HPV Virulence

I recently read an article describing a virulence factor in Human Papillomavirus (HPV) (link).  Virulence factors affect how virulent (roughly "bad") a given pathogen is.  In the case of the article, they discussed what is known as the PDZ binding motif.  Certain strains of HPV lead to the production of a protein, E6,  that has the PDZ binding motif.  Certain naturally-occurring proteins in human cells contain PDZ, so the viral proteins with the PDZ binding motifs are able to bind to these normal proteins.

Past studies have shown that viruses with the PDZ binding motif are more virulent than those without it.  This paper investigates why.  Previous studies showed a variety of things that E6 bound to, but it wasn't known exactly which of these was the worst.

The way the authors investigated this was as follows.  They started with cell lines that were already infected with PDZ binding motif carrying HPV, named HeLa and CaSKi.  They then added siRNA that was complementary to mRNA for E6.  When the two interact, they bind to each other, and are eventually degraded by the cell.  In other words, they were able to selectively turn off E6 production in the cells.  They then analyzed the expression of proteins over 72 hours, to see if any had any drastic increases.  In the presence of E6, proteins that bound to E6 would fail to function, and eventually be degraded by the cell.  However, without E6, such proteins could flourish without degradation.  As such, it is expected that without E6, the expression of naturally occurring proteins that bind to E6 would increase dramatically. 

The results showed that MAGI-1 expression increased, another protein that had been identified in other studies as binding to E6.  This result is significant.  MAGI-1 is involved in the formation of tight junctions.  Such junctions help to hold cells tightly together.  In normal, healthy tissue, such junctions are crucial to keeping everything together and ordered.  However, this is not the case for cancer cells.  Cancerous cells have to break free of surrounding cells in order to be as virulent as possible.  This way, they can grow unrestricted and metastasize.  This explains why E6 is a virulence factor in HPV.  The paper shows a causal relationship between the presence of E6 and the degradation of tight junctions.  E6 binds to such junctions, preventing them from functioning properly and leading to their degradation.  Without the tight junctions interfering, cancer cells can flourish.  It's thus in the best interest of a cancer cell to destroy such junctions, so it's in the best interest of cancer cells to contain E6 genes.

This opens doors for HPV-caused cervical cancer research.  If one could develop a drug to specifically target and somehow destroy or disable E6, then the resulting HPV virus would be far less virulent.  The virus wouldn't be harmless by any means, but it would have a far better prognosis.  I don't think this is unfeasible, but it would require an extensive amount of additional research to be performed.  This may very well be a seminal paper on the cure for HPV-caused cervical cancer.