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
Departments of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
Hepatology. 2017 Jul;66(1):57-68. doi: 10.1002/hep.29148. Epub 2017 Jun 7.
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.
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. (Hepatology 2017;66:57-68).
微小RNA-122是丙型肝炎病毒（HCV）的重要宿主因子。用RG-101（一种N-乙酰半乳糖胺偶联的抗微小RNA-122寡核苷酸）治疗，可使慢性HCV感染患者的病毒载量显著降低。在此，我们分析了RG-101治疗对抗病毒免疫的影响。32例感染HCV基因1型、3型和4型的慢性HCV患者接受了2mg/kg（n = 14）或4mg/kg（n = 14）的单次皮下注射RG-101，或接受安慰剂（每组n = 2）。在多个时间点采集血浆和外周血单个核细胞，并进行全面的免疫学分析。注射RG-101后，所有患者的HCV RNA均下降（第2周平均下降3.27 log10 IU/mL）。第8周时，28例患者中有15例检测不到HCV RNA。注射RG-101后，血浆干扰素γ诱导蛋白10（IP-10）水平显著下降。此外，自然杀伤（NK）细胞频率增加，表达激活受体的NK细胞比例恢复正常，注射RG-101后NK细胞干扰素γ产生减少。在注射RG-101后第8周HCV RNA水平检测不到的患者中，功能性HCV特异性干扰素γ T细胞反应无显著变化。在包括给药后76周HCV RNA阴性的3例患者在内的后期时间点，未观察到HCV特异性T细胞反应强度增加。
注射RG-101与NK细胞比例恢复和表达激活受体的NK细胞减少有关；然而，注射RG-101后，体外HCV特异性T细胞反应的强度和功能并未增加，这表明NK细胞而非HCV适应性免疫可能在RG-101治疗后对HCV病毒控制起作用。（《肝脏病学》2017年；66:57 - 68）
