Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response.
OBJECTIVE
Clinical significance of molecules involving innate immunity in treatment response remains unclear. The aim is to elucidate the mechanisms underlying resistance to antiviral therapy and predictive usefulness of gene quantification in chronic hepatitis C (CH-C).


METHODS
We conducted a human study in 74 CH-C patients treated with pegylated interferon alpha-2b and ribavirin and 5 nonviral control patients. Expression of viral sensors, adaptor molecule, related ubiquitin E3-ligase, and modulators were quantified.


RESULTS
Hepatic RIG-I, MDA5, LGP2, ISG15, and USP18 in CH-C patients were up-regulated at 2- to 8-fold compared with nonhepatitis C virus patients with a relatively constitutive Cardif. Hepatic RIG-I, MDA5, and LGP2 were significantly up-regulated in nonvirologic responders (NVR) compared with transient (TR) or sustained virologic responders (SVR). Cardif and RNF125 were negatively correlated with RIG-I and significantly suppressed in NVR. Differences among clinical responses in RIG-I/Cardif and RIG-I/RNF125 ratios were conspicuous (NVR/TR/SVR = 1.3:0.6:0.4 and 2.3:1.3:0.8, respectively). Like viral sensors, ISG15 and USP18 were significantly up-regulated in NVR (4-fold and 2.3-fold, respectively). Multivariate and receiver operator characteristic analyses revealed higher RIG-I/Cardif ratio, ISG15, and USP18 predicted NVR. Lower Cardif in NVR was confirmed by its protein level in Western blot. Also, transcriptional responses in peripheral blood mononuclear cells to the therapy were rapid and strong except for Cardif in not only a positive (RIG-I, ISG15, and USP18) but also in a negative regulatory manner (RNF125).


CONCLUSIONS
NVR may have adopted a different equilibrium in their innate immune response. High RIG-I/Cardif and RIG-I/RNF125 ratios and ISG15 and USP18 are useful in identifying NVR.
Asahina
Yasuhiro
Y
Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
Izumi
Namiki
N
Hirayama
Itsuko
I
Tanaka
Tomohiro
T
Sato
Mitsuaki
M
Yasui
Yutaka
Y
Komatsu
Nobutoshi
N
Umeda
Naoki
N
Hosokawa
Takanori
T
Ueda
Ken
K
Tsuchiya
Kaoru
K
Nakanishi
Hiroyuki
H
Itakura
Jun
J
Kurosaki
Masayuki
M
Enomoto
Nobuyuki
N
Tasaka
Megumi
M
Sakamoto
Naoya
N
Miyake
Shozo
S
D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis*; D015153:Blotting, Western; D024882:Drug Resistance, Viral / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D016133:Polymerase Chain Reaction; D012372:ROC Curve; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*
D000998:Antiviral Agents; D015415:Biomarkers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b