Harvard Medical School (HMS) researchers have uncovered a missing link in our understanding of how human papillomaviruses gain their foothold in the rapidly dividing cells of the skin and mucous membranes. The discovery, reported in the April 30 Cell, could lead to new treatments for a host of human papillomavirus-related conditions, from the nuisance of plantar and genital warts to life-threatening precancerous cervical lesions.

“We have uncovered a new target that could potentially lead to new antivirals. There is certainly a need because there are no specific human papillomavirus antivirals out there at this point,” said Peter Howley, the Shattuck Professor of Pathological Anatomy at HMS.

Unlike some viruses, such as influenza, HIV, and the common cold virus, which churn out copies within the confines of a single host cell that is then destroyed, human papillomaviruses invade proliferating epithelial cells and distribute their copies among subsequent generations. To maintain their integrity, and to ensure that the viral DNA is properly partitioned between daughter cells, human papillomaviruses have adopted the strategy of tying their genetic material, via the viral protein E2, to a protein found on the host’s mitotic chromosomes. But the identity of that chromosomal protein has been elusive.

Howley, Jianxin You, HMS research fellow in pathology, and their colleagues have identified the missing chromosomal link in cells infected with a bovine form of papillomavirus. By blocking the protein, BRD4, they prevented papillomavirus-infected mouse cells from becoming cancerous. Perhaps most significant, BRD4 appears to tether human papillomavirus as well.

“This suggests that if one could come up with a small molecule or chemical that could inhibit the binding of E2 to BRD4, that could be a drug lead,” said Howley. He and his colleagues are currently working with members of the Harvard University Department of Chemistry to identify such small molecules.

Human papillomavirus is a leading cause of sexually transmitted diseases in the United States. Though the genital warts resulting from such infections might be treated with human papillomavirus-specific therapies, the real beneficiaries would be women with virus-associated precancerous lesions of the cervix, said Howley. Combined with early methods of detection such as Pap smears, human papillomavirus- specific antivirals could lower the rate of cervical cancer, currently the second most common cancer in women.

“The real value of this approach for treating papillomavirus infections would be to treat precancerous cervical lesions so that they cannot establish a persistent infection and progress into cancer,” said Howley.