Lec 37 HPV Flashcards
What are low risk HPV types associated with? Which strains are low risk and which of these are most prevalent?
- ano-genital condyloma
- low grade cervical dysplasia [CIN 1]
- HPV 6 and 11 = main types of low risk
- also: 40, 42, 43, 44, 54
Which strains are high risk HPV? Which are the most prevalent?
- most prevalent: 16 [55% of cervical cancers] and 18 [15% of cervical cancers]
- less prevalent: 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
What are high risk HPV types associated with?
- high grade dysplasia
- cervical cancer
- persistent HPV is greatest risk for malignant transformation
What types of cancers [besides cervical] is HPV associated with?
70-80% of anal cancers
40-50% of vulva/vaginal cancers
40-50% of penile cancers
25-60% of oral/oropharyngeal cancers
What is a pap smear?
screening test for cervical cancer –> use exfoliated cervical cells collected transvaginally
How is HPV transmitted?
sexual transmission
What are the classifications of pap smear finding?
- NILM = negative for intra-epithelial lesion malignancy
- ASC = atypical squamous cells
- SIL = squamous intrapeithelial lesion
- LSIL = low grade SIL [mild dypslasia, CIN1]
- HGSIL = high grade SIL [moderate/severe dysplasia, carcinoma in situ [CIS], CIN2/3]
How do you get rid of HPV
most HPV clear spontaneously [including both high and low risk types]
What are co-factors for cervical cancer risk along with HPV infection?
- long term use of oral contraceptive
- high number full-term pregnancies
- tobacco smoking
- past infection with HSV-2 and chlamydia trachomatis
Does having an oncogenic form of HPV mean you will get cancer?
having oncogenic HPV is necessary but not sufficient
Why are HPV 16/18 so causative of cancer?
- they are more likely to give persistent infection rather than clear right away
- shorter latency [shorter time between infection and seeing clinically significant disease]
What are viral properties of HPV?
- non-enveloped
- DNA virus
- double stranded circular genome
- icosahedral capsid
What is structure of HPV genome?
- early E region codes for proteins that control DNA replication
- – viral replication proteins E1, E2, E3, E4
- – oncogenic transforming proteins E6, E7
- late L region codes for major capsid protein L1 and minor capsid protein L2
- non-coding upstream regulatory region
What is importance of E6 and E7 HPV protein?
they are oncogenic transforming proteins
What controls expression of E6 and E7 proteins in HPV?
- E2 viral replication protein represses E6/E7 transcription
- integration of viral genome in host DNA allows E6/E7 to be over expressed
What is function of E6 HPV protein?
- inhibits p53 protein
- —> inhibits apoptosis, promotes loss of cell-cycle control
What is function of E7 HPV protein?
- degrades pRB [retinoblastoma protein, tumor suppressor]
- —> accelerates DNA synthesis, disrupts cell cycle control
Which class of HPV antigens gives humoral immune response?
two classes of HPV antigens: early and late proteins
early: humoral immune response modest or absent
late: get consistent/strong neutralizing antibody response
What are the late protein antigens of HPV?
capsid antigens
How does HPV evade immune system?
- it doesn’t infect APCs
- infected keratinocytes less susceptible than other infected cell to CTL lysis –> little tissue destruction
- virus infects only epithelium without blood-borne phase
- poor immune response to early viral protein
- theres is variable immune response to late viral capsid proteins
How do you classify types of papillomaviruses?
L1 gene –> classified as different type if L1 nucleotide seq is at least 10% dissimilar
What type of vaccine is HPV vaccine?
- type specific sub-unit vaccine
- antigen is virus-like particle [VLP] = virus shells
What strains are in the HPV2 vaccines?
HPV 16, 18
What strains are in the HPV4 vaccines?
HPV 6, 11, 16, 18
HPV2 vs HPV4: antigen and adjuvant
HPV2
- antigen: baculovirus expression vector system in insect cells
- adjuvant: alum
HPV4
- antigen: yeast system
- adjuvant: ASO4
Is HPV2 or HP4 better at producing neutralizing antibodies to HPV16/18?
HPV2 is better
What is gardasil?
HPV4 vaccine
What is cervarix?
HPV2 vaccine
Which HPV vaccine has more potent adjuvant? What does this mean?
HPV2 –> might influence duration of immune response and cross-protection against other HPV types not in vaccine
What is the next HPV vaccine under investigation?
9 valent vaccine
What are recommendations for giving HPV2?
- girls age 11 or 12
- girls/women 13-26 who did not get all 3 doses when they were younger
ideal is to give before onset of sexual activity
What are recommendations for HPV4?
- girls and boys 11-12
- girls 13-26 or guys 13-21 who did not previously get doses
- through age 26 for msm or immunocompromised men
ideal is to give before onset of sexual activity
What are risk factors for anal cancer besides HPV?
75-80% of anal cancer related to HPV
other risk factors: number of lifetime sexual partners, receptive anal intercourse, immunosuppression
What is the anal T zone?
- transition from stratified squamous to columnar epithelium
- similar to cervical T zone
- location where vast majortiy of anal dysplastic lesions occur
What are AIN?
anal intraepithelial neoplasia = neoplastic precursor that occurs in anal t zone
What are risk factors for penile cancer?
40-50% linked to RPV
risk factors: lack of circumcision, chronic inflammation
What are risk factors for oropharyngeal cancer?
- up to 60% in US associated wtih HPV-16
- other risks: tobacco, alcohol, number of lifetime partners
Is there any test available for clinical use to determine whether female has an HPV type?
nope!
How is HPV transmitted?
- mostly penetrative sexual contact
- some non-penetrative sexual contact
What is disease associated with oral HPV?
strong association with oropharyngeal cancer
If the HPV vaccine 3 dose schedule is interrupted what do you do?
- do not need to restart series
- if series interrupted after first dose –> administer as soon as possible, separate 2nd and 3rd doses by at least 12 wks
Are there any ACIP recommendations for specific groups?
- no recommendation for those with history of dysplasia
- ACIP recommendations address certain special populations
If patient had previous cervical dysplasia should you give HPV vaccine?
no specific recommendation currently –> discuss with patient and let them make their decision
What are current ways of testing HPV?
- serology
- viral shedding
- cytology test [do with cervical cancer screening]
What are downsides of serology testing for HPV?
- under-estimates number of infected individuals
- people with current/past infection may not always develop antibodies [<70% of those with HPV will react to antibody test]
What are two types of viral shedding test for HPV?
- hybrid capture test: pooling 13 common high-risk types
- type specific test: DNA PCR type specific viral testing of E6/E7 mRNA
What is evidence of HPV infection in pap smear?
atypical cells of undetermined significance or squamouts in
How is HPV persistence currently identified?
by viral shedding not serologic testing
