunoreactivity.
24,35
The
finding of a high frequency of individuals homozygous for
KIR2DL3 and group 1 HLA-C alleles implies that they
are a population selected out by exposure to HCV. In-
deed, the frequency of this combination of genes is re-
markably similar to that found for Ab-positive RNA-
Table 6. KIR2DL3 and Group 1 HLA-C Associations in
Treatment Cohort
SVR
n (%)
No SVR
n (%) PValue (Pc) OR (95% CI)
Number of patients 107 101
2DL3Cw*01 6 (5.6) 6 (5.9) 0.92
2DL3Cw*03 24 (22.4) 8 (7.9) 0.004 (0.03) 3.4 (1.5-8.7)
2DL3Cw*07 48 (44.9) 45 (44.6) 0.96
2DL3Cw*08 13 (12.1) 6 (5.9) 0.12
2DL3Cw*12 13 (12.1) 4 (4.0) 0.03 (0.1) 3.4 (1.0-14.6)
2DL3Cw*14 4 (3.7) 2 (2.0) 0.57
2DL3Cw*16 5 (4.7) 9 (8.9) 0.22
Table 7. KIR2DL3 and Group 1 HLA-C Associations in the Spontaneously Resolving Cohort
Resolved
n (%)
Persistent
n (%)
PValue
(Pc) OR (95% CI)
Number of patients 122 219
KIR2DL3 and HLA-C alleles
2DL3Cw*01 7 (5.7) 10 (4.6) 0.42
2DL3Cw*03 38 (31.2) 42 (19.2) 0.01 (0.08) 1.9 (1.1-3.2)
2DL3Cw*07 70 (57.4) 115 (52.5) 0.38
2DL3Cw*08 12 (8.2) 11 (5.0) 0.09 (0.1) 2.06 (0.82-5.21)
2DL3Cw*12 11 (9.0) 13 (5.9) 0.26
2DL3Cw*14 1 (0.8) 3 (1.4) 0.65
2DL3Cw*16 10 (8.2) 18 (8.2) 0.99
KIR2DL3 number and HLA-Cw*03
2DL2/2DL3Cw*03 14 (11.4) 20 (9.1) 0.49
2DL3/2DL3Cw*03 23 (18.9) 20 (9.1) 0.01 (0.02) 2.3 (1.2-4.4)
HEPATOLOGY, Vol. 51, No. 4, 2010 KNAPP ET AL. 1173
negative individuals.
19
Thus, they appear to be distinct
from this subgroup of individuals on the basis of a lack of
anti-HCV Ab, but not KIR:HLA genotype. This implies
that that they do not have an additional NK cell protec-
tion above that observed with the Ab-positive, RNA-neg-
ative group of individuals. Consistent with the beneficial
association in the exposed seronegative aviremic cases, the
advantageous effect of the KIR:HLA genotype in sponta-
neous clearers was strongest in those who acquired HCV
infection from IDU, suggesting that the size of inoculum
is important. The chronically infected IDU comparator
population for the exposed seronegative aviremic individ-
uals had a frequency of KIR2DL3-C1 similar to that of a
US cohort of Caucasians with chronic HCV.
36
This im-
plies that the KIR:HLA genotypes in our population are
representative of Caucasians with chronic HCV infec-
tion, and not due to a selection bias.
KIR2DL3-C1 was associated with SVR in our IFN-
-
treated individuals, but homozygosity for these genes was
not. One possibility is that the activation of NK cells by
pharmacological doses of IFN-
can overcome the inhi-
bition mediated by other NK cell receptors and hence NK
cells that coexpress KIR2DL3 and KIR2DL1 may be an-
tiviral in this context, but not in spontaneously resolving
infection. Alternatively, KIR protection could also be re-
lated to an effect on KIR-positive T cells in IFN-
-in-
duced resolution, but NK cells in spontaneous resolution,
as individuals who are homozygous for KIR2DL3-C1
would be predicted to have more NK cells that expressed
KIR2DL3 than those who were heterozygous for either
gene. However, we cannot rule out that in all stages of
chronic infection it is related to an effect of KIR2DL3 on
the KIR-positive T cells, which are usually of the effector
memory phenotype, and can be found in chronic HCV at
similar numbers to healthy controls.
37
Furthermore, the
odds ratio is smaller for this group of individuals than for
the exposed seronegative aviremic cohort, implying that
although these alleles are associated with viral clearance
they may be less important than in spontaneously resolv-
ing infection. Thus, they are one of several factors that
determine outcome following IFN-
-based therapy, of
which the most important is viral genotype. One compli-
cating factor in the interpretation of the data is that cir-
rhosis is an adverse factor in response to antiviral therapy
for HCV. Recent work has suggested that homozygosity
for KIR2DL3-C1 is associated with the development of
cirrhosis in chronic HCV infection and that KIR and
HLA-C may affect the severity of liver disease following
transplantation for HCV infection.
36,38
Thus, the benefi-
cial effect of KIR2DL3-C1 homozygosity on viral clear-
ance may be balanced by the adverse effect that this gene
combination has on disease stage. This could be one ex-
planation as to why we have not observed KIR2DL3-C1
homozygosity as an advantageous factor in these individ-
uals.
Our observations of KIR:MHC extend to the allelic
level for HLA-C for the IFN-treated patients and also
those resolving infection. Overall, across all groups we
found a trend toward most group 1 HLA-C alleles apart
from Cw*07 being beneficial. There is no clear data that
shows that HLA-Cw*07 is a stronger binder of KIR than
other HLA-C allotypes, but it may be crossreactive with
KIR2DL1 and this crossreactivity may be relevant as a
mechanism for generating alternative inhibitory signals.
39
MHC has a complex influence on both NK cell education
and function
40
and NK cells from HLA-Cw*07-positive
individuals make significantly more IFN-
when chal-
lenged with an MHC class I-negative target than those
with other HLA-C allotypes.
40
These data suggest that
NK cells from HLA-Cw*07-positive individuals may be
“licensed” differently from those with other group 1
HLA-C allotypes. The effect of this may be to respond to
activating signals with a different magnitude of IFN-
secretion. One effect of this could be a change in the NK
cell response to HCV infection. Furthermore, KIR2DL2
and KIR2DL3 segregate as alleles at a single locus and
protection in HCV is only observed with KIR2DL3.
Thus, allelism at both the KIR and the HLA-C loci appear
to influence the outcome of HCV infection. As KIR2DL3
is sensitive to the peptide bound by HLA-C this raises the
possibility that HCV-derived peptides may also affect NK
cell reactivity. Although functional work is required to
tease out the precise mechanisms of inhibitory KIR-me-
diated protection in viral infections, our data underscore
the relevance of this gene family in the immune response
to HCV.
Acknowledgment: We thank Karen Parker and all the
hepatology specialist nurses at Southampton General
Hospital for their assistance in performing this study.
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HEPATOLOGY, Vol. 51, No. 4, 2010 KNAPP ET AL. 1175
    • "However, the mechanism by which this IFNL4 variant is associated with spontaneous and/or treatmentinduced clearance or HCV infection are still incompletely understood. In addition, variants in the killer cell immunoglobulin-like receptors (KIR) gene locus, encoding a highly polymorphic family of natural killer cell receptors, have repeatedly confirmed to be associated with response to therapy and outcomes of hepatitis C [8][9][10] . In functional studies, Ahlenstiel and co-workers demonstrated that this association might be attributed to a differential natural killer (NK) cell activation and function in the context of this KIR/HLA interaction [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity. Methods: A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both. NK cell IFN-γ response was analysed by FACS. IL-12 and IL-18 secretion of monocytes was studied by ELISA. In blocking experiments anti-IL-12/anti-IL-18 were used. Results: Following stimulation of total PBMCs with R848 we found NK cell IFN- γ responses to vary with the IL-28B genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-γ(+)NK cells. When isolated NK cells were studied no such associations were observed, indicating an indirect association between IL-28B genotype and NK cell activity. Accordingly, we found R848-stimulated monocytes of patients with a T/T genotype to be significantly less effective in triggering NK cell IFN- γ production than monocytes from carriers of a non-T/T genotype. In line with these findings we observed monocytes from T/T patients to secrete significantly lower concentrations of IL-12 than monocytes from non-T/T individuals. Conclusions: Our data indicate that monocytes from carriers of an IL-28B T/T genotype display a reduced ability to stimulate NK cell activity and, thus, provide a link between IL-28B genotype and NK functions.
    Full-text · Article · Sep 2016
    • "2. KIRs differ in the relative inhibitory or activating effects they have on NK cells (Moesta et al. 2008), and the strength of this inhibition or activation seems to affect the possibility of mortality. For both hepatitis C and hepatitis B, the genotype associated with the weakest possible inhibitory interaction involving HLA-C (homozygosity for KIR2DL3 and HLA-C1) offers an increased chance of clearing the infection (Gao et al. 2010; Khakoo et al. 2004; Knapp et al. 2010). Conversely, genotypes which encode certain highly inhibitory KIRs and their known HLA ligands are associated with delayed progression to AIDS (Martin et al. 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Killer-cell immunoglobulin-like receptors (KIRs) are encoded by one of the most polymorphic families in the human genome. KIRs are expressed on natural killer (NK) cells, which have dual roles: (1) in fighting infection and (2) in reproduction, regulating hemochorial placentation. Uniquely among primates, human KIR genes are arranged into two haplotypic combinations: KIR A and KIR B. It has been proposed that KIR A is specialized to fight infection, whilst KIR B evolved to help ensure successful reproduction. Here we demonstrate that a combination of infectious disease selection and reproductive selection can drive the evolution of KIR B-like haplotypes from a KIR A-like founder haplotype. Continued selection to survive and to reproduce maintains a balance between KIR A and KIR B. Electronic supplementary material The online version of this article (doi:10.1007/s00251-016-0935-9) contains supplementary material, which is available to authorized users.
    Article · Aug 2016
    • "HLA‐C group 2 (HLA‐C2) alleles are involved in inhibitory KIR2DL1 and in the activation of KIR2DS132333435. KIR2DL3 and its ligand HLA‐C1 have been associated with an increased likelihood of spontaneous [36,37] and treatment‐induced HCV clearance [37,38]. This association is attributed to differential natural killer (NK) cell activation and function in the context of this KIR/HLA interaction [39]. "
    [Show abstract] [Hide abstract] ABSTRACT: Human T-cell leukemia virus type 1 (HTLV-1), hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) are prevalent worldwide, and share similar means of transmission. These infections may influence each other in evolution and outcome, including cancer or immunodeficiency. Many studies have reported the influence of genetic markers on the host immune response against different persistent viral infections, such as HTLV-1 infection, pointing to the importance of the individual genetic background on their outcomes. However, despite recent advances on the knowledge of the pathogenesis of HTLV-1 infection, gaps in the understanding of the role of the individual genetic background on the progress to disease clinically manifested still remain. In this scenario, much less is known regarding the influence of genetic factors in the context of dual or triple infections or their influence on the underlying mechanisms that lead to outcomes that differ from those observed in monoinfection. This review describes the main factors involved in the virus-host balance, especially for some particular human leukocyte antigen (HLA) haplotypes, and other important genetic markers in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other persistent viruses, such as HIV and HCV.
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