Data from: Human parainfluenza virus 3 fusion protein cleavage: A key determinant of infection and spread

Human parainfluenza virus 3 (HPIV3) entry into target cells depends on a
viral fusion complex composed of hemagglutinin-neuraminidase (HN) and
fusion protein (F). In addition to attachment, HN activates F to mediate
membrane fusion, while its neuraminidase activity promotes viral release.
This creates a biological paradox: virions must repeatedly engage sialic
acid-rich substrates in the airway without prematurely triggering F, until
they reach the target cell sialic acid receptor. Unlike the F proteins of
laboratory strains that are cleaved intracellularly by furin to process F
from its pro-protein to the active form that is essential for fusion, the
F proteins of HPIV3 field strains lack a furin cleavage site and undergo
partial cleavage mediated by extracellular serine proteases. We show that
virions isolated directly from infected humans contain both cleaved and
uncleaved F. In viral migration assays, reducing the proportion of cleaved
F on virions increases the distance virions travel before infecting a
cell. Even virions bearing only uncleaved F upon egress from infected
cells can establish infection in vivo. These findings support a model in
which uncleaved F on viral surfaces permits virions to engage and
disengage sialylated substrates without undergoing premature fusion
protein triggering, allowing virions to traverse the airway. Cleavage of F
at the target cell then licenses membrane fusion, ensuring that virions
initiate infection at the correct site. HPIV3 exploits host protease
environments to produce virions with heterogeneity in F cleavage, equipped
to either establish local infection or spread to distant target cells.