HPV Flashcards
What is the papilloma virus limited to?
Epithelial cells of the skin and mucosa
What do the HPV’s cause?
Benign tumors (warts) that can lead to malignancy (mostly cervical, but also penila, anal, oral, and neck)
What age groups are warts seen on hands and faces of? age group of anogenital warts?
Children; adolescents and young adults
What HPV strains are the more prominent anogenital warts (condyloma) caused by? What should be noted about these in regards to cervical cancer?
HPV 6 or 11; they are low risk
Sub-clinical papilloma infections (SPI) are hard to detect, what strains are they caused by and what is their risk level?
HPV 16 and 18, high risk for cancer (required for the development of cervical cancer)
What two proteins play key roles in development of cancer? How?
E6 and E7, they bind and eventually remove or inactivate two TSGs, p53 and Rb
How is HPV transmitted?
Direct contact with warts or contaminated fomites
How are HPV infections kept in check?
Innate immunity; this means most do not present with common warts and it limits the number of adolescents/adults presenting with anogenital warts
Is HPV perhaps the most common STD in the US?
You betcha
What is the treatment of warts? Why does recurrence happen?
Physical destruction of warts, but recurrence is common because the virus remains in the basal layer of skin
What does the subunit vaccine for HPV consist of? what has the FDA approved it for?
It contains the L1 capsid protein; approved as an anti-cancer vaccine
What type of DNA does HPV have?
Circular, ds-DNA genomes that are about 8 kb pairs, therefore they are on the small end of DNA virus genome complexity
What kind of capsid does HPV have?
Icosahedral
What is the capsid of HPV composed of?
Two proteins, L1 and L2 (L is for “late” because these are products of genes transcribed after DNA replication), they self-assemble to form capsids
Is the HPV capsid enveloped? What does this mean for the virus?
No, so this contributes to the stability of virus particles on skin and fomites
In cells permissive for HPV growth, what happens to the virus?
It replicates and assembles in the nucleus, released by lysing cells
In non-permissive cells, what happens with HPV?
Late gene expression does not occur and instead of virus production, infection leads to formation of transformed cells = cells capable of producing tumors
How is the genome of HPV maintained in benign tumor cells (warts)?
Extrachromosomally (similar to bacterial plasmid) in 40-50 copies
In malignant tumor cells (cervical carcinomas), how is HPV handled?
A portion of the virus genome is integrated into the host chromosome
What are the 5 features of transformed cells?
1) Immortal
2) No longer contact inhibited in cell culture
3) No longer require serum-derived growth factors
4) No longer anchorage-dependent for growth in cell culture
5) Can lead to tumor formation in syngeneic animals
In HPV, what do the early (E) genes encode? Which are of particular importance?
The proteins needed for replication and transformation; E6 and E7
What does E6 of HPV do?
Binds to TSG p53 and leads to degradation
What does E7 of HPV do?
Binds to TSG Rb and inactivates it
What do the combined efforts of E6 and E7 do?
Uncontrolled growth of the cells which leads to tumor formation
In malignant HPV cells, where only a portion of the virus genome is integrated into the host chromosome, what does this mean for the genes of E6 and E7?
The E6 and E7 genes must be intact
Because a viral regulatory protein is disrupted when the virus genome is integrated into the host chromosome, what happens to E6 and E7 levels?
They are expressed at elevated levels compared to expression from the extra-chromosomally maintained copies of the genome found in benign tumor cells
What does the elevated expression of E6 and E7 from integrated genomes is believed to be a reason for what?
Why the tumor cells become malignant rather than remain benign
Where do HPVs initially infect?
Germinal cells in the basal layer of the skin (non permissive cells, so virus particles are not produced and the cells are transformed)
What happens to HPV infected germinal cells?
They mature and migrate to the skin surface, and as they differentiate into keratinized epithelia, the cells become permissive and produce virus progeny
What is the result of the germinal cell being infection with HPV?
A benign wart, due to proliferation of transformed germinal cells, which shed virus
Why can warts return after treatment?
Treatment destroys the wart but does not eliminate the virus genome from the non-permissive germinal cells which serve as renewable source of infected keratinocytes
What are the 7 diseases caused by HPV?
1) Common and plantar warts (verruca vulgaris)
2) Flat warts (verruca plana)
3) Anogenital warts (condyloma acuminata and condyloma plana): HPV 6 and 11
4) Sub-clinical papilloma infection (SPI): HPV 16, 18, 31
5) Cervical, penile, anal, oral, and neck cancers: HPV 16, 18, and 31
6) Infantile laryngeal papillomas: HPV 6 and 11
7) Epidermodysplasia verruciforms
In what time frame do most warts of HPV disappear by?
2 years
What are laryngeal papillomas?
Chronic, benign warts in the respiratory tract that generally first appear before the age of 5 (rare). Associated respiratory distress = 3% of patients die annually
What is epidermodysplasia the result of?
An inherited defect in cellular immunity; they done fight off HPV infections effectively and present with numerous lesions throughout life
Where do common and flat warts usually occur?
Hands or face of children or young adults
Where do plantar warts occur?
Soles of the feet - can be painful and require removal
What are penile, vulvar, or perianal warts caused by? How can they present?
HPV 6 and 11; can present as condyloma acuminata or condyloma plans
Why is SPI so important?
Its link to cervical cancer
How are microscopic lesions of SPI seen best?
Under 10x magnification after brushing the infected area with 5% acetic acid, which turns the warts white
What does a Pap smear detect in HPV?
Koilocytotic (vacuolated cytoplasm) squamous epithelial cells which are indicative of HPV infection
What % of cervical dysplasias are caused by HPV?
90%; but most will not lead to invasive cancer
What warts are most prevalent in children and young adults?
Common and plantar
What is the incidence of HPV in US women?
A wide range of 15-60% depending upon population studied and methods used to detect
What is most commonly responsible for prominent anogenital warts?
HPV 6 and 11; they are very low risk for causing cervical cancer
What fraction of sexual partners of HPV positive people will become infected?
About 2/3rds and few will manifest warts due to effective immune response
What percentage of cervical cancers are HPV 16 and 18 responsible for (they lead to SPI)?
70%; HPV 31 is the third most likely cause
SPI raes are 4x higher in adolescents than in women over 35, what does this suggest?
Most infections are eradicated; but 35 y/o and older have higher incidence of abnormal Pap smears, which suggests that persistent infections and other events lead to cervical cancers
What are the two known cofactors in development of cervical cancer?
Smoking and co-infection with HSV
How are laryngeal papillomas acquired?
At birth, in up to 50% of cases. HPV 6 and 11 are most common sources, risk to newborn from 1 in 100-1000 if the mother has genital warts at time of deliver
Can HPV be grown in routine cell culture?
No
How is Dx of common, plantar, and anogenital warts usually made?
Appearance
For inconclusive or abnormal Pap smears, what must be done?
A colposcopy to look for dysplasia
Is there an FDA approved test for detecting HPV DNA?
Yes
Why is effectiveness of condoms controversial in HPV?
They do not cover all of the areas of skin that come in contact during intercourse (use your imagination)
What is the FDA approved vaccine? What does it cover and what is in the vaccine?
Gardisil, it is quadrivalent (HPV 6, 11, 16, 18) and is a recombinant, subunit vaccine in which one of the capsid proteins (L1) is expressed in yeast and self assembles into capsid like structures
What is Gardisil being promoted as?
An anticancer vaccine for females (recently males) between ages of 9-26
When do warts usually return?
Immunosuppression or pregnancy
What are the methods of removal of a wart? (6)
1) BCA or TCA which denatures the proteins and causes chemical destruction, surrounding tissue can burn/become irritated
2) Cryotherapy (must minimize scarring)
3) LEEP removes cells involved in cervical dysplasia
4) Podofilox is a gel, active ingredient = anti-mitotic agent (not for pregnancy)
5) Imiquimod = topical agent that stimulates localized interferon and cytokine production (not for pregnancy)
6) Intralesional interferon injection
What has limited the number of cervical cancer deaths in the US?
Pap smear/early detection
Where do cervical carcinomas continue to be a prominent, fatal cancer?
Developing countries; vaccine aims to spare people from this cancer
