LITERATURE REVIEW

Literature Review



Literature Review

Summary of Articles

The incubation period for HPV 16 to give rise to cervical cancer is quite long and rather variable.  It has been estimated that among HPV 16-positive women, the median incubation period from first detected HPV infection to cervical carcinoma in situ was between 7 and 12 years.

Human papillomavirus type 16 (HPV-16) is the cause of cervical cancer. The HPV genome encodes three transforming proteins, E5, E6 and E7. E6 and E7 are the main transforming proteins of HPV, while the role of E5 is still poorly understood. Using three dimensional organotypic raft cultures we show that HaCaT human keratinocytes expressing HPV-16 E5 form a very perturbed epithelium, with simultaneous hyperkeratinization of some cells and defective differentiation of other cells. The basal layer is disturbed and many cells invade the collagen matrix. Many cells among the differentiated layers show characteristics of basal cells: progression through the cell cycle, expression of cytokeratin 14, lack of cytokeratin 1 and production of matrix metalloproteases (MMP). Using deletion mutants which encompass the three hydrophobic domains of E5, we have assigned the ability to promote invasion of the matrix to the first hydrophobic domain, and the capacity to induce MMP9 to the C-terminal four amino acids. We also show that invasion and production of MMP9 can be dissociated, as mutants that are still capable of invasion do not produce MMP9 and vice versa.

Rationale for the Articles

HPV is one of the most common STDs among sexually active young people. The CDC estimates that 20 million people in the US are infected with HPV 16 and that every year, there are about 5.5 million new infections.

A study by the CDC on prevalence of HPV 16 in the US showed that the prevalence of HPV-16 was at least two-fold higher in women compared to men. Women of all races had an HPV-16 prevalence of 17.9 percent, compared to 8 percent for men. African-American women age 20 to 29 had the highest prevalence of HPV-16 at 36 percent.

Moreover, E5 (but not mutant E5) induces a 23- to 40-fold increase in the lipid raft component, ganglioside GM1, on the cell surface and mediates a dramatic increase in caveolin-1/GM1 association. Since gangliosides strongly inhibit cytotoxic T lymphocytes, block immune synapse formation and are expressed at high levels on the surface of many tumor cells, our results suggest a potential mechanism for immune evasion by the papillomaviruses. Additionally, surface gangliosides are known to enhance proliferative signaling by the epidermal growth factor (EGF) receptor, providing a possible mechanistic basis for observations that EGF signaling is enhanced in E5-expressing cells. Finally, the upregulation of caveolin-1 and ganglioside GM1 at the plasma membrane of E5-expressing cervical cells provides potential new therapeutic targets and diagnostic markers for high-risk HPV infections.

Papillomaviruses (PV), small oncogenic viruses that infect mucosal and cutaneous epithelia, have also developed the ability to interfere with the expression and/or transport of MHC class I to the cell surface, thus potentially evading the host immune response and the viral protein ...