Department of Applied Biochemistry, Institute of Biotechnology, TIB 4/3-2, Technische Universität, Gustav-Meyer-Allee 25, 13355 Berlin, Germany.
J Virol. 2011 Dec;85(24):13409-19. doi: 10.1128/JVI.00621-11. Epub 2011 Oct 5.
Coevolution of virus and host is a process that emerges in persistent virus infections. Here we studied the coevolutionary development of coxsackievirus B3 (CVB3) and cardiac myocytes representing the major target cells of CVB3 in the heart in a newly established persistently CVB3-infected murine cardiac myocyte cell line, HL-1(CVB3). CVB3 persistence in HL-1(CVB3) cells represented a typical carrier-state infection with high levels (10(6) to 10(8) PFU/ml) of infectious virus produced from only a small proportion (approximately 10%) of infected cells. CVB3 persistence was characterized by the evolution of a CVB3 variant (CVB3-HL1) that displayed strongly increased cytotoxicity in the naive HL-1 cell line and showed increased replication rates in cultured primary cardiac myocytes of mouse, rat, and naive HL-1 cells in vitro, whereas it was unable to establish murine cardiac infection in vivo. Resistance of HL-1(CVB3) cells to CVB3-HL1 was associated with reduction of coxsackievirus and adenovirus receptor (CAR) expression. Decreasing host cell CAR expression was partially overcome by the CVB3-HL1 variant through CAR-independent entry into resistant cells. Moreover, CVB3-HL1 conserved the ability to infect cells via CAR. The employment of a soluble CAR variant resulted in the complete cure of HL-1(CVB3) cells with respect to the adapted virus. In conclusion, this is the first report of a CVB3 carrier-state infection in a cardiomyocyte cell line, revealing natural coevolution of CAR downregulation with CAR-independent viral entry in resistant host cells as an important mechanism of induction of CVB3 persistence.
病毒和宿主的共同进化是在持续性病毒感染中出现的一个过程。在这里，我们在新建立的持续性柯萨奇病毒 B3（CVB3）感染的心肌细胞系 HL-1（CVB3）中研究了 CVB3 和心脏中 CVB3 的主要靶细胞心肌细胞之间的共同进化发展。HL-1（CVB3）细胞中的 CVB3 持续性代表了一种典型的带毒状态感染，从仅一小部分（约 10%）感染细胞中产生高水平（10（6）至 10（8）PFU/ml）的感染性病毒。CVB3 持续性的特征是 CVB3 变体（CVB3-HL1）的进化，该变体在原始 HL-1 细胞系中表现出强烈增加的细胞毒性，并且在培养的原代心肌细胞和体外原始 HL-1 细胞中的复制率增加，而在体内它无法建立鼠类心脏感染。HL-1（CVB3）细胞对 CVB3-HL1 的抗性与柯萨奇病毒和腺病毒受体（CAR）表达的减少有关。CAR 表达的降低部分被 CVB3-HL1 变体通过非 CAR 依赖性进入抗性细胞来克服。此外，CVB3-HL1 保留了通过 CAR 感染细胞的能力。使用可溶性 CAR 变体导致对适应病毒的 HL-1（CVB3）细胞的完全治愈。总之，这是在心肌细胞系中首次报道的 CVB3 带毒状态感染，揭示了 CAR 下调与抗性宿主细胞中非 CAR 依赖性病毒进入的自然共同进化是诱导 CVB3 持续性的重要机制。
