The just-ended January is cervical health awareness month. A major concern in this area of human health is cervical cancer. Human papillomavirus (HPV) is well-known to be connected with this cancer. We asked Keith Dunker, who is known for his work on intrinsically disordered proteins, to discuss the HPV virus and its relationship to cervical cancer.
What can you tell us about cervical cancer and HPV?
HPV infection very likely plays a role in the development of more than 90% of cervical cancers. Of the > 100 strains of HPV, ~ 40 strains infect the genital tract, and just two of these HPV strains appear to be responsible for about 70% of cervical cancers. Most HPV infections cause benign skin growth (e.g. common warts) that usually resolve over time; only a few sometimes lead to cancer.
What roles do disordered proteins play in HPV infection?
Upon infection, viruses of all kinds including HPV hijack the cellular biochemistry and machinery for the production of new viruses. Researchers around the world are showing that nonstructured or disordered viral proteins play key roles in the viral takeover. Intrinsic disorder’s inherent flexibility enables one viral protein to interact with multiple partners and have multiple effects, thus enabling just a few proteins to hijack the cell.
How did you study the disordered proteins in HPV?
In our studies of disordered proteins in general, we have developed software to predict disorder from amino acid sequence. We applied our disorder predictors to all of the proteins of HPV, comparing the proteins from cancer-causing strains with the proteins from strains that don’t cause cancer. Just two HPV proteins, E6 and E7, showed significantly more predicted disorder in the cancer-causing strains. This was interesting because these two proteins had previously been shown to be the crucial proteins responsible for the development of cancer. Our results suggest that the cancer-causing HPV strains might use this extra disorder for interacting with cellular components in a way that sometimes leads to the development of cancer.
How close are we to knowing how E6 and E7 promote the development of cancer?
The steps by which E6 and E7 lead to the development of cancer have not yet been determined. First, like many viral proteins involved in hijacking the cell’s biochemistry, E6 and E7 each interact with many protein partners and thereby affect many cellular functions. This is true for both the cancer-causing strains and the non-cancer causing strains. One serious limitation is that there have been many more studies on the molecular biology of cells infected with the cancer-causing strains, so it is very unclear which interactions occur following infection by cancer-causing strains but don’t occur or have important differences when the HPV infection is by a strain that doesn’t cause cancer. Simply put, which of these many interactions are important for the development of cancer? We hope our bioinformatics research on this problem can be of help. Indeed, some data are providing provocative information about steps likely involved in the development of cancer. Se we are getting closer to an understanding.
Does this work have long-term potential with regard to human health?
Several researchers around the world are using the new knowledge regarding the biological functions of intrinsically disordered protein as the basis for entirely new approaches for drug discovery. Even if we someday achieve success with these new approaches, treatment of HPV-associated cancer will in addition require the identification of the key steps carried out by E6 and E7 leading to cancer. None of this will be achieved very soon. But in the case of cervical cancer, we don’t have to wait for these developments. According to the Center for Disease Control and Prevention, Pap smears and HPV testing are recommended for early detection, and HPV vaccinations are recommended for protection against infection. By these currently available approaches, cervical cancer is largely preventable.