1. Removal of VP2 N termini lowers the energy required for exposing the VP1-specific region (VP1SR), but acidic pH prevents this rearrangement until it is specifically triggered, perhaps in a particular endosomal microlocale. VP1 termini have phospholipase A2 (PLA2) activity required for bilayer transit.
MVM binds to ~5 × 105 sialic acid–bearing receptors per cell surface. All interactions are neuraminidase susceptible, but many may just serve to accumulate virus. Which interactions mediate productive infection is unknown.
PLA2 activity allows intact virions to exit the vesicle without major endosomal disruption, but local disruption may occur given that wild-type virions can complement entry defects of PLA2 mutants.
Virus is internalized from the surface (occluded) predominantly via clathrin-mediated endocytosis. Much of the internalized virus will recycle to the cell surface at later times.
VP1SR remains exposed during transit to the nucleus, likely following release from a perinuclear vesicle cluster given that cytoplasmic injection of VP1-specific antibodies blocks productive infection.
Virions enter the nucleus intact, perhaps via cooperative karyopherin-mediated transit through the nuclear pore.
Alternatively, nuclear entry may be enabled by inducing transient local disruption of the nuclear membrane, in a process mimicking entry into mitosis.
Productive infection is bafilomycin sensitive, proceeding through a low-pH hydrolytic compartment(s), where residual exposed VP2 N termini and exposed NS1-associated tether nucleotides are removed.
Virions remain silent and apparently undetected in the nucleus until the cell enters S phase under normal cell cycle control.
The complementary viral strand is synthesized in S phase by cellular machinery, creating the duplex template required for viral gene expression. Transcription ensues only if the virus has the correct left-end hairpin axial structure. NS1 and NS2, expressed from the P4 promoter, create the host environment needed for productive infection and inhibit cellular DNA replication.
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