Persistent CVB3 infection in a cardiomyocyte cell line led to the evolution of a highly cytotoxic viral variant and host cell resistance via CAR downregulation and CAR-independent viral entry.
Demonstrates that CVB3 persistence in cardiomyocytes is facilitated by host receptor downregulation and viral adaptation for alternative entry pathways.
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.
Pinkert et al. (Thu,) conducted a other in Coxsackievirus B3 (CVB3) infection. Persistent CVB3 infection vs. Naive cells was evaluated on Viral persistence, cytotoxicity, and CAR expression. Persistent CVB3 infection in a cardiomyocyte cell line led to the evolution of a highly cytotoxic viral variant and host cell resistance via CAR downregulation and CAR-independent viral entry.
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