A natural subviral agent of human hepatitis B virus (HBV), hepatitis delta virus (HDV) requires only the envelope proteins from HBV in order to maintain persistent infection. HBV surface antigens (HBsAgs) can be produced either by HBV replication, or from integrated HBV DNA regardless of the replication. The functional properties of the integrant-generated HBsAgs were examined using two human HCC-derived cell lines Hep3B and PLC/PRF/5 that contain HBV integrants, but do not produce HBV virions and have no signs of HBV replication. Both cell lines were able to support HDV replication, and assembly/egress of HDV virions. Neither of the cell lines was able to produce substantial amounts of the PreS1-containing HDV... More
A natural subviral agent of human hepatitis B virus (HBV), hepatitis delta virus (HDV) requires only the envelope proteins from HBV in order to maintain persistent infection. HBV surface antigens (HBsAgs) can be produced either by HBV replication, or from integrated HBV DNA regardless of the replication. The functional properties of the integrant-generated HBsAgs were examined using two human HCC-derived cell lines Hep3B and PLC/PRF/5 that contain HBV integrants, but do not produce HBV virions and have no signs of HBV replication. Both cell lines were able to support HDV replication, and assembly/egress of HDV virions. Neither of the cell lines was able to produce substantial amounts of the PreS1-containing HDV particles. HDV virions assembled in PLC/PRF/5 cells were able to infect primary human hepatocytes, while Hep3B-derived HDV appeared non-infectious. These results correlate with the findings that the entire open reading frame (ORF) for the large (L) envelope protein that is essential for infectivity was present on HBV RNAs from PLC/PRF/5 cells, while the L ORF that was truncated and fused to inverted pre-core sequences was found using RNAs from Hep3B cells. This study demonstrated for the first time that at least some of HBV DNA sequences naturally integrated during infection can produce functional small and large envelope proteins capable of the formation of infectious HDV virions. Our data indicated that in vivo chronic HDV infection can persist in the absence of HBV replication (or when HBV replication is profoundly suppressed) if functional envelope proteins are supplied from HBV integrants.
