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

Abstract

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.

Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease

“…These observations are also reflected in animal models of persistent asymptomatic infection with EBOV [39]. Recently, a model for the persistence of acute viral infections, such as those observed in paramyxoviruses, has been proposed [40]. EBOV has a similar genome organisation and replication strategy to paramyxoviruses.…”

“…EBOV has a similar genome organisation and replication strategy to paramyxoviruses. In this model, as the adaptive immune response develops during infection, genome variants are selected in which replication is suppressed [40]. This would lead to persistent infection at low levels, and the switch back to a lytic stage would be associated with amino acid reversions causing virulence [40].…”

“…In this model, as the adaptive immune response develops during infection, genome variants are selected in which replication is suppressed [40]. This would lead to persistent infection at low levels, and the switch back to a lytic stage would be associated with amino acid reversions causing virulence [40]. In the paramyxovirus, parainfluenza virus type 5 (PIV), a single amino acid change in the viral P protein, a key component of the viral RNA polymerase complex, was found to control the switch from persistence to lytic replication [40].…”

“…This would lead to persistent infection at low levels, and the switch back to a lytic stage would be associated with amino acid reversions causing virulence [40]. In the paramyxovirus, parainfluenza virus type 5 (PIV), a single amino acid change in the viral P protein, a key component of the viral RNA polymerase complex, was found to control the switch from persistence to lytic replication [40]. The observation of the attenuating N572S, Q986R and F2061S variants in the EBOV L protein was associated with reduced polymerase activity and correlated with lower viral load in patients.…”

Innate Intracellular Antiviral Responses Restrict the Amplification of Defective Virus Genomes of Parainfluenza Virus 5

“…To determine whether the efficiency of activation of the IFN- promoter correlated with the presence of DVGs, nucleocapsids were purified from cells infected with the on September 2, 2020 by guest http://jvi.asm.org/ Downloaded from vM5 and vM6 virus stocks described above and subjected to high throughput sequencing as described previously (51). ViReMa software (52) was used to detect and characterise DVGs.…”