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Tissue Antigens ISSN 0001-2815

REVIEW ARTICLE

Innate and adaptive genetic pathways in HCV infection


R. Buchanan, T. Hydes & S. I. Khakoo
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

Key words
hepatitis C; immunity, adaptive; immunity,
innate; interferon; interleukins
Correspondence
Salim Khakoo
Faculty of Medicine
University of Southampton
Mailpoint 811
Level E South Academic Block
Southampton General Hospital
Tremona Road
Southampton SO16 6YD
UK
Tel: +023 8079 6671/5099
Fax: +023 8051 1761
e-mail: S.I.Khakoo@soton.ac.uk

Abstract
Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic
factors that govern it. Polymorphisms affecting both the innate and adaptive immunity
determine the outcome of exposure. However the innate immune system appears to
play a greater role in determining treatment-associated responses. Overall the effects
of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host
genetics determines the disease phenotype has not been as intensively studied. This
review summarizes our current understanding of innate and adaptive immunogenetic
factors in the outcome of HCV infection. It focuses on how they relate to resolution
and the progression of HCV-related liver disease, in the context of current and future
treatment regimes.

doi: 10.1111/tan.12540

Introduction

Resolution of HCV

Hepatitis C virus (HCV) is an enveloped RNA virus. It infects


up to 160 million people worldwide and causes thousands of
deaths each year from complications of liver diseases including
cirrhosis, liver failure and hepatocellular carcinoma. (1) In
general, following exposure a minority (2040%) of individuals will clear the virus. However in some circumstances,
such as following exposure to contaminated anti-rhesus D
immunoglobulin, the rate of spontaneous clearance may be
greater than 50%. This may be related to both host and viral
factors. Immunogenetic studies of clearance of HCV, both spontaneously and under the influence of type I interferons, have
identified genetic determinants that are associated with viral
clearance. These include polymorphisms affecting both innate
and adaptive immune systems and have acted as molecular signposts for understanding the immunology of hepatitis C. Such
findings originally gave opportunities for novel immunotherapeutic strategies. However with the recent advent of a range of
directly acting anti-viral therapies this is becoming less important. Nevertheless they continue to give useful insights into
how the immune system interacts with RNA viruses, may be
important for stratification of patients for different therapeutic
regimens and could underpin the development of a preventative
vaccine for HCV.

Innate immunity

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The categorization of individuals into the easily identifiable


groups of chronically infected (anti-HCV Ab positive, HCV
RNA-positive) and spontaneously resolved (anti-HCV Ab positive, HCV RNA-negative) has meant that immunogenetic studies can be reasonably well controlled, in comparison to diseases
of low prevalence where healthy individuals are compared to
those with the disease of interest. Identification of disease association factors was originally performed using candidate gene
approaches but the advent of genome-wide technologies produced one of the spectacular results in the field of infectious
disease immunogenetics.
IFNL3 (IL-28B)

The role of IFNL3 polymorphisms in determining HCV


resolution was showed in 2009 following four landmark
genome-wide association studies (GWAS) (25). All four
studies identified single nucleotide polymorphisms (SNPs),
rs12979860 (860) and rs8099917 (917), lying just upstream
of the IFNL3 gene, to be associated with the response to
PEGylated interferon/ribavirin (PI/RBV) treatment to chronic
HCV infection (Figure 1). This was remarkable in determining
outcome in diverse populations from the USA (European and
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Genetic pathways in HCV

R. Buchanan et al.

Figure 1 A number of different single nucleotide polymorphisms (SNPs) around the IFNL3/4 region are associated with the outcome of hepatitis C
virus (HCV) infection. This diagram illustrates the location of these SNPs around this region, their relationship with both the IFNL3 and IFNL4 genes and
a summary of their associations on the outcome of HCV infection. (G, HCV genotype, IFNL, interferon lambda, SVR, sustained virological response,
PI/Rib, PEGylated interferon/Ribavirin).

African-American individuals), Europe, Japan and Australia,


without the presence of discernable additional positive signals.
In the USA cohort of genotype 1 (G1) infection, in patients of
both European and Afro-Caribbean ancestry the 860-CC allele
was protective (5, 6), and the 917-TT genotype was associated
with increased responsiveness to PI/RBV in G1 patients from
Australia, Japan and Switzerland (24). Importantly both
SNPs predicted spontaneous, as well as treatment-associated
resolution (7).
The association between IFNL3 and treatment outcome in
HCV Genotype 2 (G2) and Genotype 3 (G3) is less clear. Some
data have associated the 860-CC genotype with sustained virological response (SVR) in HCV G2 and HCV G3 when combined with rapid virological response (RVR: an early marker
of treatment success) results; but these studies failed to show
a correlation with the 917 genotype (8). Importantly in direct
232

comparisons the effects of 917-TT on the outcome of therapy in G2/3 patients are much lower than for G1/4 patients
(4). This association has been shown in one study for HCV
genotype 2 but it is restricted to only those patients who do
not mount an RVR (4). Others have failed to show a correlation with SVR but have associated the 860-CC genotype with
RVR at 4 weeks in HCV G3 patients (9). At odds with data
suggesting that the 860-CC genotype in G2/3 infected individuals is associated with protection, is the observation that this
genotype has a higher prevalence in G2/3 infected patients than
in non-infected controls. This implies that individuals with the
860-CC genotype are less able to spontaneously resolve G2/3
infection (10). The statistical knock-on effect from this is that
more study power is required to identify a protective effect in
G2/3, than G1 infection. A recent study by Eslam et al. looked
at a large cohort of 736 patients who were infected with a
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R. Buchanan et al.

mixture of HCV G2 (n = 149) and HCV G3 (n = 587) from


Australia and Europe. This showed there was a significant association between SVR and the favourable 860-CC and 917-TT
genotypes (11). Thus the association between IFNL3 genes and
SVR rates following treatment of HCV G2 and G3 infection
is present, but less marked than for G1 infected patients. On
the basis of current data this is most probably to be related
to lower protective effect of IFNL3 on G2/3 infection, and
therefore a reduction in statistical power of disease association
studies.
Newer regimes
HCV treatment is undergoing a step change and it is likely that
in the near future we will be using directly acting anti-viral
therapies, rather than interferons, as first line. In G1 infection
PEG/RBV is now given with a protease inhibitor. Boceprevir
and Telaprevir are first generation drugs, with response rates
>50% better than with the PEG/RBV alone. Both the 860-CC
and 917-TT genotypes are associated with significantly higher
rates of SVR in treatment nave patients (1214). This is not
surprising given that in this group of patients IFN responsiveness is still a key factor in their outcome. This association has
not however been shown in treatment experienced patients. Retrospective sub-group analysis of the RESPOND 2 trial and the
REALIZE data, as well as a smaller study in an East Asian population showed that in treatment experienced patients, who are
by definition less interferon responsive, the impact of the IFNL3
gene is at best limited (1416).
Interferon free regimes for hepatitis C promise more effective
treatment, shorter duration of therapy and fewer side effects.
The major limitation for the introduction of these therapies is
currently their prohibitive cost. Early studies suggested IFNL3
might still play a role in predicting patient outcome. In 2012
Chu et al. reviewed the significance of IFNL3 on data from the
INFORM study published 2 years earlier. This dose escalation
study assessed viral response to Mericitabine plus Danoprevir at 14 days in a mixture of treatment experienced and nave
patients. In total 83 out of 87 patients in the study were genotyped for the 860 SNP and patients with the 860-CC polymorphism had a slightly greater mean reduction in viral RNA than
those without (17). A larger trial, SOUND C2, looked at treatment response to Faldaprevir and Deleobuvir in 362 treatment
nave patients and showed a clear relationship between SVR at
12 weeks and the 860-CC allele (18).
However, the association between SVR and IFNL3 860-CC
has not been observed elsewhere. Poordad et al. looked at
the combination of ABT-450/r-Ombitasvir, Dasabuvir and ribavirin in treatment experienced, cirrhotic patients and showed
no association (19). Further studies have looked at other combinations of polymerase inhibitors with and without ribavirin
in treatment nave, experienced, cirrhotic and non-cirrhotic
patients and have failed to show any relationship between the
two (2022).
2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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Genetic pathways in HCV

Overall the role for IFNL3 genotyping in interferon free


regimes is very limited. The astonishing success of these therapies means few patients are failing to respond or relapse and
therefore it is difficult to show any meaningful associations
with treatment failure. It will be interesting to see whether any
associations are unmasked if SVR rates fall as interferon free
therapy is made freely available to decompensated cirrhotic
patients.
Spontaneously resolving infection
In addition to treatment induced resolution 860-CC has
been shown to be associated with spontaneous resolution
of HCV infection. This effect has been confirmed for the
917-TT SNP, across multiple ethnicities and also in a single
source outbreak (4, 23, 24). However in a large multicenter
GWAS study a second signal was found in the HLA class II
region, indicative of additional pathways to resolution in this
cohort (25). Conversely, IFNL3 protection may not extend
to exposed uninfected individuals. These individuals are
at high-risk of HCV infection due their injection drug-use
behaviour, remain negative for anti-HCV Ab, but can have
T cell responses (26, 27). In a UK study of such individuals
there was no over-representation of the protective IFNL3
genotype as compared with those with chronic HCV infection.
Furthermore there was a significantly lower frequency of this
genotype as compared with the anti-HCV Ab-positive individuals. Thus in spontaneous resolving HCV infection multiple
pathways to clearance of infection may coexist in a specific
population (28).
Mechanistic insights
The 917 and 860 SNPs are in strong linkage disequilibrium
(LD) with each other and also a SNP in the coding region of
IFNL3 and one in the 3 UTR (29). Despite the strength of the
correlations the mechanism by which these SNPs determine
resolution is not clear. IFNL3 is a type III interferon and a
simple model would be that the protective SNPs are associated
with higher levels of IFNL3 and hence lead to an enhanced
immune response. This is a plausible model, however it should
also be noted that higher levels of interferon-stimulated genes
(ISGs) are associated with lower levels of SVR following
PEG/RBV treatment. Early studies were unable to elucidate
consistent correlates of SNPs with IFNL3 at protein or mRNA
levels. Similarly the coding SNP has not been associated with
altered activity.
More recently it has been shown that the protective SNPs
marked an insertion-deletion (indel) in the 5 non-coding
region of the gene (TT/-G polymorphism rs368234815, previously ss469415590 in chromosome 19). This deletion (-G)
at rs368234815 (815) is associated with production of a novel
179aa protein, designated IFNL4 which has been shown to
exert potent antiviral properties in vitro with similar efficacy
to IFNL3 (30). Although in strong LD with 860-TT it has been
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Genetic pathways in HCV

possible to compare the impact of each genotype by studying


discordant individuals.
IFNL4 has a stronger association with a decline in HCV
RNA within the first 28 days of PEG/RIB treatment in
African-American patients, and in Caucasian patients it
was significantly better at predicting SVR in HCV and human
immunovirus (HIV) co-infected individuals (3133). These
findings are consistent with the observation that IFNL4 is
associated with a worse clinical outcome, and at a cellular level
a dampened antiviral response (34).
Possible mechanisms have been proposed to explain why
this occurs, several studies have associated IFNL4 with higher
background levels of ISGs which has previously been shown
to paradoxically attenuate interferon responsiveness in the context of HCV infection. Other data have identified an association
between the TT allele of the indel and an augmented IFNL3
response (32, 35, 36). In reality IFNL4 may exert its effects
through a combination of both mechanisms. The link between
the IFN lambda family and ISG induction is poorly understood.
However, a recent study by Duong et al. identified an association between IFNLR1, IFNL3 and IFNL4 in liver biopsy specimens. IFNL4 has recently been shown to act via IFNLR1 and
therefore it may be reasonable to suggest it is the differential
expression of the receptor rather than the ligand that has the
impact on ISG transcription (30, 37).
An additional model has been proposed in which a protective
SNP (rs4803217), in LD with rs12979860, has been found
in the 3 non-coding region of the IFNL3 gene (Figure 1)
(29). This SNP is associated with more robust expression
of IFNL3 by impairing mRNA-mediated degradation of the
IFNL3 transcript.
Overall, it is increasingly clear that other SNPs, in tight
LD with IFNL3 exert influence over the host response to
HCV infection, and that although IFNL3 has proved to be an
excellent genetic marker for predicting the response to HCV
infection and treatment, it is certainly not the sole effector gene
which underpins the mechanism by which this occurs. Although
progress has been made this mechanism remains opaque and
warrants further research.
Other innate immune genes

Whilst IFNL3 provides the most consistent genetic association in HCV, other innate polymorphisms also play a role.
The killer cell immunoglobulin-like receptors (KIR) are a
multi-gene family that control NK cell, and to a lesser extent
T-cell, activity. As a polymorphic multi-gene family they may
not be represented well on the arrays used for GWAS studies
and therefore dedicated molecular typing strategies are required
identify genes associated with HCV outcome. The KIR and
their MHC class I ligands have been shown to be associated
with the outcome of HCV infection in a number of studies.
The first association reported was between the inhibitory
KIR2DL3 in combination with its group 1 HLA-C ligands and
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R. Buchanan et al.

spontaneous resolution in both Caucasians and African Americans (38). This favourable allelic combination was validated
in a large Puerto-Rican cohort and has also been associated
with SVR to dual therapy, with mapping to the allelic level
and seronegativity in the high risk exposed-seronegative
group (39, 42). This has been rationalized as KIR2DL3 having a weaker binding affinity for group 1 HLA-C alleles,
than KIR2DL2, which segregates as an allele of KIR2DL3.
KIR2DL2 also has a higher affinity for group 2 HLA-C alleles. More recently it has been shown that KIR2DL3-positive
NK cells respond more efficiently to changes in peptide
repertoire than KIR2DL2-positive cells (43). Therefore the
mechanism underlying this association may be complex. The
absence of a KIR2DL3:group 1 HLA-C interaction appears
to be detrimental to HCV outcome in a number of different
populations (4446).
However similar findings have not been showed in all studies.
Significant other allelic associations include a protective role
of KIR3DS1 and HLA-Bw4 against chronicity and for treatment response, independent of KIR2DL3:HLA-C1 (38). This
stands true for HIV co-infected patients also (47). Furthermore
the protective influence of KIRs appears to be maintained in
the era of triple therapy, with the KIR3DL1:HLA-BBw4 genotype being favourable for SVR (48). Additionally KIR2DS3 a
component of the B group of haplotypes may be detrimentally
associated with HCV outcome. Interestingly KIR susceptibility factors appear to synergize with the non-protective 860-TT
IFNL3 SNP, as showed for both KIR2DS3 (49) and HLA-C2
homozygosity (45).
Functional correlates of NK cell activity with KIR outcome
have been less easy to define. It is clear that NK cells are important for resolving HCV infection (50), however the role of KIR
in these studies has been less clear. KIR-positive NK cells are
activated in the acute phase of HCV infection (51). Expansions
of KIR-positive NK cells have been noted in individuals resolving HCV infection (52). Furthermore in exposed seronegative
individuals it is the frequency of KIR+, NKG2A NK cells,
which appears most related to outcome (53). These studies have
all analysed peripheral blood and it may be that the liver compartment may need to be studied to identify NK cells which
have been directly exposed to HCV.
Finally the complexity of the KIR system is showed in a study
showing that KIR2DL2 may enhance the protective effect of
HLA-B*57 (54). This association is particularly interesting as
it is not because of a direct KIR:ligand effect on NK cell activation, but a possible synergistic interaction between KIR2DL2
and the adaptive immune response. The strength of this work
is that KIR2DL2 augments protection related to HLA class I
alleles for HIV and HTLV3 in addition to HCV. One hypothesis for this is that KIR2DL2 on CD8 T-cells may prevent
activation-induced cell death when the T-cell receptor engages
with an HLA-B57:peptide complex, perhaps preventing T-cell
exhaustion following HCV infection.
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R. Buchanan et al.

Adaptive immunity

Human leukocyte antigens

Functional studies have shown the role of both CD4 and CD8
T cell responses in the spontaneous clearance of HCV infection (55). Given this and the diversity of HLA genes it is not
surprising that HLA determinants have been extensively studied in the outcome of HCV infection. Importantly polymorphisms in the HLA class II region associated with spontaneous
resolution of HCV have been identified by a non-hypothesis
driven approach in addition to the multiple candidate gene
studies (25). This confirmed the findings of previous smaller
studies from France, UK and Italy that HLA-DQB1*0301 was
protective (25, 56, 57), although a large US-based study only
observed this association in black patients whilst showing different protective alleles, DQB1*0501 and DRB1*0101 in Caucasian patients (58). Additionally HLA-DRB1*1101, which is
in LD with HLA-DQB1*0301 has been found to be protective in a number of populations (59, 60). This was originally
shown in a European study and subsequently in a US cohort.
In an attempt to address discrepancies across studies a US
group recently performed high resolution HLA genotyping on
a multi-racial cohort of more than 700 US women (61). Protective alleles against chronicity included DRB1*0101, B*5701,
B*5703, and C*0102. DQB1*0301 was also protective in-line
with other studies, but only amongst HIV negative women.
DRB1*0301 was associated with failure to resolve in this
population.
DRB1*0101, DRB1*0401 and DRB1*15 were shown to promote resolution in the Irish cohort of individuals exposed to
G1 HCV through contaminated anti-rhesus D immunoglobulin
(62). In the case of DRB*1101, which is also protective against
chronicity (59), several HCV-derived epitopes potentially presented by this MHC molecule have been identified, although
a single immunodominant epitope has yet to be defined (63).
However this data is lacking for the other HLA class II
alleles.
HLA class I alleles, especially HLA-B alleles have shown
protective effects on the outcome of HCV infection. HLA-B*27
has been shown to be protective in an cohort of Irish women
infected with HCV G1b from a single source (62). This HLA
variant selects for a cluster of HCV escape mutations within
the HLA-B*27 specific viral epitope which can evade recognition by cytotoxic T-lymphocytes (CTLs). However these
variants may be restricted by an associated viral fitness cost
(64). Similar associations were not found in an East German cohort which included patients infected with G1b HCV
through contaminated anti-rhesus D immunoglobulin (65). In
addition, Neumann-Haefelin et al. showed that the positive
effect of HLA B*27 is restricted to G1 virus, as the G3a epitope
peptide is not recognized by CD8 T cell lines raised against the
G1 virus (66).
Other HLA class I alleles have been associated with HCV
chronicity. The Irish anti-D study associated HLA B*08 with
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Genetic pathways in HCV

viral persistence. This has also been observed in a US population but again was not observed in East German patients (62,
65, 66). Other HLA class I alleles associated with a negative
outcome, include HLA-A*2301 and HLA-C*04 in linkage disequilibrium with HLA-B*53 (67).
In HCV G2 infected patients from Ghana, expression of
HLA-B*57 is significantly protective against chronicity (68).
This is corroborated in an HCV G1 pre-dominant US population, although the association was much weaker (67, 69).
Genotype-specific variations are seen between translated viral
sequences from HCV G1a and HCV G2 HLA-B*57 restricted
epitopes, which may result in improved recognition and subsequent viral clearance in HLA*B57 positive patients. This
theory is supported by the fact that some sequences within
HCV G2 epitopes have showed stronger binding to HLA-B*57.
Conversely escape from HLA-B57 response CTL responses
may result in chronicity (69). Additionally the generation of
peptide epitopes is complex, involving proteasomal cleavage
of viral peptides, transport into the endoplasmic reticulum,
and then loading onto the HLA class I molecule. Many of
these genes are located within the MHC and tapasin is located
on the centromeric end of the locus, distant from the HLA
class I alleles. Tapasin has a non-synonymous coding SNP
in exon 4 and the G allele of tapasin was associated with
protection against chronic HCV infection in association with
HLA-B or HLA-C alleles with aspartate at residue 114 of
the MHC class I heavy chain. This residue forms part of
a putative tapasin binding region. This protection correlated
with CTL activity, and was found in a European, but not
US population (70).
HLA allele diversity clearly has a significant impact on
whether HCV is cleared spontaneously or develops into a
chronic infection. However, these associations, such as many
aspects of the immunogenetic response to HCV are both hostand virus-specific and therefore should be interpreted within the
context of host ethnicity and viral genotype (Figure 2).
Polymorphisms affecting the cytokine response

Immune cell behaviour is dictated by cell to cell interactions but also largely by the cytokine microenvironment in
which they reside. In general cytokines of the Th1 and Th2
groups have been studied. Th1 cytokines including IL-12,
tissue necrosis factor (TNF)- and IFN induce a strong
cytotoxic T-cell response, whereas the cytokines, IL-10,
IL-13 and transforming growth factor (TGF)- promote a
more regulatory environment. The former is more conducive
to creating a stronger CD8 T-cell response and viral clearance. A number of polymorphisms within cytokine genes
have been shown to influence HCV outcomes (Table 1) (7,
7184). It is worth noting however that none of these polymorphism reached significance in the four GWAS studies,
again showing the overwhelming strength of the IFNL3
effect.
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Genetic pathways in HCV

genotype and the likelihood of developing HCC (87). The association between the IFNL3 860 genotype and HCC is also
unclear. Comparison of 167 explanted livers, which included
61 with and 106 without HCC, showed a significant association with the TT genotype, whereas there was no association in
268 Spanish patients with chronic HCV (88, 89).
Natural-killer cells

Figure 2 The outcome of hepatitis C virus (HCV) infection has different


protective genetic associations that vary according to population studied,
viral genotype and outcome measured. This diagram illustrates the
interrelationship between these factors and four key factors human
leukocyte antigen (HLA) class I, HLA class II, KIR and the IFNL3/4 genes.
(G, HCV genotype).

Genetic inuences of disease progression


IFNL3 and interferon lambda

IFNL3 is clearly associated with resolution of HCV either spontaneously or with treatment. Recent data has looked at the
association with disease progression. Sato et al. published a
meta-analysis in 2014, which evaluated the impact of the 860
and 917 polymorphisms on liver fibrosis, inflammation and
steatosis. The analysis included 28 studies from Asia, Europe
and the United States and included over 10,000 patients (85).
Liver fibrosis was positively associated with 860-CC genotype
in pooled and treatment nave patients. There was also a significant association with the 860-CC genotype and inflammatory activity in the liver and severe steatosis in treatment nave
patients. The 917-TT genotype was weakly associated with a
reduced risk of developing severe steatosis and consistent with
the 860-CC findings it was also weakly associated with an
increased risk of fibrosis (85).
There is little and conflicting data analysing the link between
hepatocellular carcinoma and IFNL3 polymorphisms. Sato
et al. studied the age of onset of HCC in 351 Asian patients
with biopsy proven HCC and compared it to the IFNL3 917
SNP. TG and GG genotypes were associated with a significantly
lower age of onset than the homozygous TT allele (86). However, Joshita et al. looked at 511 Japanese patients of whom
69 had HCC and identified no correlation between IFNL3 917
236

In addition to resolution, the influence of KIR genotype


on disease progression following HCV infection has been
studied. The activating KIR3DS1:HLA-Bw480I epitope combination is known to be protective against the development
of HCC in the presence of CHC (41). Surprisingly however
KIR3DS1:HLA-Bw480T has been associated with poorer overall survival in patients with HCC followed curative treatment,
whereas KIR2DL2:HLA-C1 and KIR2S5 have been linked
to a longer time to recurrence rate, with the latter also been
associated with higher overall survival (90). This is interesting
as these are the alleles which are non-protective in HCV treatment outcomes, suggesting a role for activating KIRs as well
as KIR2DL2 in preventing cancer development and prognosis.
Importantly KIR2DL2 is part of the B group of haplotypes
which contain larger numbers of activating KIRs, and so may be
acting as a marker for an activating KIR phenotype. Similarly
activated NK cells are known to be protective against fibrosis
because of their ability to kill stellate cells and release IFN.
Conversely a recent study of 145 Brazilian patients showed
no association between all 16 KIR genes and progression to
fibrosis and cirrhosis. Although this finding may need to be confirmed in a second cohort because of a slight lack of study power
(91). The KIR ligand genotype, HLA-C1C2 however was found
to be present at higher frequencies in patients with advanced
fibrosis and cirrhosis in this study. It therefore appears that
whereas KIRs and their ligands continue to exert an effect on
HCV disease progression, interactions with malignant cells and
the intrahepatic environment including stellate cells are influenced by different alleles to those involved in viral clearance.
Future outlooks

Progress in HCV infection has moved rapidly, from its discovery in 1989 to cure rates of nearly 100% in phase 3 clinical
studies. It is however noteworthy that Duggal et al. only
ascribed 15% of variation in resolution of HCV infection to the
findings of their GWAS study (25). The future for the understanding of genetic variations in determining HCV-related
outcomes could certainly take a leap forward in the era of
next generation sequencing. These technologies have made it
possible to map a whole human genome in days, or even hours,
with rapidly declining financial costs. Whole exome sequencing, involving the analysis of protein-coding genes only, has
reduced costs further while being functionally focused. In
practice however the strength of these techniques appears to
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Tissue Antigens, 2015, 85, 231240

R. Buchanan et al.

Genetic pathways in HCV

Table 1 Summary of association between HCV resolution and cytokine polymorphisms


Gene

Single nuclear polymorphism

Clinical inuence

IL-12

3-UTR A allele of the p40 subunit of


IL-12

IFN

Promoter region at position -764 of


IFN

TNF

TNF-238A allele

IL-18

Polymorphisms within the IL-18


binding protein

Linked to protection against chronicity in addition to improved SVR


rates. It has also been associated with seronegativity in high risk
groups in UK but not German Caucasians
Associated with both spontaneous resolution and interferon
response. This is probably a result of the favourable G allele having
a high binding afnity for the transcription factor NFB, leading to
increased IFN expression
Linked to chronicity in a European population, although this has not
been reproduced in other Caucasian cohorts and was conversely
found to be protective in black individuals. In terms of treatment
outcomes, there is a consensus among studies that there is no
effect of any TNF variants within the Caucasian population
The IL-18 binding protein has the capability of binding both IL-18 and
IFN. It has been shown to inuence spontaneous clearance in a
large scale candidate gene analysis from the United States
Association with spontaneous viral clearance

IL-10

TGF-

Regulatory polymorphisms within


the IL-18 gene promoter
Allelic variation within the
-108A + -819T + -592A haplotype
and 108 bp10.R + -3575T +
-2763 + -108A + -819T + -592A
extended haplotype
IL-10-592A
IL-10-1082GG
IL-10-1082GA
SNPs leading to poor IL-10
production
Promoter polymorphisms within
TGF-, including the C allele of
the SNP found at -509
Mutations leading to low levels of
TGF-

References
(7174)

(75)

(7682)

(6)

(83)

Inuence sustained virological response

(79, 84)

Associated with spontaneous clearance


Associated with chronicity
Associated with spontaneous clearance
Accelerate progression to brosis

(92)
(92)
(79, 92)

Associated with spontaneous clearance

(93)

Associated with spontaneous clearance

HCV, hepatitis C virus; IL, interleukin; SNPs, single nucleotide polymorphisms; SVR, sustained virological response; TNF, tissue necrosis factor.

lie in their ability to identify novel single mutations for rare


genetic disorders. Our current understanding of even baseline
variation in the human genome is rudimentary. Therefore
dissecting pathways in conditions with more complex genetic
associations, such as HCV, will require very large study populations, not least because of the heterogeneity at both host
and viral levels that has been encountered in these studies.
Perhaps different populations will provide different pieces in
this immunogenetic jigsaw. It will be important to understand
how these factors interact in order to give a complete picture.
At present it appears that different individuals resolve hepatitis
C through discretely acting protective pathways, but fail to
resolve infection through the interaction of non-favourable
polymorphisms, or indeed the absence of favourable polymorphisms which appear to synergise to dramatically reduce the
chance of resolving (28, 49). One model could be:
p(resolution) = p(A and not B) or p(not A and B)
or p(A and B) = [p(A) p( B )]
+ [p( A) p(B)] + [p(A) p(B)]

2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Tissue Antigens, 2015, 85, 231240

(1)

p(non resolution) = p(not A) and p(not B)


= P( A) P( B)

(2)

where A and B are favourable factors from discrete immune


pathways.
In these equations protective factors are additive, but their
absence is multiplicative. This provides a possible explanation
for the large increase in odds ratios observed when considering
susceptibility to chronic infection. Understanding how protective and susceptibility factors work together will be important
to gain the complete immunogenetic picture.
Whilst understanding the genetic polymorphisms and the
outcome of HCV is the first step in stratified medicine, immediate clinical benefits may be limited in this era of directly
acting anti-viral drugs which can clear HCV in virtually all individuals. However the possibility of emerging drug resistance,
understanding which individuals may progress to cirrhosis and
HCC, and the pursuit of a vaccine should drive the use of the
newest technologies to answer this next generation of questions
for hepatitis C.
237

Genetic pathways in HCV

Conict of interest

Salim Khakoo has received an educational grant from Bristol


Myers Squibb. Ryan Buchanan has a received a Gilead fellowship award.

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