2nd Paper

HPV, a new epidemic

Cancer is a very frightening disease. It seemingly targets people at random, striking them down with ease. The survivors are hailed above many others for the ordeal they have gone through. Many cancers may be caused by a single mistake in the coding in the DNA of one cell. Cervical cancer, on the other hand, is caused by a virus, HPV. HPV, Human papillomavirus, is a category of viruses that contains more than 100 similar viruses. Some forms of HPV cause warts or papillomas that are generally benign or non cancerous. The issue with HPV comes from the more than 40 types that are genital HPV. They are passed through the same methods as STIs. Some of these HPV strands merely cause warts whereas others can cause cervical or other rarer types of genital cancer. Cervical cancer is developing into one of the biggest health threats to women today.

In the United States around 11,070 women will be infected with cervical cancer and 4000 women will die from cervical cancer in 2008 alone according to the American Cancer Society. This presents HPV as a clear threat in the US, but also it threatens countries beyond its borders. Around the world cervical cancer is the third most common form amongst women. Around 500,000 women will develop it each year with about half (274,000) dying as a result of the cancer.[1] In the United States the number of cases that continue to death is reduced in comparison to many nations because of the large number of options for treatment in the US that are no available in other nations.

The problem with HPV is not that there is no treatment. There are methods of identification, treatment, and prevention, but they are only available in some places in the world. These methods target the most virulent and dangerous forms of HPV. HPV-16 and HPV-18 are the two major cervical cancer causers and may account for as much as 70% of cervical cancer cases globally. [1] Despite the imminent threat posed by this virulent strand there is hope. A vaccine has been developed that effectively prevents HPV 16 and 18 from changing the cells to cause cervical cancer. To understand how this takes place, a closer look at how HPV infects cells is necessary.

TP53 Website

When HPV infects a cell two E6 and E7 proteins act as oncoproteins.[2] Oncoprotein is simply a term to establish the E6 and E7 proteins as cancer causing factors. These proteins coded in HPV 16 and 18 play a role in the development of cervical cancer upon contraction of the HPV virus. E6 works by negating the effects of the p53 tumor suppressor protein.[3] P53, protein 53, functions in cell regulation causing it to be a cancer suppressant. When a cells DNA is damaged by any means p53 causes repairs to take place or tells the cell to destroy itself. When p53 is damaged or inactivated the potential for cancer development is much higher. E6 binds to p53 and causes it to be inactive removing part of the cells tumor suppression.[4]

E7 proteins also affect the infected cell. They bond to Rb tumor suppressors preventing them from functioning. Rb plays a key role in regulation of cell proliferation, survival and differentiation, and regulates cellular division. [5] The combined affect of both E6 and E7 proteins drastically reduces the host cell’s ability to prevent its transformation to a cancerous cell, which may potentially for a carcinogenic tumor.

Not only do E6 and E7 play a vital role in the disabling of human cell’s cancer defenses, they also play a vital role in the life of the HPV virus. Later in the viruses infection process they play instrumental roles in the stability of different portions of the virus. It has bee shown that a mutated E7 protein in HPV16 affects the viruses ability to amplify its DNA in later infection processes.[2] Also it has been discovered that E6 and E7 cause polyploidy in human keratinocytes.[6] This process directly contributes towards the progression of cancer.

When the tumor suppressors are turned off in HPV target cells they can cause cancer. It is how these proteins can be stopped from disabling the cells regulation devices that holds the key to prevention. There are many supposed methods of treating HPV and preventing it, but the most exciting is the HPV vaccine. Two vaccines on the market in the US and other countries, produced by Gardasil and Cervarix, are being used to target the sexually transmitted strands of HPV.

VLPs assembled from L1 protein of HPV-16~~CDC, HPV and HPV Vaccine

The vaccine is made up of virus-like particles(VLPs) that are assembled from HPV.[7] HPV16 and 18 are the two strands that it mainly targets.[7] The goal, as with most vaccines, is to create an immune response to a non lethal threat in order to develop the body’s natural defenses before an actual assault. With antibodies present HPV strands will find it difficult to infect the cells and thus will not be able to cause cervical cancer.[8] Although one problem is that the antibodies generated by VLPs are extremely type specific and will only affect particular strands of the HPV virus. It’s not too much of an issue because HPV-16 and HPV-18 account for around 70% of cervical cancer cases and therefore if only those were prevented it would put a large dent in cervical cancer cases world wide.

This process by which HPV works and how the vaccine developed will allow prevention provided continued treatments as its viable protection period is only 4.5 years. [8] The vaccine is a major contribution towards a reduction in the cases of cervical cancer and HPV infections in the US. The problem is the ability to fight HPV in third world countries, who account for more than 80% of the cervical cancer deaths in the world[1]

There are many sources to the inability to properly treat these countries. Money and government distrust are just a couple. Money is one of the larger factors. If the vaccine would be able to make it to a third world country the price of the treatments to provide the immunity would need to be drastically marked down compared to US standards. A price close to $1 or $2 would be more viable for regions that have very low per capita, making the vaccine affordable.[1] Another big issue is the competition amongst importance of vaccinations in the developing nations. There is conflict amongst whether the prevention and treatment of the wide spread of STIs, such as HIV, is more important than the treatment and prevention of HPV.

The vaccine should be given to girls before they reach an age of active sexual activity. Once HPV has been contracted the vaccine cannot fight it, but merely prevent the infection of other strands of HPV. In the United States girls around age 12, before sexual activity, should be vaccinated in order to prevent the infection.[1] In an attempt to develop better methods of distributions over cultural barriers, Merck and GlaxoSmithKline recently received a 27.8 million dollar grant from the Bill and Melinda Gates Foundation to research methods of better distribution of HPV vaccine throughout developing nations. [9]

HPV is a problem, but it has a solution. Like many diseases before it a manmade vaccine is able to provide immunity to the most dangerous strands, HPV16 and HPV18. By the activation of an immune response to dead HPV cells the body develops immunity. The oncoproteins E6 and E7 will not have a chance to block the effectiveness of P53 and rb tumor suppressors. This will lessen the threat of cervical cancer to the female population on not only the US, but the whole world. If programs and projects can be developed to spread the vaccine to the farthest corners of the globe HPV may be put in the past as another disease that man has nearly eradicated from the earth, though this disease will also be removed from developing nations also.

1. Agosti, J.M. and S.J. Goldie, Introducing HPV vaccine in developing countries--key challenges and issues. N Engl J Med, 2007. 356(19): p. 1908-10.

2. Oh, S.T., M.S. Longworth, and L.A. Laimins, Roles of the E6 and E7 proteins in the life cycle of low-risk human papillomavirus type 11. J Virol, 2004. 78(5): p. 2620-6.

3. Huibregtse, J.M. and S.L. Beaudenon, Mechanism of HPV E6 proteins in cellular transformation. Semin Cancer Biol, 1996. 7(6): p. 317-26.

4. Zamzami, N. and G. Kroemer, p53 in apoptosis control: an introduction. Biochem Biophys Res Commun, 2005. 331(3): p. 685-7.

5. Wenzel, P.L., et al., Rb is critical in a mammalian tissue stem cell population. Genes Dev, 2007. 21(1): p. 85-97.

6. Patel, D., et al., Human papillomavirus type 16 E6 and E7 cause polyploidy in human keratinocytes and up-regulation of G2-M-phase proteins. Cancer Res, 2004. 64(4): p. 1299-306.

7. Lowy, D.R. and J.T. Schiller, Prophylactic human papillomavirus vaccines. J Clin Invest, 2006. 116(5): p. 1167-73.

8. Harper, D.M., et al., Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet, 2006. 367(9518): p. 1247-55.

9. Studying HPV Vaccine Rollout Barriers In Developing Countries Is In Merck's, GSK's Self-Interest, Editorial Says. 2006 3/7/2008 [cited; Available from: http://www.medicalnewstoday.com/articles/46492.php.