Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
PLoS One. 2014 Jan 27;9(1):e86567. doi: 10.1371/journal.pone.0086567. eCollection 2014.
Hepatitis C virus (HCV) leads to chronic infection in the majority of infected individuals due to lack, failure, or inefficiency of generated adaptive immune responses. In a minority of patients, acute infection is followed by viral clearance. The immune correlates of viral clearance are not clear yet but have been extensively investigated, suggesting that multispecific and multifunctional cellular immunity is involved. The generation of cellular immunity is highly dependent upon how antigen presenting cells (APCs) process and present various viral antigens. Various structural and non-structural HCV proteins derived from the open reading frame (ORF) have been implicated in modulation of dendritic cells (DCs) and APCs. Besides the major ORF proteins, the HCV core region also encodes an alternate reading frame protein (ARFP or F), whose function in viral pathogenesis is not clear. In the current studies, we sought to determine the role of HCV-derived ARFP in modulating dendritic cells and stimulation of T cell responses. Recombinant adenovirus vectors containing F or core protein derived from HCV (genotype 1a) were prepared and used to endogenously express these proteins in dendritic cells. We made an intriguing observation that endogenous expression of F protein in human DCs leads to contrasting effects on activation and apoptosis of DCs, allowing activated DCs to efficiently internalize apoptotic DCs. These in turn result in efficient ability of DCs to process and present antigen and to prime and stimulate F protein derived peptide-specific T cells from HCV-naive individuals. Taken together, our findings suggest important aspects of F protein in modulating DC function and stimulating T cell responses in humans.
丙型肝炎病毒（HCV）在大多数感染者中导致慢性感染，原因是适应性免疫反应缺乏、失败或效率低下。在少数患者中，急性感染后病毒被清除。清除病毒的免疫相关性尚不清楚，但已进行了广泛研究，表明多特异性和多功能细胞免疫参与其中。细胞免疫的产生高度依赖于抗原提呈细胞（APCs）如何处理和呈递各种病毒抗原。来自开放阅读框（ORF）的各种结构和非结构 HCV 蛋白已被牵涉到树突状细胞（DCs）和 APCs 的调节中。除了主要的 ORF 蛋白外，HCV 核心区域还编码一个交替阅读框蛋白（ARFP 或 F），其在病毒发病机制中的功能尚不清楚。在当前的研究中，我们试图确定 HCV 衍生的 ARFP 在调节树突状细胞和刺激 T 细胞反应中的作用。制备了含有 F 蛋白或源自 HCV（基因型 1a）的核心蛋白的重组腺病毒载体，并用于在树突状细胞中内源性表达这些蛋白。我们观察到一个有趣的现象，即 F 蛋白在人 DC 中的内源性表达对 DC 的激活和凋亡产生相反的影响，使激活的 DC 能够有效地内化凋亡的 DC。这反过来又使 DC 有效地处理和呈递抗原，并刺激来自 HCV 未感染者的 F 蛋白衍生肽特异性 T 细胞。总之，我们的发现表明 F 蛋白在调节 DC 功能和刺激人类 T 细胞反应方面具有重要意义。
