HPV Flashcards
HPV belongs to what family of viruses?
papillomaviruses
describe the structure of HPV
- small
- non-enveloped
- ds dna virus
how is HPV transmitted generally?
- through sexual contact / close personal touching
- # 1 STD globally
- most prevalent STD in the us
is HPV a family of viruses or a single subset?
- family
- 100s have been identified
what is the clinical presentation of HPV?
- majority = asymptomatic
- gentical warts = most common symptom
- cervial dysplasia can also occur - precursor for cervical cancer which can occur if left untreated
- other cancers can also occur but are less common (head/neck, anal, penile)
who experiences the majority of the HPV disease burden, men or women?
women
what would is indicated by a patient who has antibodies for HPV but receives a negative PCR test? what are the limitations of such a result?
- indicates that the person has been exposed to HPV at some point in their live
- but it does not dictate whether an infection has happened, if an infection has occured in the past or if an infection is currently present
what are the risk factors for cervical cancer? (5)
- lack of effective screening
- smoking
- multiparity (multiple kids)
- long-term use of oral contraceptives
- HPV
what are the risk factors for HPV? (6)
- age
- sex
- lack of condom use
- age of first inercourse/number of partners
- not beign circumsized
- co-infections (especiallly if other STIs)
why is age a risk factor for hpv?
- maturation of cervical mucosa
- cells that compose the cervix change as women mature (younger cells are most susceptive to HPV)
why does circumcision reduce the risk for hpv?
- the foreskin cells are sesceptible to hpv
- there is less surface area which decreases the risk of spreading
how is hpv transmitted specifically?
through endothelial cells not liquids
what is the natural cycle of an hpv infection? are all of these steps reversible?
normal cervix => hpv infection => initiated cancer => benign tumor => malignant tumour
-all are reversible except from benign to malignant
where does “regression” occur in the hpv cycle?
from initated stem cell cancer back to hpv infection
where does “clearence” occur in the hpv cycle?
from hpv infection to normal cervix
describe the anatomy of the cervix
composed of 3 sections:
- external os: opening to vagina (stratified squamous)
- endocervical canal (glandular epithelium)
- internal os: opening to uterus (stratified squamous)
what is the transformation zone?
area of the cervix where the squamous epithelium of the external os meets the glandular epithelium of the endocervical canal
what is the significance of the transformation zone with respect to hpv?
this is the area where hpv infects susceptible cells
what are the 3 possible outcomes after hpv infection of the transformation zone?
(1) clearance: the majority of infections result in viral clearance within 2 years of the infection
- immune system is engaged
(2) persistance: infection does not clear on its own
- hpv tethers itself to host dna and continuously repiicates at low levels building up a reserve
- the immune system is not engaged
(3) progression: small portion progress to initiated cervical cancer stem cells
describe initiated cervical cancer stem cells
- these cells have undergone genetic transformation as a result of the hpv infection
- are able (if left unchecked) to generate a benign cervical tumor
viral gene expression of the hpv genome is thought to be related to:
the state of differentiation of the infected epithelium
describe microabrasions as a mechanism for hpv infection
- sexual intercourse causes microtears within the genital tract due to friction
- hpv uses these as a portal of entry
what are basal keratinocytes
- hpv travles down and infects these
- these are the cervival cells at the layer farthest from the lumen
- from here there are two equally possible ways the virus can continue the infection process
define viral assembly as one of the 2 possible processes of hpv infection
- differentiation of hpv infected cells
- as infected keratinocytes differentiate they move up towards the mucosa bringing the virus with them
- the virus enters different stages of gene expression
- when they reach the lumen, the virus has assembled and is infectious
- virus is released into surrounding tissues spreading the infection
does viral assembly usually lead to hpv-mediated cancer?
no
where do the different stages of gene expression occur during viral assembly?
(1) suprabasal layer
(2) terminal karatinocyte
what is the type of gene expression associated with the suprabasal layer?
early stages: producing proteins that encode for viral dna
what is the type of gene expression associated with the terminal keratinocyte
late stages: producing proteins that encode for structural proteins
explain chromosomal integration as one of the 2 possible processes of hpv infection
- the virus integrates its genome into the host dna
- this can result in uncontrollable oncoprotein production and host cell transformation
does chromosomal integration usually lead to hpv-mediated cancer?
yes
can chromosomal integration and viral assembly happen at the same time?
yes
what is the mechanism of persistance for hpv? what is the result of this?
- chromosomal integration - disrupts normal cell cycle leading to uncontrolled cell division and the accumulation of genetic damage
- this damage can lead to cervical dysplasia (endothelial lesions) and abnormal growth of squamous cells on the cervix
- this is a premalignant transformation
is cervical intraepithelial dysplasia curable?
yes
what genes are associated with severe dysplasia?
E6 and E7 hpv oncoproteins
what is the function of the E7 protein?
- inhibits pRB to stop cell cycle arrest
- i.e. this is the primary transforming protein that facilitates the proliferation of disregulated cells
what is the function of the E6 protein?
- interferes with the normal function of p53 (decides if cells should be marked for apoptosis - usually would happen if too many were produced (E7))
- allows for further cell disregulation
what are the hpv genotypes for patients with low risk of hpv
6, 8, 11
-genital warts
what are the hpv genotypes for patients with probable high Irisk of hpv
26, 53, 66
-precancerous lesions
what are the hpv genotypes for patients with high risk of hpv
16, 18
-cervical cancer
what can explain the higher risk subtypes of hpv?
oncoproteins (E6/E7) have a higher binding affinity for the p53 and pRB proteins and are therefore more disruptive to cells
_____ might be an important biomarker for distinguishing hpv infection from benign tumors?
- it has been observed that the hpv genome is integrated into host cell dna in a high portion of patients with high grade carcinoma
- not necessary for integration though
describe how progression of the hpv infection can result in cervical cancer
- accumulation of endothelial cells disrupts the organized structural appearance of epithelial tissue
- disorganization extends through the upper layers and to the surface of the epithelium
what is used to classify the degree of a cervial lesion?
progression of abnormal cell growth
what are the requirements for CIN1?
abnormal cell growth in the lower 1/3 of the cervical endoethium
what are the requirements for CIN2?
abnormal cell growth in the lower 2/3 of the cervical endoethium
what are the requirements for CIN3?
abnormal cell growth >2/3 above the basal membrane
what is the intermediate precursor to cervical cancer?
CIN3
when does invasive cancer ensue? (when does it become the ultimate consquence)
- when the abnormal cells break through the basal membrane and infect the dermis
- when it gets to the basal membrane the virus sheds its capsid and the viral dna enter host cell
- this is where E6 and E7 take action
- result is a worse phv infection and cervical cancer
what gene is used to identify hpv?
L1
what are key steps in preventing cervical cancer? (5)
- screening (pap smear)
- triage results (bethesda screening system triages results from pap smear)
- colposcopy - used to get a closer look at concerning results
- treatment
- post-treatment follow up
describe screening tests used for hpv and why they are useful
- progression of hpv is linked to histologic and cytologic appearance of the cervical tissue
- histology = study of the entire tissue (can be invasive)
- cytology = study of isolated tissue (very effective for early stage detection)
- both have similar classification systems
describe a pap smear procedure
what are the advantages of this method?
- involves the use of a cervical brush to scrape surface mucosal cells off of the cervix
- these cells are then immediately smeared onto a slide or swirled in alcohol and then dispensed onto slides to be analyzed for precancerous changes
- relatively cheap and quick
what is the purpose of the brethesda screening system?
what are the possible results?
- interprets pap smear results
- the system has standardized diagnostic categories for the different stages of cervical cancer
- results can be either:
(1) normal squamous mucosa
(2) atypical squamous cells of undetermined significance
(3) low grade squamous intraepithelial lesion
(4) high grade squamous intraepithelial lesion
(5) carcinoma
describe normal sqamous mucosa
- no evidence of abnormal cells
- basal cells are maturing into healthy epithelium
describe atypical squamous cells of undetermined significance (ASCUS)
- mild atypia but not quite LSIL
- nuclei are mildly enlarged
- no suggestion of perinuclear clearing
describe low grade squamous intraepithelial lesion (LSIL)
- nuclei are enlarged and dark with perinuclear clearing
- may be binucleated
- begining of hpv infection
- cells are infected but not pre-malignant tumors
describe high grade squamous intraepithelial lesion (HSIL)
- loss of clearing with busy looking epithelium because each cell has more nucelus than cytoplasm
- indicated the infection has been present for an extended period of time
- pre-malignant and will likely progress to carcinoma
describe carcinoma
- hpv infected cell has progressed to an invasive squamous cell carcinoma
- viral dna is integrated into host cell dna
- normal regulation has been altered
- cells may not resemble normal structure at all
what is the traditional method for management of ASCUS or LSIL results?
the individual will be sheduled to repeat the pap smear in 6 months and is referred to a colposcopy
what is the traditional method for management of HSIL or carcinoma results?
indivdual is sent to colposcopy
how long does the progression from CIN1 - CIN2 or from CIN2 - CIN3 take?
months
how long does the progression from CIN3 - carcinoma take?
years
how is hpv able to stay under the radar of the immune system? (5)
- doesnt lead to apoptosis (usual trigger for immune response)
- replicates cells without altering them to much
- has proteins that shut down the innate immune response -delays the adaptive response
- downregulates th1 and th2 to supress the adaptive immune response
describe the process of a colposcopy
when is this preformed?
- preformed when theres concerning pap smear results
- gynecologist uses a colposcope (special microscope) to magnify the cervix for better visualization of the tissue
what happens if there are abnormal areas identified during the colposcopy?
gynecologist will biopsy the tissue, which is sent to path where it is analyzed to confirm the presence of hpv or cervical cancer
what do treatment methods depend on?
biopsy results
define cryotherapy
- surgical procedure used to freeze an destroy abnormal cervical tissue
- speculum is inserted into vagins, cyroprobe with nitrogen gas is used to freeze the tissue
- dead cervical tissue then sheds in the following weeks
define loop electrosurgical excision procedure (LEEP)
- loop of electrical wire is passed through the cervical os to remove a half donut-shaped piece of cervical tissue
- this tissue is then sent to path
define cold knife cone biopsy
a scalpel is used to exise the abnormal tissue
what are the preffered treatments? why?
- LEEP and cold knife
- bc physicians have clear margins and can ensure the abnormal tissue is removed
what is the post-treatment follow up for cryotherapy, LEEP and cold knife cione biopsy?
what happens if results are normal?
- colposcopy and a pap smear
- if results are normal the patient returns to routine screening
compare and contrast the test for the presence of hpv dna from collected cervical cells and a pap smear
- checks for the presence of viral dna where the pap smear checks for morphological changes to the cervical epithelial cells
- not covered by ohip, faster
- beneficial for confirming if suspicious results are truly abnormal
- can also be used to indicate hpv post-treatment
how are the hpv vaccines made? are they non-infectious? why or why not?
- with recombinant technology
- virus like particles of the L1 protein are inserted into recombinant plasmid
- non-infectious - lack live particles
can hpv vaccines provide protection of you are already exposed?
no
describe Gardasil
- 2006
- first protected against hpv 6,8,18 and 18
- now protects against 9 types
describe Ceravix
- 2010
- females btwn 9 and 45
- hpv 16,18
