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Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti‐MicroRNA‐122, RG‐101
Author(s) -
Stelma Femke,
van der Ree Meike H.,
Sinnige Marjan J.,
Brown Anthony,
Swadling Leo,
de Vree J. Marleen L.,
Willemse Sophie B.,
van der Valk Marc,
Grint Paul,
Neben Steven,
Klenerman Paul,
Barnes Eleanor,
Kootstra Neeltje A.,
Reesink Hendrik W.
Publication year - 2017
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29148
Subject(s) - hepatitis c virus , immunology , immune system , medicine , dosing , interferon , peripheral blood mononuclear cell , viral load , natural killer cell , hepatitis c , virus , biology , cytotoxic t cell , in vitro , biochemistry
MicroRNA‐122 is an important host factor for the hepatitis C virus (HCV). Treatment with RG‐101, an N ‐acetylgalactosamine‐conjugated anti‐microRNA‐122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic HCV infection. Here, we analyzed the effects of RG‐101 therapy on antiviral immunity. Thirty‐two chronic HCV patients infected with HCV genotypes 1, 3, and 4 received a single subcutaneous administration of RG‐101 at 2 mg/kg (n = 14) or 4 mg/kg (n = 14) or received a placebo (n = 2/dosing group). Plasma and peripheral blood mononuclear cells 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 interferon‐γ‐induced protein 10 (IP‐10) levels declined significantly upon dosing with RG‐101. Furthermore, the frequency of natural killer (NK) cells increased, the proportion of NK cells expressing activating receptors normalized, and NK cell interferon‐γ production decreased after RG‐101 dosing. Functional HCV‐specific interferon‐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 postdosing. Conclusion : 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, suggesting that NK cells, but not HCV adaptive immunity, may contribute to HCV viral control following RG‐101 therapy. (H epatology 2017;66:57–68).