Immune phenotype and function of NK and T cells in chronic hepatitis C patients who received a single dose of anti-miR-122, RG-101.

Journal article

MicroRNA-122 (miR-122) is an important host factor for the hepatitis C (HCV) virus. Treatment with RG-101, a GalNAc conjugated anti-miR-122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic hepatitis C (CHC) infection. Here, we analyzed the effects of RG-101 therapy on antiviral immunity. 32 CHC patients HCV genotype 1, 3 and 4 received a single subcutaneous administration with RG-101 at 2 mg/kg (n=14), 4 mg/kg (n=14) or placebo (n=2 per dosing group). Plasma and PBMCs were collected at multiple time points and comprehensive immunological analyses were performed. Following RG-101 administration, HCV RNA declined in all patients (mean decline at week 2: 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma IP-10 levels declined significantly upon dosing with RG-101. Furthermore, the frequency of NK cells increased, the proportion of NK cells expressing activating receptors normalized and NK cell IFN-γ production decreased, after RG-101 dosing. Functional HCV-specific IFN-γ-T cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post RG-101 injection. No increase in the magnitude of HCV-specific T cell responses was observed at later time points, including 3 patients who were HCV RNA negative 76 weeks post dosing. CONCLUSIONS: Dosing with RG-101 is associated with a restoration of NK cell proportions and a decrease of NK cells expressing activation receptors. However, the magnitude and functionality of ex vivo HCV-specific T cell responses did not increase following RG-101 injection. Our data suggests that NK cells, but not HCV adaptive immunity may contribute to HCV viral control following RG-101 therapy. This article is protected by copyright. All rights reserved.

Authors: Stelma, F; van der Ree, M; Sinnige, M; Brown, A; Swadling, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Hepatology
• Volume: 66
• Issue: 1
• Pages: 57–68
• Publication date: 2017-03-01
• Acceptance date: 2017-03-03
• DOI: 10.1002/hep.29148
• ISSN: 1527-3350
• Language: English
• Keywords: virus-specific T cell; ISG; anti-miR; TRAIL; miR-122; Hepatitis C virus