studies

690A AASLD ABSTRACTS HEPATOLOGY, October, 2015
mice compared with wild-type mice displayed elevated plasma
ALT (150 +/-11.94 vs 108+/-4), and more fat accumulation
in the liver. These data suggest that BHB production by the
beta-oxidation pathway, and sensing by GPR019a, protects
from alcohol induced acute liver injury.
Disclosures:
The following authors have nothing to disclose: Yonglin Chen, Irma Garcia-Martinez,
Xinshou Ouyang, Rafaz Hoque, Wajahat Z. Mehal
980
Interferon lambda 3 (IL28B) and interferon lambda 4
genotypes and resistance-associated variants in HCV
genotype 1 and 3 infected patients
Kai-Henrik Peiffer, Lisa Sommer, Simone Susser, Julia Dietz, Dany
Perner, Caterina Berkowski, Stefan Zeuzem, Christoph Sarrazin; J.
W. Goethe University, Medizinische Klinik 1, Frankfurt am Main,
Germany
Background and aims: In the era of pegylated interferon
(Peg-IFN) single nucleotide polymorphisms (SNPs) in the interferon
lambda 3 (IFN-L 3, also known as IL28B) and interferon
lambda 4 genes (IFN-L4) were strong predictors for achieving
SVR in patients with hepatitis C virus (HCV) infection. For many
direct acting antiviral (DAA) combination regimens only weak
or no correlation with IFN-L SNPs was observed. However, little
is known about a potential selection of resistance-associated
variants (RAVs) by IFN-L genotypes, which may influence virologic
treatment response. This study aims to analyze the prevalence
of rare and common RAVs in NS3, NS5A and NS5B
to currently approved DAAs in a large European population
in correlation to IFN-L3 and IFN-L4 genotypes. Materials and
methods: Samples of 633 patients chronically infected with
HCV genotype 1a (n=259), 1b (n=323) and 3 (n=51) were
genotyped for rs12979860 (IFN-L3, also known as IL28B) and
ss469415590 (IFN-L4) by real-time PCR. RAVs in NS3, NS5A
and NS5B were detected via population-based sequencing and
correlated with the IFN-L SNPs. Results: No significant correlation
was found between IFN-L genotypes and rare and common
RAVs within NS3 and NS5B genes (i.e. Q80K, C316N and
S556G/N/R). In contrast, the NS5A RAV Y93H was detected
frequently in HCV genotype 1b (14%) and was significantly
associated with the beneficial rs12979860 (IFN-L3) C/C- and
the ss469415590 (IFN-L4) TT/TT-genotype (p=0.0005 and
p=0.0016, respectively). Therefore, prevalence of the Y93H
variant is much higher in IFN-L3 C/C (27%) and IFN-L4 TT/TT
(28%) than in non-C/C (10%) and non-TT/TT (10%) genotyped
patients respectively. In addition, Y93H was found to be significantly
associated with higher viral loads independent from
the IFN-L genotype (p=0.000936 in all HCV genotypes). Summary:
The major NS5A RAV Y93H is significantly associated
with the presence of beneficial IFN-L3 and IFN-L4 SNPs and a
high baseline viral load in HCV genotype 1 infected patients,
which may explain a lack or inverse correlation of treatment
response with IFN-L genotype in NS5A inhibitor containing
IFN-free regimens and might be of clinical interest for consideration
of IFN-free treatment options for patients with known
IFN-L3 or IFN-L4 status. In addition Y93H was found to be
associated with a higher viral load independent from the IFN-L
genotype, which may partially explain in HCV genotype 1b the
known paradox phenomenon of higher viral loads in patients
with the beneficial IFN-L3 genotype.
Disclosures:
Stefan Zeuzem - Consulting: Abbvie, Bristol-Myers Squibb Co., Gilead, Merck
& Co., Janssen
Christoph Sarrazin - Advisory Committees or Review Panels: Bristol-Myers
Squibb, Janssen, Merck/MSD, Gilead, Roche, Abbvie, Janssen, Merck/MSD;
Consulting: Merck/MSD, Merck/MSD; Grant/Research Support: Abbott, Roche,
Merck/MSD, Gilead, Janssen, Abbott, Roche, Merck/MSD, Qiagen; Speaking
and Teaching: Gilead, Novartis, Abbott, Roche, Merck/MSD, Janssen, Siemens,
Falk, Abbvie, Bristol-Myers Squibb, Achillion, Abbott, Roche, Merck/MSD, Janssen
The following authors have nothing to disclose: Kai-Henrik Peiffer, Lisa Sommer,
Simone Susser, Julia Dietz, Dany Perner, Caterina Berkowski
981
MicroRNA-130a inhibit HCV production through regulating
host immune responses and lipid metabolism
Xiaoqiong Duan 1 , Limin Chen 1,2 ; 1 Institute of Blood Transfusion,Chinese
Academy of Medical Sciences (CAMS) /Peking
Union Medical College (PUMC), Chengdu, China; 2 Toronto General
Research Institute,University of Toronto, Toronto, ON, Canada
Background & Aims: MicroRNAs (MiRNAs)a class of small
non-coding RNAs that regulate messenger RNA (mRNA)
expression, play pivotal role in the regulation of viral infections.
In our previous study, we demonstrated that over-expression
of miR-130a inhibited HCV replication by restoring
the host innate immune response. But the detailed mechanism
remains unclear. In this study, we aimed to identify and validate
the potential target genes of miR-130a to explore the
possible regulation mechanism between miR-130a and host
immune responses in the context of HCV infection. Methods:
Four algorithms, miRanda, TargetScan, PITA and RNAhybrid
were used to predict the potential targets of miR-130a. To validate
the target genes, MiR-130a mimic were transfected to
Huh7.5.1 cells for 48h and total RNAs were extracted and
reverse-transcribed to cDNA. Quantitative real-time PCR and
western blot were used to measure target gene expressions
with or without miR-130a overexpression. Results: Three potential
target genes pyruvate kinase (PKLR), interleukin 18 binding
protein (IL18BP) and low density lipoprotein receptor (LDLR)
were identified by software algorithms and validated by qRT-
PCR. miR-130a over-expression inhibited the expression levels
of PKLR, IL18BP and LDLR significantly both mRNA and at protein
levels. Functional analysis suggested that these genes are
involved in lipid metabolism and host immune response. Quite
interestingly, Cholesterol-25-hydroxylase (CH25H), an interferon-stimulated
gene playing critical role in lipid metabolism
and anti-HCV innate immunity, was stimulated by miR-130a. In
addition, miR-130a overexpression increased the expression
levels of interferon γ (IFNγ) and inhibited HCV entry, possibly
through its targeting to IL18BP and LDLR, respectively. Conclusion:
miR-130a inhibits HCV production through regulating
host immune responses and lipid metabolism. Mir-130a may
be developed as a potential drug candidate for the treatment
of HCV infection.