Human cytomegalovirus and human herpesvirus 6 genes that transform and transactivate

This review is an update on the transforming genes of human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6). Both viruses have been implicated in the etiology of several human cancers. In particular HCMV has been assoc iated with cervical carcinoma and adenocarcinomas of the prostate and colon . In vitro transformation studies have established three HCMV morphologic t ransforming regions (intr), i.e., mtrI, mtrII, and mtrIII. Of these, only m trII (UL111A) is retained and expressed in both transformed and tumor-deriv ed cells. The transforming and tumorigenic activities of the mtrII oncogene were localized to an open reading frame (ORF) encoding a 79-amino-acid (Ra ) protein. Furthermore, mtrII protein bound to the tumor suppressor protein p53 and inhibited its ability to transactivate a p53-responsive promoter I n additional studies, the HCMV immediate-early protein IE86 (IE2; UL122) wa s found to interact with cell cycle-regulatory proteins such as p53 and Rb. However IE86 exhibited transforming activity in vitro only in cooperation with adenovirus EIA. HHV-6 is a T-cell-tropic virus associated with AIDS-re lated and other lymphoid malignancies. In vitro studies identified three tr ansforming fragments, i.e., SalI-L, ZVB70, and ZVH14. Of these, only SnlI-L (DR7) was retained in transformed and tumor-derived cells. The transformin g and tumorigenic activities of SnlI-L have been localized to a 357-aa ORF- I protein. The ORF-I protein was expressed in transformed cells and like HC MV mtrII, bound to p53 and inhibited its ability to transactivate a p53-res ponsive promoter HHV-6 has also been proposed to be a cofactor in AIDS beca use both HHV-6 and human immunodeficiency virus type I (HN-I) have been dem onstrated to coinfect human CD4(+) T cells, causing accelerated cytopathic effects. Interestingly, like the transforming proteins of DNA tumor viruses such as simian virus 40 and adenovirus ORF-1 was also a transactivator and specifically up-regulated the HIV-1 long terminal repeat when cotransfecte d into CD4(+) T cells. Finally based on the interactions of HCMV and HHV-6 transforming proteins with tumor suppressor proteins, a scheme is proposed for their role in oncogenesis.