Cytokine profile and viral diversity in the early seronegative stage of community-acquired hepatitis C virus (HCV) infection

Most Hepatitis C virus (HCV)-infected subjects develop chronic infection, whereas a minority clear the virus in the early phase of infection. We analyzed factors associated with outcome (chronicity vs clearance) during the preclinical seronegative phase of community-acquired HCV infection. Among 17.5 million blood donations in the years 2000-2016, 126 blood donors were found to be HCV RNA-positive/anti-HCV-negative. All were contacted after 0.5-12.7 years and 40 responded and provided blood sample. Hypervariable region 1 was analyzed by ultradeep pyrosequencing and cytokines in serum were quantified by Luminex (R&D Systems) multiplex immunoassay. Twenty-one (52.5%) donors were found to be HCV-RNA-positive, while 19 (47.5%) were HCV RNA negative (none received antiviral treatment). All but one seroconverted to anti-HCV. Donors with resolving hepatitis did not differ significantly from donors with chronic infection with respect to age, genotypes, IL28B polymorphisms, number of viral variants, nucleotide diversity per site or the overall number of nucleotide substitutions. However, the former group had significantly higher levels of IL-1beta, IL-1RA, IL-6, IFN-gamma and FGF-2 in serum. In our study of community-acquired acute hepatitis C approximately half of all subjects eliminated the virus spontaneously, and this clearance was associated with marked cytokine response in the early seronegative stage of infection.

绝大多数丙型肝炎病毒（Hepatitis C Virus, HCV）感染者会进展为慢性感染，仅少数感染者可在感染早期自发清除病毒。本研究旨在分析社区获得性HCV感染的临床前血清学阴性阶段中，与感染转归（慢性化 vs 病毒清除）相关的影响因素。在2000年至2016年间总计1750万份献血样本中，共检出126名献血者为HCV RNA阳性/抗-HCV（anti-HCV）阴性。研究人员于随访0.5至12.7年后对所有126名献血者进行了联络，其中40名回应并提供了血液样本。采用超深度焦磷酸测序技术对高变区1（Hypervariable Region 1, HVR1）进行分析，并通过Luminex（R&D Systems）多重免疫分析法对血清中的细胞因子进行定量检测。最终检出21名（52.5%）献血者仍为HCV RNA阳性，19名（47.5%）转为HCV RNA阴性（所有受试者均未接受抗病毒治疗）。除1名受试者外，其余所有献血者均出现抗-HCV血清阳转。相较于慢性感染组献血者，病毒清除组献血者在年龄、病毒基因型、IL28B基因多态性、病毒变异株数量、每位点核苷酸多样性及总核苷酸替换数等方面均无显著差异。但病毒清除组献血者的血清中IL-1β、IL-1RA、IL-6、IFN-γ及FGF-2的表达水平显著升高。本项针对社区获得性急性丙型肝炎的研究显示，约半数受试者可自发清除病毒，且该病毒清除效应与感染早期血清学阴性阶段的显著细胞因子应答密切相关。