Human papilloma virus E6 and E7 proteins support DNA replication of adenoviruses deleted for the E1A and E1B genes.
The action of transforming proteins from small DNA tumor viruses seems to be remarkably similar between different viruses, as they all use pRb and p53 pathways as cellular targets. This leads to deregulation of host cell cycling, which in turn creates an environment favorable for viral replication. Based on this, we hypothesized that regulatory proteins from human papillomaviruses (HPVs) can functionally trans-complement viral DNA replication of adenoviruses deleted for the E1A and E1B genes (AdE1-). To test this, we constructed AdE1- vectors expressing the human papilloma virus 16 (HPV-16) proteins E6 and E7. Expression of both E6 and E7 from these vectors partially complemented adenoviral DNA replication activity in vitro, in SK-Hep1 cells and primary human astrocytes, as well as in vivo in mouse liver. AdE1- vectors expressing E6 and E7 also increased hepatocellular DNA synthesis in vivo. Efficient AdE1- DNA replication was detected in HPV-associated cervical carcinoma cells but not in primary human cells. Linking the expression of regulatory oncoviral proteins to DNA replication of E1-mutant adenoviruses may provide a rationale for antitumor strategies.
Steinwaerder
D S
DS
Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
Carlson
C A
CA
Lieber
A
A
D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000821:virology; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication; D005260:Female; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000821:virology; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D004247:DNA