The Establishment Of Coxsackievirus B3 Persistent Infection In ECV304 And The Primary Study Of Its Mechanism

Although Enteroviruses are mainly described as responsible for acute diseases, their role in severe chronic pathology has been also established. Coxsackievirus have been detected by PCR analysis cardiac specimens from patients presenting with dilated cardiomyopathy, These findings suggested a persistent infection with viruses that underwent, genetic changes precluding viral particle release. To support this hypothesis, we developed a model system of Coxsackievirus B3 (CVB3) chronic infection in ECV304 cell line. The nucleotide sequences of the genome were analyzed during establishment of the chronic phenotype. This study revealed that at day 120 of chronic infection, several mutations were observed: one mutation at nucleotide 662, the end of 5' non-translated region (5'NTR); two mutations in the P1-A region (16P-G, 18K-N); one mutation in the P3-AB, which translated VPg protein (1486H-Y); one mutation were detected in the 3C region(1696E-K); and 3 mutations in the P3-D region (1745R-K, 1849A-T, 2098P-L). The impact of these mutations on viral replication have been analyzed. And we come to a conclusion that mutations at P3-D region and P3-AB region may contribute to the persistent infection. The Viruses with these mutations displayed a phenotype with a significant reduction of replication. Of course, it needs to be proved by reverse genetics. This model allowed the description of molecular changes observed in the genome of CVB3 during the establishment of a chronic infection phenotype, and may be helpful for the understanding of the mechanisms leading Enteroviruses to develop chronic infections in man.