Human Papilloma Virus

1. Human Papilloma Virus Basic biology, infection, and psychological effects.

2. What is HPV? • Papillomaviruses are small, approximately 52-55nm in diameter.  • They are non-enveloped, icosahedra particles. This shape is made up of 12 pentameric and 60 hexameric capsomers arranged on a T=7 lattice.  • Their carpsid is composed of two proteins, a major (L1) and minor (L2). SEM image of a Human Papilloma Virus and a computer model showing the structure of the virus.

3. They are DNA viruses. • HPV is part of the family known as Papovaviruses, which was named for it’s three main members: PApillomavirus, POlyomavirus, and simian Vacuolating Agent. They are found in many vertebrates, and exhibit high species specificity. • This family contains two genera of oncogenic viruses, Papilloma and Polyoma viruses. • The Papillomavirus’ genome is circular, d/s DNA approximately 8,000bp in size. Many of the HPV genomes have been sequenced and have a genetic organization similar to that of HPV-16, one of the oncogenic strains.

4. How Does HPV Work? • HPV infects the basal cells of the dermal layer, and early gene expression occurs in these cells.  • Late gene expression and high copy DNA synthesis occurs only in terminally differentiated epidermal cells. • This implies a link between differentiation and gene expression, although the nature of this link is unknown. • Some strains of HPV are able to transform host cells on their own, whereas others require cofactors.

5. Expression of the Papillomavirus genomeis very complex and not well understood, because it has at least seven promoters, exhibits many alternative splicing patterns, and has an unknown link to cell differentiation.

6. HPV Infection OutcomesE6 and E7 interact with many cellular proteins, which influence the outcome of infection.

7. How Does HPV “Cause” Cancer? In high-risk HPV strains 16,18,31,39,45 and 59: • Protein E6 interacts with p53 in the host cell and promotes it’s degradation via the ubiquitin dependent pathway. • Protein E7 complexes with retinioblastoma protein (Rb), thereby inactivating it. • Rb and p53 are both tumor suppressors, involved in DNA repair and cell death.

8. HPV and Cervical Cancer In 1995 a study by the International Biological Study on Cervical Cancer more than 1,000 specimens of invasive cervical cancer were tested for the presence of HPV via a polymerase chain reaction-based assay and found that: • HPV DNA was present in 93% of the tumors, with no difference in presence across the 22 participating countries. • HPV-16 was present in 50% of specimens. • The other strains present included 18, 45, 31,39 and 59 in descending order of prevalence.

9. Can HPV Cause Other Types of Cancer? A 2005 study entitled “Sensitive detection of Human Papillomavirus in cervical, head/neck, and schistosomiasis-associated bladder malignancies” found that: • “Virtually all tested cervical cancers and schistosomiasis-associated bladder cancers, and a plurality of head/neck cancers are associated with HPV DNA in the tumor.” • HPV DNA was present in 35%of head and neck cancers analyzed (253 samples). • HPV DNA was present in 98%of cervical cancers analyzed. • HPV DNA was present in all 27 samples of schistosomiasis-associated bladder cancer analyzed. • In another study, HPV DNA was found in 25 of 29 samples of breast carcinoma. Strains 11 and 6 were most prevalent.

10. The Bad News • Cervical cancer is the second leading cause of cancer death among women world wide. • Reliable testing of men has yet to be developed. • An estimated 75%of women in the U.S. will be exposed to HPV at some point in their lives.

11. …And Now The Good News • 70% of women infected with HPV clear the infection through natural means within two years. • It may take 10 to 15 years for an HPV infection to develop into cancer. • Vaccines are currently in development against oncogenic strains.

12. Vaccine Development In the August issue of The Journal of Virology Johns Hopkins Medical Institute published a paper entitled “Development of a DNA Vaccine Targeting Human Papillomavirus Type 16 Oncoprotien E6.” In it they liked DNA encoding CRT to an 10-mer E6 peptide, in varying combinations. They then vaccinated and boosted groups of mice with pcDNA3-E6, pcDNA3-CRT, pcDNA3-CRT/E6, or pcDNA3-CRT/mt E6. One week after the last vaccination they inserted 50,000TC-1 tumor cells subcutaniously.

13. Reported Effectiveness of Vaccine In addition to the above results being shown in vivo, the presence of E6-specific CD8+T cells was demonstrated, and deemed necessary for an appropriate anti-TC-1 tumor response.

14. Capsid Protein Antigen-based Vaccine In addition, work is being done on a live oral adenovirus vaccine in which a series of recombinants are constructed that express the major capsid protein of HPV. Preliminary studies on oral vaccination with VLPs composed of recombinant HPV-L1 shows a complete prevention against persistent HPV infection.

15. Stress and Anxiety Associated With a Positive Pap Smear • Surveys of women who have received a borderline or mildly diskaryotic pap smear, resulting in an HPV positive diagnosis show extremely high levels of stress and anxiety. • Women who undergo a colostomy and come up HPV negative have reduced levels of stress and anxiety, but report still worrying that “it might come back” and “give them cancer.”

16. Why Does Anxiety Persist After an HPV Negative Re-evaluation? • Women report not feeling well informed. • They demonstrate an unrealistic expectation of the risks associated with HPV. • They report not understanding medical procedures preformed on them. • Young women report the highest levels of stress and anxiety due to abnormal pap smears.

17. How to Reduce Stress After Receiving an Abnormal Pap Smear • As we have all learned stress negatively effects the ability of the immune system to clear infection. It is therefore especially important for women with HPV to minimize stress. Meditation may ease anxiety.

18. Yoga or meditative practice may help ease anxiety • Gardening or other outdoor activities can elevate mood and keep your mind busy. • Participation in sports can alleviate anxious energy and give you an endorphin rush. • If necessary, take a step back from high-stress commitments, such as work or volunteer efforts – all you’ve got is your health. • Support your immune system via herbal remedies. • Most importantly, educate yourself on procedures and research on HPV as much as possible. This will allow you to feel more confidant about your choices and future, as well as give you a more accurate perspectives on the risk of actually developing cancer.

19. Things to Do (or Not Do) Drink plenty of water. Avoid doing things that might compromise your system – drug/alcohol use, sleep deprivation, or exposure to sick people. Do not have unprotected sexual contact, even with long term partners – you could be re-infecting each other. Wash your hands regularly. Get plenty of fresh air. DO NOT SMOKE! Sleep as much as you can stand to. Relax via deep breathing: I suggest breathing in and out eight counts each while imagining the virus particles in your body being expelled or washed away by the power of the breath. It sounds funny I know, but just try it, okay? Herbal Remedies Echinacea root tea is especially good. Garlic on an in everything if your stomach can handle it. Avoid dairy at all costs, especially non-organic. Goosegrass as a tea or tincture to support lymphatic system function. For lymphatic cleansing a day of fast followed by two days of fluid food only – that means fruit and veggie juice, not milk shakes and beer. Bearberry, Yarrow, and Couchgrass can be used in combination as an infusion to clear the urinary tract of microbes. Blue Flag, Burdock and Sarsaparilla are especially good for infections of the reproductive tract. A bitter, such as wormwood or strong coffee, may be used to stimulate a gut meditated immune response. Carly’s Suggestions on Immune System Support.

20. Bibliography • “Papovaviruses” www.tulane.edu/~dmsander/WWW/335/Papovaviruses.html • “Papillomavirus” web.uct.ac.za/depts/mmi/stannard/papillomavirus • “Psychological impact of human papilloma testing in women with borderline or mildly diskaryotic cervical smear test results: cross sectional questionnaire study.” May 29, 2004, www.bmj.com. Maissi et al. • “Women’s uncertainties, coping, and moods regarding abnormal papanicolaou results.” University of Wisconsin-Madison. October 8, 1999. Lauver et al. • “Women’s experience of coping with a positive Pap smear: a register-based of women with two consecutive Pap smears reported as CN1.” Acta Obstetricia et Gynecologica Scandinavica August 2003. Idestrom et al. • “Adverse psychological consequences of positive cytological screaning.” Fox Chase Cancer Center, September 2004. Lerman et al. • “Viable adenovirus…Transcriptional unit.” PNAS, March22, 2005. Berg et al. • “Progress on new vaccine stratagies against chronic viral infections.” Journal of Clinical investigation, August 16, 2004. Berzofsky et al.