Hepatitis delta virus (HDV) infection of individuals infected
with hepatitis B virus (HBV) is associated with more severe
liver damage and an increased risk of fulminant disease. HDV
is a single-stranded RNA virus that encodes a single protein,
the delta antigen, which is expressed in two forms, small (S-HDAg)
and large (L-HDAg). Here we show that although HDV
ribonucleoproteins are mainly detected in the nucleus, they
are also present in the cytoplasm of cells infected with HDV
or transfected with HDV cDNA. Making use of an heterokaryon
assay, we demonstrate that HDV ribonucleoproteins shuttle
continuously between the nucleus and the cytoplasm. In the absence
of HDV RNA, both forms of the delta antigen are retained in
the nucleus, whereas in the absence of the delta antigen, HDV
RNA is predominantly detected in the cytoplasm. Coexpression
of HDV RNA and S-HDAg (which binds to the viral RNA and contains
a nuclear localization signal) results in nuclear accumulation
of the viral RNA. This suggests that HDV RNA mediates export
of viral particles to the cytoplasm whereas the delta antigen
triggers their reimport into the nucleus.