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Human Papilloma Virus

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Human Papilloma Virus
Basic biology, infection, and
psychological effects.
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.
• 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.
Many of the HPV genomes have been
sequenced and have a genetic organization
similar to that of HPV-16, one of the
oncogenic strains.
• The Papillomavirus’ genome is
circular, d/s DNA
approximately 8,000bp in size.
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.
Expression of the
Papillomavirus
genome is 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.
HPV Infection Outcomes
E6 and E7 interact with many cellular proteins, which influence the
outcome of infection.
p53
bax
p21
E6
interactions
E7
interactions
A poptosis
G row th A rrest
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.
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.
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.
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.
…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.
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, pcDNA3CRT, pcDNA3-CRT/E6, or pcDNA3-CRT/mt E6. One
week after the last vaccination they inserted
50,000TC-1 tumor cells subcutaniously.
Reported Effectiveness of Vaccine
20 m ice
5 D N A 3-E 6
5 D N A 3-C R T
5 D N A 3-C R T /E 6
5 D N A 3-C T R /m t E 6
C halanged
C halanged
C halanged
C halanged
5/5 tum ors persist
5/5 tum ors persist
0/5 tum ors persist
4/5 tum ors persist
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.
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.
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.”
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.
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.
• 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.
Carly’s Suggestions on Immune System Support.
Herbal Remedies
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?
•
•
•
•
•
•
•
Echinacea root tea is especially good.
Garlic on an in everything if your stomach
can handle it.
Avoid dairy at all costs, especially nonorganic.
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.
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.
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