Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA; HemoShear, Charlottesville, VA 22902, USA.
Cell Host Microbe. 2014 Feb 12;15(2):190-202. doi: 10.1016/j.chom.2014.01.007.
Hepatitis C virus (HCV) infection can result in viral chronicity or clearance. Although host genetics and particularly genetic variation in the interferon lambda (IFNL) locus are associated with spontaneous HCV clearance and treatment success, the mechanisms guiding these clinical outcomes remain unknown. Using a laser capture microdissection-driven unbiased systems virology approach, we isolated and transcriptionally profiled HCV-infected and adjacent primary human hepatocytes (PHHs) approaching single-cell resolution. An innate antiviral immune signature dominated the transcriptional response but differed in magnitude and diversity between HCV-infected and adjacent cells. Molecular signatures associated with more effective antiviral control were determined by comparing donors with high and low infection frequencies. Cells from donors with clinically unfavorable IFNL genotypes were infected at a greater frequency and exhibited dampened antiviral and cell death responses. These data suggest that early virus-host interactions, particularly host genetics and induction of innate immunity, critically determine the outcome of HCV infection.
丙型肝炎病毒（HCV）感染可导致病毒慢性化或清除。尽管宿主遗传学，特别是干扰素 lambda（IFNL）基因座的遗传变异与自发性 HCV 清除和治疗成功相关，但指导这些临床结果的机制仍不清楚。我们使用激光捕获显微切割驱动的无偏系统病毒学方法，以单细胞分辨率分离和转录分析接近 HCV 感染的和相邻的原代人肝细胞（PHH）。先天抗病毒免疫特征主导了转录反应，但在 HCV 感染的和相邻细胞之间在幅度和多样性上有所不同。通过比较高感染频率和低感染频率的供体，确定与更有效的抗病毒控制相关的分子特征。具有临床不利 IFNL 基因型的供体的细胞以更高的频率感染，并表现出抑制的抗病毒和细胞死亡反应。这些数据表明，早期的病毒-宿主相互作用，特别是宿主遗传学和先天免疫的诱导，对 HCV 感染的结果具有决定性作用。
