Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

Abstract

BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α-based therapies to IFN-α-free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia. METHODS.We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed. RESULTS.On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed. CONCLUSION.These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV. TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180. FUNDING. Intramural Programs of the National Institute of Allergy and Infectious The Journal of Clinical Investigation C l i n i C a l M e d i C i n e3 3 5 3 jci.orgVolume 124 Number 8 August 2014We next evaluated on-treatment serum protein levels of select chemokines and cytokines and observed similar expression at baseline and during treatment comparing patients who achieved SVR versus those who relapsed (Supplemental Table 3). Serum levels of the IFN-inducible cytokine IP-10, the protein product of the CXCL10 gene that was downregulated in liver (Figure 2A), correlated significantly with baseline viral load ( Figure 3A). Expression decreased rapidly on-treatment, regardless of treatment outcome, and increased with relapse ( Figure 3B). Viral kinetic and IP-10 decline were significantly correlated ( Figure 3C and Table 1). IL-10 and IFN-γ decreased modestly during treatment, while expression of most other proteins did not change, including TGF-β1 and TIMP1, which are associated with hepatic fibrosis (Supplemental Table 3 and ref. 25).To assess whether a similar pattern of gene expression changes could be observed in the periphery, we performed microarray mRNA analysis in PBMCs collected before treatment, early in treatment (day 6-11), and at EOT (week 24) and identified a significant decrease of IFN signaling during treatment (Supplemental Figure 2 and Supplemental Table 4). qRT-PCR analysis in PBMCs confirmed rapid and sustained downregulation of I...

Activation of Type I and Type III Interferons in Chronic Hepatitis C

“…As type I IFN has been shown to negatively control pDC numbers in various in vitro infection models, it was thus suggested that type I IFN might negatively regulate pDC numbers during HCV infection. A recent immunohistochemistry analysis in fact failed to detect any pDCs both in pretreatment and end-of-treatment human liver biopsies [40]. …”

Hepatocellular Carcinoma Occurrence and Recurrence after Antiviral Treatment in HCV-Related Cirrhosis. Are Outcomes Different after Direct Antiviral Agents? A Review

“…Similar studies showed that the rapid decline of HCV viral load by DAAs was associated with restored HCV specific memory T cell dedifferentiation, lymphocyte deactivation and normalized natural killer cell function [42][43][44]. Mir-122, which plays a central role in orchestrating hepatocarcinogenesis was recently found to be decreased in serum samples after IFN-free therapy [45]. IFN-free therapy leads to the downregulation of type II and III IFNs, their receptors and IFN stimulated genes [46].…”

HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection

“…HLA-A*0201-restricted HCC-specific peptides of AFP [137][138][139][140][141][142][143][144][145] (PLFQVPEPV), NY-ESO-1 157-165 (SLLMWITQC), MAGE-A3 112-120 (KVAELVHFL), MAGE-A10 [254][255][256][257][258][259][260][261][262] (GLYDGMEHL), SSX-2 [41][42][43][44][45][46][47][48][49] (KASEKIFYV) and p53 [149][150][151][152][153][154][155][156][157] (STPPPGTRV) at purities ranging from 82.78 to 97.99% were also obtained from ProImmune Ltd. For these HCC-associated epitope-specific peptides, corresponding PE-labeled MHC class I dextramers were obtained from Immudex (Copenhagen, Denmark). Further, HBV-specific 15-mer overlapping peptides covering the core (4 pools from 41 peptides) and polymerase regions (8 pools from 165 peptides) were purchased from ProImmune Ltd. Also, HLA-A*0201-restricted HBV-specific peptides Core [18][19][20][21][22][23][24][25][26][27] (FLPSDFFPSV), Env [183][184][185][186][187][188]…”

“…PBMC from cirrh-to-No HCC patients (n = 17) isolated at TS, EOT, and FU were stimulated with the specific peptides in vitro. HBVspecific Core [18][19][20][21][22][23][24][25][26][27] , Env [183][184][185][186][187][188][189][190][191] , Pol 578-581 , and Surf 185-194 control peptide stimulations were used in selected patients with no HBV coinfection to secure the quality of staining (see online suppl. Fig 7).…”

“…For HCC arising from underlying cirrhosis in the context of therapy-induced HCV clearance, it is not known whether this is the case. Some recent studies suggest that IFN-free DAA therapy may alter the concentration of soluble inflammatory mediators (SIM) [18] and may evoke immune reconstitution of intrahepatic interferon-stimulated genes [19]. Whether or not such immunological changes influence the prevailing T cell immune surveillance machinery of HCC is still unclear.…”