9. Papillomavirus 1 Flashcards
describe the papillomavirus structure and genome. is it enveloped or naked?
dsDNA virus in an icosahedral capsid
naked
what is the family of papillomavirus?
papillomaviridae
what baltimore class is papilloma?
class I (dsDNA)
what cells does papilloma infect?
infects keratinocytes with differentiating epithelia in skin and mucosa
what does the papilloma life cycle depend on?
depends on the differentiation program that keratinocytes undergo in the epithelia
what is unique about how papilloma affects cells?
papilloma must infect cell AND induce differentiation
what type of lesions does papilloma cause?
hyper-proliferative benign or malignant lesions of skin and mucosa
how many types of papilloma virus are there? what is different between them?
there are >200 types, each with a preference for certain anatomical locations
how was papilloma first discovered?
made extract of common warts and infected human subjects –> they got warts
then found that cell-free filtrate of common warts can transfer infection
therefore, warts are caused by a virus
how was the oncogenic potential of papillomavirus discovered?
cottontail (wild) rabbits were found to have lesions from papillomavirus –> made extract of these lesions and infected domestic rabbits –> caused malignancy
when was HPV first associated with cervical cancer?
in 2008
other than those 3 genuses, what type tissue do all other genuses infect?
cutaneous
what are 3 genuses of papillomaviruses? what type of tissue do they infect?
- Genus ALPHA –> cutaneous and mucosal
- Genus BETA –> cutaneous
- Genus GAMMA –> cutaneous
what 2 genuses most commonly cause lesions?
beta and gamma
what genus causes cancer?
MUCOSAL alpha genus
what determines different HPV types?
if the L1 open reading frame is >10% different than other known types, it is a new type
what determines different HPV variants?
if the L1 open reading frame is <10% different than other known types, it is a new variant which can still have significant effects (sometimes more than different types)
how is mucosal HPV transmitted?
sexually
what are 4 results of mucosal HPV?
- cervical and anogenital cancers
- oropharyngeal cancers
- genital warts
- laryngeal papillomas
what type of HPV are cervical and anogenital cancers caused by?
HIGH-RISK types –> HPV16, 18
what type of HPV are genital warts and laryngeal papillomas caused by?
LOW-RISK types –> HPV6, 11
are HPV cancers hard to treat?
no they respond well to radiation
how do oropharyngeal cancers from HPV compare to oropharyngeal cancers from other causes (alcohol, smoking)?
HPV oropharyngeal cancer is more common nowadays but easier to treat than orophrayngeal cancer from other causes
what is layngeal papillomas? what is it caused by?
lesions in throat of young children
due to newborn being infected by an infected mother during vaginal birth
how are cutaneous HPVs transmitted?
by contact
what are the 3 things that cutaneous HPV causes?
- plantar warts
- common warts
- flat warts
what type of HPV causes plantar warts?
HPV1
what type of HPV causes common warts?
HPV 2,4,29
what type of HPV causes flat warts?
HPV 3,10,28,49
do all HPVs cause cancer?
no, only high risk HPV
what is the only genetic predisposition we know of for HPV?
epidermodysplasia verruciformis
what is epidermodysplasia verruciformis (EV)?
rare genetic disease characterized by higher risk for skin carcinoma on sun-exposed skin due to higher sensitivity to specific HPVs
what type of HPV are EV patients susceptible to?
BETA-HPVs like HPV5 and HPV6 that are present in the skin
how do beta-HPVs affect normal ppl vs EV ppl?
normally sit in the skin and don’t cause any mutations but EV ppl develop cancer
what causes EV?
mutations in EVER1, EVER2, and CIB1 genes
why are EV patients susceptible to beta-HPV?
normally, EVER1, EVER2, and CIB1 proteins form a complex involved in the innate immune response of keratinocytes to beta-HPVs
in EV patients, this response is lost –> become susceptible to beta-HPV
What is one of the most common STIs?
HPV
- who can be infected with HPV?
- what % of women are infected in their lifetime?
- what is the average length of infection?
- are all infections diagnosed?
- both men and women can be infected
- 50-70% of women are infected during their lifetime
- normally lasts 8-12 months
- most infections not diagnosed!
describe the progression of HPV infection
- inoculation
- incubation for 1-8 months
- first lesion develops and virus proliferates
- immune response begins
- 6-8 months after first lesion, either will go into remission or infection will persist
what determines whether infection will persist or go into remission?
we don’t know! there isn’t a genetic factor that determines this
what percent of people have cervical dysplasia?
4%
what percent of people have condylomas?
1%
what are condylomas?
benign genital wart
what percent of people have viral nucleic acids (DNA or RNA) found via PCR?
10%
What percent of people have antibodies to HPV capsid proteins?
60%
why do most people have have antibodies to HPV capsid protein?
bc virus is everywhere –> we’ve been able to mount an effective immune response
what percent of people have no sign of prior or active infection?
25%
what is the purpose of HPV screening?
to identify cervical lesions that could progress or have progressed to cancer
what is a PAP test?
cytological test to look at abnormal keratinocytes in cervical tissue
describe molecular detection of HPV
PCR of PAP sample can detect viral nucleic acids (DNA/RNA), mainly high-risk HPV
when do HPV patients get colposcopy?
if PAP test is abnormal and high-risk HPV nucleic acids are present –> must perform colpsocopy
what is colposcopy?
direct visualization of lesions from biopsies for histology, often coupled with treatment
how can you visualize HPV lesions in cervix?
bathe cervix with vinegar, lesions turn white
what are 3 treatments for HPV?
- physical ablation
- cytotoxic agents
- immunomodulation
what antiviral drugs are used for HPV?
no antiviral drugs are available
what is an example of an immunomodulation agent?
Imiquimod
what is Imiquimod used for?
benign genital warts
what does imiquimod do?
cream to stimulate cells to make certain cytokines to fight against
what are vaccines made of?
virus-like particles VLPs made by expression of L1 in yeast or insect cells
how does L1 form virus-like particles?
self-assembles into capsid-like particles to trigger immune response
what are the 3 HPV vaccines?
- Cervarix
- Gardasil
- Gardasil 9
why are there multiple HPV vaccines?
because antibodies for 1 type won’t protect from other type, need to target multiple HPV types
what is the role of HPV vaccines?
to provide high levels of antibodies to protect against cervical cancer and condylomas
what does the papillomavirus contain?
1 viral genome wrapped in histones
why is the papilloma genome wrapped in histones?
bc genome comes from nucleus of the host
what is the symmetry of papillomavirus?
icosahedral
what is the T number of papilloma?
7
describe the pentamers and subunits of papilloma capsid
72 pentamers of L1 which interact thru long tails for stability –> 360 subunits
NO HEXAMERS
what makes papillomavirus different from other T=7 virus?
capsid of papilloma has 360 subunits, other T=7 viruses have 420 subunits (missing 60 subunits bc would make up hexamers normally [T-1]10 = 60)
describe L2
- how many copies?
- location
12 copies of minor capsid protein L2 are on the inside of the capsid and may help with packaging the genome
describe the cryo-EM structure of the HPV capsid
- 72 L1 pentamers
- 12 pentamers surrounded by 5 neighbours
- 60 pentamers surrounded by 6 neighbours
what percent of HPV-associated cancers are cervical cancers?
80%
how does the incidence of cervical cancer correlate to access of cervical screening programs?
less cervical cancer when more access to screening
describe the presence of oropharyngeal cancers in high-income countries
incidence of cancer is increasing in high-income countries but the total number of cases remains small
what does virus infect? what does it lead to?
virus infects undifferentiated basal cells but produces new virions in differentiated cells
describe the entry of papilloma in basal cells
L1 binding to heparan sulfate proteoglycans triggers clathrin-dependent endocytosis
describe the genome of papilloma in basal cells in basal cells
genome is established as an episome in the nucleus and replicated by E1 and E2 to 50-100 copies –> not integrated in genome, remain as episome
what are the 5 steps of papilloma lifecycle in a differentiation epithelium?
- infection of basal cells
- oncogene-induced cell proliferation
- genome amplification
- late gene/capsid protein expression
- packaging and release of virions
what are the 2 oncogenes in papilloma?
- E7
- E6
what is the role of E7?
E7 forces differentiated cells to enter S-phase
what is the role of E6?
E6 prevents their death by apoptosis
what occurs during oncogene-induced cell proliferation?
- E7 forces differentiated cells to enter S phase
- E6 prevents their death by apoptosis
- cells express host DNA replication factors
what happens during genome amplification?
viral episomes are replicated by E1 and E2 to >1000 copies/nucleus
what are 2 of the last genes to be expressed?
- L1
- L2
how does papillomavirus grow in differentiating epithelium?
infects basal layers, then cells differentiate and virus releases by desquamation
