The switch between acute and persistent paramyxovirus infection caused by single amino acid substitutions in the RNA polymerase P subunit

Paramyxoviruses can establish persistent infections both in vitro and in vivo, some of which lead to chronic disease. However, little is known about the molecular events that contribute to the establishment of persistent infections by RNA viruses. Using parainfluenza virus type 5 (PIV5) as a model we show that phosphorylation of the P protein, which is a key component of the viral RNA polymerase complex, determines whether or not viral transcription and replication becomes repressed at late times after infection. If the virus becomes repressed, persistence is established, but if not, the infected cells die. We found that single amino acid changes at various positions within the P protein switched the infection phenotype from lytic to persistent. Lytic variants replicated to higher titres in mice than persistent variants and caused greater infiltration of immune cells into infected lungs but were cleared more rapidly. We propose that during the acute phases of viral infection in vivo, lytic variants of PIV5 will be selected but, as the adaptive immune response develops, variants in which viral replication can be repressed will be selected, leading to the establishment of prolonged, persistent infections. We suggest that similar selection processes may operate for other RNA viruses. Author summary As well as causing acute infections that result in mild to serious disease, many RNA viruses can establish prolonged or persistent infections in some infected individuals, that occasionally lead to chronic or reactive disease. Little is known about the molecular mechanisms involved in the establishment of such infections. Using parainfluenza virus type 5 (PIV5) as a model, we show how lytic and persistent variants of the virus can be selected on the basis of single amino acid substitutions and propose that the selection of persistent variants as the adaptive immune response develops following an acute infection might be a mechanism these viruses have evolved to enhance their transmission rates. As well as being of fundamental interest, understanding the molecular basis by which RNA viruses establish persistent infections may improve our understanding of virus epidemiology (and hence improve the control of virus infections) and of virus:host interactions that influence the relationship between virus persistence and chronic/relapsing disease. Furthermore, the knowledge of how RNA viruses, such as PIV5, establish persistent infections may lead to improve vaccine design since vectors which can establish persistent infections may induce longer-lasting more robust immunity.