Kondo Yasuteru, Machida Keigo, Liu Helene Minyi, Ueno Yoshiyuki, Kobayashi Koju, Wakita Takaji, Shimosegawa Tooru, Lai Michael M C
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, USA; Division of Gastroenterology, Tohoku University, Sendai City.
J Infect Dis. 2009 Mar 1;199(5):726-36. doi: 10.1086/596739.
A lymphotropic hepatitis C virus strain (HCV, SB strain, hereafter "SB-HCV") has been shown to infect established T cell lines (Molt-4 and Jurkat) and primary human naive CD4(+) T cells. During T cell development and activation, transient expression of CD44 splicing variant 6 (CD44v6) plays a significant role.
SB-HCV was used to infect Molt-4 cells, and their cellular proliferation and CD44 expression was examined.
SB-HCV-infected Molt-4 cells expressed a significantly lower level of the CD44v6 isoform. The infected cells could be divided into 2 carboxyfluorescein succinimidyl ester (CFSE) groups, CFSE-high (indicating low proliferation activity; 34.2% of the cells) and CFSE-low (indicating high proliferation activity; 62.5% of the cells), whereas uninfected cells consisted of only a CFSE-low population. Of the CFSE-high cells, 82.4% were positive for the HCV protein NS5A, whereas only 1.2% of the CFSE-low cells were positive for this protein. Among the HCV proteins, NS5A alone caused the down-regulation of CD44v6 expression. After cells were stimulated with phorbol myristate acetate, the amount of phosphorylated mitogen-activated protein (MAP) kinase was significantly reduced in CFSE-high, SB-HCV-infected Molt-4 cells. After Fas ligand stimulation, SB-HCV-infected Molt-4 cells had increased cleavage of caspase 8 and 3 and enhanced apoptosis, compared with the rates of cleavage and apoptosis in control groups, indicating that SB-HCV infection increased Fas-mediated apoptosis.
HCV replication in T cells suppresses cellular proliferation and enhances susceptibility to Fas signaling by inhibiting CD44v6 signaling and expression.
一种嗜淋巴细胞性丙型肝炎病毒株（HCV，SB株，以下简称“SB-HCV”）已被证明可感染已建立的T细胞系（Molt-4和Jurkat）以及原代人幼稚CD4(+) T细胞。在T细胞发育和激活过程中，CD44剪接变体6（CD44v6）的瞬时表达起重要作用。
用SB-HCV感染Molt-4细胞，并检测其细胞增殖和CD44表达。
SB-HCV感染的Molt-4细胞表达的CD44v6异构体水平显著降低。感染细胞可分为2个羧基荧光素琥珀酰亚胺酯（CFSE）组，CFSE高（表明增殖活性低；34.2%的细胞）和CFSE低（表明增殖活性高；62.5%的细胞），而未感染细胞仅由CFSE低群体组成。在CFSE高的细胞中，82.4%的细胞HCV蛋白NS5A呈阳性，而CFSE低的细胞中只有1.2%的细胞该蛋白呈阳性。在HCV蛋白中，仅NS5A导致CD44v6表达下调。用佛波酯肉豆蔻酸酯刺激细胞后，CFSE高、SB-HCV感染的Molt-4细胞中磷酸化丝裂原活化蛋白（MAP）激酶的量显著降低。与对照组的裂解率和凋亡率相比，Fas配体刺激后，SB-HCV感染的Molt-4细胞中caspase 8和3的裂解增加，凋亡增强，表明SB-HCV感染增加了Fas介导的凋亡。
HCV在T细胞中的复制通过抑制CD44v6信号传导和表达来抑制细胞增殖并增强对Fas信号的敏感性。
