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New papillomavirus target could lead to specific antiviral drugs for precancerous cervical lesions

RD4. Though little was known about it, a mouse homolog had been identified as a mitotic chromosome-associated protein. "It immediately jumped out at us that this could very well be the mitotic tether that we had been looking for," said Howley.

The researchers performed a series of experiments, each of which would confirm the hunch. To begin, they used immunofluorescence staining to see where E2 and BRD4 resided in infected mouse cells. Both localized to the mitotic chromosomes. In fact, biochemical tests showed that the proteins did interact. Next, they blocked BRD4 with a competitive mutant, or dominant negative, version of the protein. Sure enough, upon immunofluorescence staining, E2 no longer appeared to be associated with the mitotic chromosomes.

Most exciting, the researchers found that when the dominant negative BRD4 competitors were introduced into mouse cells turning cancerous by a strain of bovine papillomavirus, the cells' rate of transformation to cancer declined by over 90 percent. "All the evidence pointed to BRD4 as the receptor for E2," said You.

That is probably true of human papillomavirus as well. You and colleagues found that human papillomavirus E2 interacts with BRD4. In fact, the region on the E2 protein that binds BRD4 is highly conserved in all species of papillomavirus. "That suggests to us that BRD4 is probably the common target for all the papillomavirus E2 proteins," said Howley.

As it turns out, papillomaviruses are not the only viruses that have the task of maintaining and partitioning their viral genome in a dividing cell. Epstein-Barr and Kaposi's sarcoma herpesviruses face a similar challenge. "To date, none of the mitotic receptors for any of these other viruses has been found," said Howley. He and his colleagues are currently exploring the possibility that BRD4 is the mitotic tether for these viruses as well--and that drugs targeting BRD4 could be used to treat an even broader array of infections.
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29-Apr-2004


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