UNM scientists have uncovered new mechanisms by which human papillomavirus, or HPV, infects cells. Their research, published in the journal PLoS Pathogens, challenges previous understandings of how HPV makes its crucial move from the cell membrane into the interior of the cell and marshals strong evidence for alternative ways the virus works to hijack host cell functions to cause infection.
"This research both sheds light on the transmission of a common virus and lays the groundwork for developing new ways to prevent infection," said Michelle Ozbun, one of the study's authors. Ozbun is professor of molecular genetics and microbiology and co-leads the Women's Cancers Research Program at the UNM Cancer Center.
HPV is actually a group of more than 100 related viruses, 30 of which can be sexually transmitted. While most sexually transmitted HPV infections are not life-threatening and often go away without treatment, persistent infection from certain high-risk forms of the virus can cause cancer. HPV infections cause five percent of cancers worldwide, Ozbun said, including virtually all cases of cervical cancer and a rising number of oropharyngeal cancers, affecting the throat, in the United States.
Both cervical and oral cancers are serious public health issues. The incidence of oropharyngeal cancers arising from HPV infections has more than doubled in 30 years. Though cervical cancer rates in the U.S. have dropped during that time thanks to Pap smear screening, nearly half a million women worldwide are diagnosed each year, and a quarter of a million lose their lives to the disease. Two Food and Drug Administration-approved vaccines, Gardasil and Cervarix, can prevent infections by the two HPV types that cause most cervical cancers and related oral cancers. UNM researchers are working to create new vaccines to combat the remaining HPV types associated with cervical and oral cancers – an accomplishment that would pave the way to eliminating these diseases.
"Understanding the precise molecular moves that HPV makes to infect cells is essential to devising means of disabling this virus and potentially other microbes that may use similar pathways for infection," Ozbun said.
Viruses have evolved many strategies for entering and commandeering cells, typically by taking over normal cell functions. Like other microbes, HPV enters the cell through a multi-step process. The first step involves binding to long-chained sugar molecules on the cell surface called HSPGs. After gaining this initial toehold, HPV must find a way to transfer to secondary receptors that ferry the virus inside the cell, where infection can take place. Previous research had pointed to the activities of a particular HPV protein in facilitating the transfer of the virus from HSPGs to these secondary receptors.
The recent UNM study, pioneered by Zurab Surviladze in Ozbun's research group, challenges this understanding. The team's research suggests that HPV pursues an altogether different and more devious strategy for entering the cell. Rather than detaching from HSPGs on the cell surface, HPV is first incorporated into an active complex with HSPGs and growth factors, proteins that play a crucial role in cell signaling and proliferation, and then released in this new form. The resulting HPV-HSPG-growth factor complex is essentially a floating Trojan horse. Instead of directly binding to secondary receptors, as previously thought, HPV seems to use its HSPG and growth factor disguise to gain indirect access to growth factor receptors, proteins to which complementary growth factors bind, like keys fitting into locks. The interactions involved in this indirect binding activate signals that traffic the virus into the cell interior and facilitate infection.
Under the researchers' new HPV infection model, the virus usurps normal mechanisms for growth factor interactions within the cell membrane, using growth factor signaling and binding to its advantage and the disadvantage of the soon-to-be infected cell. More research needs to be done to confirm and refine this model, Ozbun said. But the findings bring new clarity to the cellular mechanisms of HPV infection and suggest new targets for blocking infection by this common and occasionally deadly virus.
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