HPV – Flashcard
Unlock all answers in this set
Unlock answersquestion
Features of the Papillomaviruses
answer
- small, non-enveloped virus with a circular dsDNA genome - live a lot LONGER than enveloped viruses!!
question
Transmission of HIV vs. HPV
answer
- HIV is enveloped, so won't transmit well outside of cells without mucus contact or blood- needs to be transmitted in blood or fluid - HPV is NON-ENVELOPED. can even be transmitted from fomites (objects)
question
Specifcity of HPV
answer
- HPV are SPECIES specific!!! - can't get it across species - humans = human HPV
question
How many types of HPV have been identified?
answer
- over 100 types!! - 80 have been sequenced - believed that over 200 types exist
question
How common is HPV in the general population
answer
- is UBIQUITOUS!! - most commonly viral sexually transmitted infection (STI) globally!
question
Where in the world is the highest and lowest prevalence of HPV?
answer
- highest in Africa - lowest in Europe - but just an estimate!!
question
How common is cervical cancer?
answer
- globally, cervical cancer is the second most frequent cancer in women!!! - HPV causes virtually ALL cases of cervical cancer and approx. 4% of all cancers!!
question
What other cancer can HPV be responsible for besides cervical?
answer
- vaginal, vulvar, penile and anal cancers
question
HPV and death
answer
- cervical cancer rates are significantly higher in areas without cytology screening programs!!! - when they have screening problems, death = lower! - death rate is indicator of screening programs
question
HPV screening programs for detection
answer
- screening programs good at detecting the majority of cervical cancers (squamous cell carcinomas) - NOT very good at detecting cervical adenomcarcinomas
question
How much of the population is exposed to HPV at some point?
answer
- approximately 75% of the population is exposed to HPV at some point!!
question
How much of the population exposed to HPV develop genital warts? cancer?
answer
- very small proportion of individuals develop genital warts - even smaller proprotion develop cncers
question
PCR in detection of HPV
answer
- PCR amplifies DNA - if the snippet you take doesn't have HPV in it - PCR is good for viruses that are prevalent in body, but for viruses that are localized into small portions of tissues (HPV) is a very bad diagnostic - UNLESS you have a genital wart and want to ask whether wart has HPV, use PCR
question
What is a problem with serologic investigations of HPV?
answer
- serologic response to a pathogen wanes over time - person can become negative over time even after vaccination!! - so 75% may be an UNDERESTIMATE of pop. exposed to HPV
question
How do the majority of HPV transmission occur?
answer
- as a result of sexual contact or close personal contact (skin to skin) with an infected person - insertive and/or receptive sex is not necessaray!! contact with a mucous membrane appears to be sufficient
question
How can you reduce HPV transmission
answer
- condoms appear to reduce transmission, but do not provide complete protection
question
Fomite-mediated transmission
answer
- risk of fomites mediated transmission is not clear - but probable
question
When is the HPV vaccine administered (usually)
answer
- grade 8s - because majority haven't had sexual contact
question
HPV vaccine
answer
- is a PREVENTATIVE vaccine - if you already have it then won't help
question
Is the vaccine administered to girls or boys
answer
- usually girls, but could be beneficial to vaccinate men - more men with genital warts than women, so starting to vaccinate boys so they don't give it to women
question
What factors can increase risk of HPV? (7)
answer
- sex - age - age of first sexual intercourse - co-infections - male circumcision - condom use - lifetime number of partners
question
How does circumcision affect HPV acquisition?
answer
- circumcision = reduced risk - foreskin is made up of squamous epithelial cells on inside - if circumcised, this target surface area is gone!!
question
How does age affect HPV acquisition?
answer
- significant rise in HPV prevalence around the age of onset of sexual activity, and declines with age - dramatic increase in CERVICAL CANCER between 20-45 years of age!!!
question
How does co-infection affect HPV acquisition?
answer
- increased risk of acquisiton with other STIs
question
HPV genotypes
answer
- lots of different genotypes!!! - genotypes 16 AND 18 are the 2 highest for cervical cancer!!! - genotypes 6 and 11 are highest for anal warts
question
Clinical conditions of HPV
answer
- lots of different clinical presentations - ex. laryngeal (oral sex exposes throat area to HPV) - different genotypes can cause presentations in different areas
question
What genotypes of HPV are the vaccines against?
answer
- 16 and 18 (for cancer) - 6 and 11 (for anal warts)
question
What happens to the majority of HPV infections?
answer
- result in viral clearance and development of type-specific immune response!! - unclear what the immune mechanisms associated with clearance of HPV
question
Infection vs. Disease
answer
- infection = having/acquiring the pathogen - disease = pathogenesis of the pathogen
question
What happens to the 10% of infections that are not immediately cleared?
answer
- goes to pre-cancerous lesions - but 90% of that regresses!!! - associated with pre-screening, immunological function etc. - really small percentage of the infected develop cervical cancer
question
What is development of invasive cancer closely linked to?
answer
- INTEGRATION of viral DNA!!
question
What proteins are overexpressed in episomal or itnegration of viral DNA?
answer
- E6 (targets p53) - E7 (targets pRB) - leads to increase in cell proliferation, decrease in repair
question
How many base pairs are in the HPV genome
answer
- approx. 7900
question
How many ORFs are in HPV genome?
answer
- 8 open-reading frames (ORFs)
question
What do ORFs in HPV genome ecnode for?
answer
- 6 early proteins - 2 late structural proteins - these proteins have a HIGE impact on what happens in the HPV environment!!
question
How is viral gene expression related to state of differentiation of the infected epithelium?
answer
- suprabasal epithelial cells- early gene expression (originally gets infected and expresses these early genes) - terminally differentiated karatinocytes- late gene expression
question
Mechanisms of HPV disease (5/6 steps)
answer
1. micro abrasion(s) in the mucosa of epithelium (small portion is now torn!) 2. infects basal ketatinocytes (are actively replicating) 3. differentiate and move to distal mucosa 4. viral assembly as cells move to mucosa (distal movement of infected cells) 5. infectious virus shed (6?). can get chromosomal integration (not always) - cycle repeats
question
Chromosomal integration
answer
- only happens in keratinocytes (BASAL LAMINA cells)- then proteins will be expressed not matter what as a consequence of replication!! - thought to be the factor that is the increased risk for cancer!! - important for development of malignant disease but not sufficient
question
HPV viral DNA replication in basal cells
answer
- occurs in episomal fashion - at a LOW rate of 50-100 copies/cell - not gue agmounts of viral turnover
question
What happens to the infected basal cells?
answer
- enter the suprabasal cell layer - associated with increased expression of early and late proteins (E4, E5, E6, E7) - only expresses E1/E2 at first, then as cells migrate further up to surface start expressing these other early proteins
question
What happens when the viral cells get close to the surface
answer
- start expressing late proteins (ASSEMBLY proteins) L1 and L2!!! these proteins have huge impact on cell!! - viral assembly occurs in the terminally differentiated epithelial cells - virions are then released in to the surrounding tissue, infection spreads
question
What does integration of the HPV genome into chromosome result in?
answer
- uncontrollable oncoprotein production and host cell transformation
question
What are other important mechanisms thought to play an important role in cancer development?
answer
- DNA methylation - chromosomal instability - telomerase activity
question
DNA methylation
answer
- silences certain genes - if you get abarrencies in DNA methylation system, don't know which ones are silenced and which ones are not
question
How does integration of DNA affect HPV GENOME
answer
- interrupts the E2 open-reading frame (ORF) - expression of E2 normally down regulates E6 and E7 - lack of E6/7 inhibition results in ubiquitinalation of p53 and pRB (retinoblastoma suppressor proteins) proteins - loss of cellular p53 and pRb allows for cell with DNA damages to divide (increases risk of cancer development)
question
Where is often the site of integration?
answer
- a chromosomal fragile site
question
Cervical intraepithelial dysplasia
answer
- a premalignant transformation and abnormal growth of squamous cells on the surface of the cervix - due to viral disruption of cell-cycle and accumulation of genetic damage
question
CIN
answer
- cervical intraepithelial neoplasia - not cancer, and is usually curable - CIN grading scale!!
question
CIN grading scale
answer
- 1, 2, 3, invasive carcinoma - CIN 1 = mild dysplasia - CIN 2 = moderate dysplasia - CIN3 = severe dysplasia - Invasive carcinoma
question
HPV innate immunity
answer
- innate immune system is first line of defence - cervical mucosa has LOTS of immune surveillance!! lots of immunologic mechanisms that survey the genital mucosa - looks for molecular pattern- if it looks like non-self tries to get rid of it
question
What receptors are important in innate immunity
answer
- TOLL-LIKE receptors!! - very old pattern recognition molecules - identifies old dsDNA
question
How does HPV suppress the innate immune system
answer
- HPV E6 and 7 inhibit TLR9 (toll-like receptor) gene transcription!! - also disregulate interferon regulatory genes (dampens immune responses), and up-regulates TGF-b - does not elicit danger signals curcial for activation of APCs and immune cells!!
question
Why does HPV not elicit danger signals?
answer
- is not cytolytic!! doesn't lyse cells - quiet virus so no immune response - no active inflammatory markers
question
How does HPV affect CD4 cells?
answer
- alters the way the immune response is tailored - TH1 CD4 response (CTLs) is switched to TH2 response!! - get immune dampening MHC
question
E5 protein of HPV
answer
- inhibits acidification of endosomes - downregualtes MHC class I expression. major impact on immune recognition and NK cells!!!
question
Why doesn't HPV downregulation of MHC molecules activate NK cells?
answer
- increased viral protein expression only occurs in keratinocytes avascular area - limited access for immune system - replicates where NK cells do NOT circulate!!
question
HPV vaccines
answer
- 2 types: quadravalent and bivalent - both made with recombinant technology in which proteins form virus-like particles (VLPs) of the L1 protein! - are noninfectious and lack live biological products!!
question
Quadravalent vaccine
answer
- HPV types 16, 18, 6, 11 - Gardasil
question
Bivalent vaccine
answer
- HPV types 16 and 18 - cervarix
question
What is the major basis of protection against infection with the vaccines
answer
- neutralizing serum IgG that transudates from capillaries to the gential epithelial mucosa, and binds to viral particle
question
Efficacy of vaccine
answer
- efficacy of 96% or more against the combined endpoint of CIN1, CIN2/3 due to HPV 6, 11, 16 or 18 up to a mean of 3.7 years after vaccination among females aged 15-26 years
question
levels of HPV16 and 18 antibodies after vaccines
answer
- up to 24 months after dose 1, levels of the antibodies in secretions and serum are strongly correlated
question
Impact of vaccine
answer
- in australia, significantly reduced the proportion of men that were diagnosed for genital warts at their first visit - huge plummet in genital warts
question
What new type of vaccine is being developed
answer
9- valent vaccine - about equivalent to quadrivalent!
question
4 major steps in cervical cancer development
answer
1. infection of the metaplastic epithelium at the cervical transformation zone 2. persistence of infection 3. progression of persistently infected epithelium to cervical precancer 4. invasion through the basement membrane beneath the epithelium
question
What percentage of HPV infections persist (aren't cleared)
answer
- 10%
question
How long does it take most people to clear HPV infection
answer
- 1-2 years
question
What type of epithelium does HPV infect?
answer
- usually infects the cervical TRANSFORMATION ZONE! - boundary between 2 different types of epithelium, where it is changeable!! (shifts back and forth between type of epithelium)
question
What are the 2 types of epithelium in the cervix?
answer
- squamous (on exocervix) - columnar glandular (along canal)
question
How do infecting viral particles reach the germinal cells in the basal layer
answer
- through tiny tears to the mucosa (microscopic lesions) - genital HPV infections are transmitted mainly by mucosa-to-mucosa contact
question
In taking biopsies/pap smears, where should the physician sample from?
answer
- the transformation zone!!
question
Types of HPV
answer
- over 40 different types of HPV infect the epithelial lining of angogenital tract
question
How many subtypes of HPV are associated with cervical risk (considered high-risk)
answer
15!! - three other types are probable high-risk types
question
How many subtypes of HPV are considered low-risk?
answer
- 12 types - seldom cause cervical cancer - typically symptom is genital wart
question
What are the 2 most common high risk HPV subtypes?
answer
- HPV16 and HPV18 - are responsible for 70% of cervical cancer and about 50% of cervical pre-cancer!!
question
What 2 types of HPV are most responsible for genital warts?
answer
- HPV6 and PHV11 - responsible for about 90% of genital warts
question
What is the strongest factor that affects the risk of viral persistence/progression?
answer
- HPV subtype
question
How long is the lag time between infection and appearance of the first microscopic evidence of pre-cancer
answer
- can be as short as 5 years!! - histological pre-cancer often diagnosed in as short as 2 years time - but typically takes 25-35 years to go through whole course
question
Within 24 months (after you acquire the infection), what are the levels of cleared, persistent, progressed infections
answer
- majority cleared - some persisted - VERY FEW progressed
question
How many genes does HPV code for?
answer
- 8
question
What are the primary HPV oncoproteins?
answer
E6 and E7
question
What are the most important cellular targets of the HPV oncoproteins?
answer
- p53 (E6 inhibits) - pRB (E7 inhibits)
question
Normal pattern of expression for HPV proteins
answer
- early proteins responsible for replication or the viral genome occur early and deep down in epithelium - as they mature, the virus starts to transition to producing all the late proteins that are responsible for packing etc.
question
What are the 4 diagnostic classifications of tissue biopsies for HPV
answer
- normal - low grade squamous intraepithelial lesion- LSIL (viral infection but not pre-cancer) - high grade squamous intraepithelial lesion- HSIL- pre-cancer (progression) - carcinoma
question
HSIL
answer
- progression toward invasive carcinoma - virtually guaranteed that there is a high-risk HPV
question
Carcinoma
answer
- invasive disease that can spread to other places and kill you! - (intraepithelial in HISL and LISL = non-invasive. happening within the epithelium)
question
How does the cytoplasm content in cells change as the dysplasia gets more severe?
answer
- cells have less cytoplasm and more nucleus - become blue on the stain and lose ability to mature normally!!
question
Histology of normal cervical mucosa vs. high grade
answer
in high grade: - lots more nuclei- look BLUER - see more mitosis!! usually when you take a biopsy, the probability of finding a cell in mitotic phase is very low. but see lots of them in neoplasia processes
question
What could be an important biomarker in distinguishing HPV infection from precancer
answer
- integration of the HPV genome into the host genome!! - but integration might not be necessary to cause invasion (not all women with invasive cancers have measurable integration)
question
External risk factors for carcinoma for women ALREADY WITH HPV
answer
- MINOR compared with the extremely high risk of the most carcinogenic HPV subtype - lack of screening is most important!! - also smoking, multi-parity, long-term use of oral contraceptives
question
What does cervical cancer prevention invovle
answer
- screening (Pap smear) - triage of equivocal results - colposcopically guided biopsy of abnormal screening results - decision whether to treat - treatment - post-treatment follow-up - return to normal screening if possible
question
Pap smears
answer
- scraping/brushing of tissue surface - not chunks of tissue but are single layer of cells - generates a recommendation for the family physician
question
Screening
answer
CYTOLOGY!! (study of cels) - Bethesda System - Normal - ASCUS - LSIL - HSIL - Carcinoma
question
Bethesda
answer
- ASCUS- equivolca changes (atypical squamous cells of undetermined significance) - LSIL: viral infection but not pre-cancer - HISL- pre-cancer (progression)
question
Glass Slide
answer
- smear cells out on glass slide - but these days, can just take the little brush/spatual and send it off to the lab - more organized process of spreading cells out in a monolayer
question
Pap smear LSIL
answer
- abnormal nuclei are bigger and may have perinuclear halos
question
Pap smear HSIL
answer
- almost all nucleus!! - precancer cells have high nucleus to cytoplasmic ratio
question
Pap smear carcinoma
answer
- have very prominent red nucleoli - other than that, look like HSIL
question
Triage
answer
- normal: repeat every three years (pap smear?) - ASCUS and LSI: repeat Pap in 6 months then if still abnormal refer to colposcopy - HSIL/carcinoma: straight to colposcopy
question
Colposcopy
answer
- basically like using a microscope to look at the cervix - much more high resolution - applies certain products to cervix to highlight lesions - decide whether or not to do a biopsy
question
Treatment options
answer
- depends on biopsy diagnosis and age of patient treatment - could be: cyrotherapy, LEEP (loop electrosurgical excision procedure), cold knife cone biopsy
question
LEEP
answer
- excise method - burns through tissue and cauterizes as you got to reduce bleeding
question
Cold knife cone
answer
- removes a large, cone-shaped piece of the cervix to look for precancerous cells or cancerous material
question
Cyrotherapy
answer
- necrosis, which results from the freezing and thawing of cells??
question
Post treatment follow up
answer
- colposcopy and Pap smear - return to routine screening
question
HPV Screening in Ontario
answer
- if you're willing to pay $100 you can get an HPV test as part of your screening algorithm
question
Direct HPV testing
answer
- testing negative provides greater reassurance - can indicate who should go to colposcopy efficiently - can be used post colposcopy if no pre-cancer is found - can be used to confirm cure post treatment
