HPV 2 Flashcards
higher incidence cervical cancers in? rare in?
married women, widows, prostitutes. virgins, nuns.
hpv16, 18 isolated from
cerv cancer biopsies, cloned in 1983/4
papillomaviruses
small, non-enveloped, circular dsDNA genome
HPVs are species specific & widespread among what
mammals
how many types HPVs ID’d? sequenced? exist ?
100 ID’d, 80 seq’d, 200 exist based on partial seq frags
is HPV serological prevalence ubiquitous in pop?
yes, most common STI globally
global HPV prevalence
normal cytology reports, MA-compiled data, some studies used PCR, others used serology.
highest & lowest HPV prevalence
africa highest, europe lowest. (US numbers suggest prevalence rates higher)
cervical cancer freq
2nd most freq cancer in women
HPV causes ? cases of cerv cancer
all cases of cerv cancer. approx 4% all cancers
HPV also responsible for proportion of VVAP cancers
vaginal, vulvar, anal, penile cancers
cerv cancer rates 10x higher in areas w/o
w/o cytology screening
screening programs good at detecting most cerv cancers (aka?) but not good at detecting ?
(aka squamous cell carcinomas) but hard to detect adenocarcinomas
HPV exposure
~high. 75% pop at some point
incubation period HPV
unclear. 3 months - several yrs
HPV infection in US
60% have presence of Abs (neg HPV test), 10% HPV dna pos but colposcopy neg, 4% colposcopy pos (1% get gential warts, less get cancers)
most HPV transmissions occur
from sex/ skin-skin contact w infected person
is insertive/receptive sex necessary
no. contact w mucous memb is enough
condoms decr transmission but
dont protect completely
risk of fomites mediated transmission
not clear but probable. (share inanimate objects)
HPV transmission for M/F
M - penile cancer
F - cervical cancer
both - genital warts, anal cancer, etc
incr risk of cervical cancer w ?
sex, age, age of 1st sex, co-infections, M circumcision, condom use, lifetime # partners
HPV prevalence incr when?
around age of onset of sex. decline w age!
dramatic incr in cerv cancer cases bw what age
20 - 45
incr risk of HPV prevalence w what
other STIs (like HIV)
HPV types 16, 18 (high risk, lead to pre/cancerous lesions)
cause 70% cerv cancer cases (squamous cell)
HPV 6, 11 types (low risk, lead to condylomata acuminata)
cause 90% genital warts cases
HPV infection clin manifestations
cutaneous , anogenital warts. epidermadysplasia verruciformis. resp papillomatosis. other HPV infections
cutaneous warts
~asymptomatic, 50% resolve within 1 yr, rare but can degrade into carcinomas
anogenital warts
past history of anal warts, incr anal cancer 10x risk. vulvar condylomata acuminata
epidermadysplasia verruciformis
autosomal recessive genodermatosis linked to gene in xsome 17. appear in 1st decade of life, transformto invasive squamous carcinoma (malig)
respiratory papillomatosis
hoarseness. altered cry & resp fail, often for infants. obstruct trachea, lungs. require excision
other HPV infections
most common = oral squamous pappillomas. involve diff mucus membs (eyes, mouth)
HPV genome how many bps? ORFs which encode what proteins?
7900 bps, 8 ORFs - encode 6 early proteins, 2 late structural ones.
viral gene exp linked to differentiation state of infected epithel
suprabasal epithel cells - early gene exp. terminally differentiated karatinocytes - late gene exp.
HPV disease mech (aidasi)
- micro abrasion in mucosa
- infect basal keratinocytes
- differentiate, move to distal mucosa
- viral assembly as cells move to mucosa
- infectious virus shed
- xsomal integration
most infections result in
viral clearance (mechs unclear), develop type-specific immune response
development of invasive cancer closely linked to
viral DNA integration
integration of viral dna leads to
overexpress E6, E7 to target p53, pRB. which incr cell prolif, decr repair > mutations > CIN > invasive cervical cancer
in basal cells, HPV viral dna replic occurs where, in what fashion, at what rate?
in squamous epithel cells. episomal fashion. low rate. 50-100 copies/cell
infected basal cells enter what
suprabasal cell layer, assoc w incr exp of early, late proteins E4 5 6 7
viral assembly occurs in what cells
terminally differentiated epithel cells (exp of L1, L2 proteins)
what occurs after viral assembly
virions released into tissue, infection spreads
viral integration takes place where?
in small proportion of basal lamina cells
viral integration is important for?
develop malignant disease (but not sufficient)
integration of HPV genome into xsome leads to
uncontrollable oncoprotein prod, host cell transform
other mechs playing key role in cancer develop incl.
DNA methylation, xsomal instability, telomerase activation
severe dysplasia assoc w
incr gene exp of E6 E7 which interfere w p53
what does p53 do
mediate if a cell is stable enough to undergo cell prolif or should be marked for apoptosis
viral interence of cell host mechs. dna integration interrupts what
E2 ORF
site of integration is often
xsomal fragile
expression of E2 does what
downregulate E6, 7
E6, 7 ~results in ubiquitination of
p53 & pRB (retinoblastoma tumor suppressor protein)
loss of cellular p53& pRB allows cell w dna damage to
divide, incr risk of cancer development
hpv infection, progression. virus disrupts ?
cell cycle control, promote uncontrolled cell div & accum gene damage.
cervical intraepithel dysplasia
pre-malignant transform & abnormal growth of squamous cells on cervix surface
CIN cervical intraepithelial neoplasia is a cancer?
NO. it’s usually curable
CIN 1, 2, 3
1 - mild dysplasia (HPV infection)
2 - moderate
3 - severe dysplasia/carcinoma in situ (integrate HPV genome, upregulate viral oncogenes)
… invasive carcinoma
progression of cervical disease after HPV infection
ASCUS/LSIL - HPV infection koliocytosis/CIN1.
HSIL - CIN2/3.
innate immune system (1st line of defence)
does NOT prevent HPV entry
HPV E6, 7 implicated in
inhib TLR9 (dsDNA) gene transcription
HPV has unique evasion mech to
replicate undetected by immune system
HPV downregulates
interferon regulatory genes (dampening immune responses)
HPV upregulates
TGF-b
what is TGF-b
potent immuno-modulator. quench immune activation
HPV infection does not elicit danger signals which would lead to
activation/trafficking of APCs & immune cells
HPV NOT a cytolytic virus since
causing cell death would be potent immune activator
HPV NOT assoc w viremia so
inflammatory markers not activated
E5 protein does what
inhib acidification of endosomes & downregulate MHC class I expression
MHC class I
impact immune recognition by CD8+ T cells
incr viral protein exp only occurs in
keratinocytes, avascular areas (limited access for immune system)
2 licensed vaccines on market
gardasil (9 valent) & cervarix (bivalent for types 16, 18)
how is gardasil & cervarix made?
recomb tech. proteins form VLPs virus like particles of L1 protein (non-infectious, lack live biological prods)
major basis of protection against infection
neutralize serum IgG that transudates from capillaries to genital epithel mucosa & binds to viral particle
up to 1 yr after dose 1, HPV16 & 18 antibodies in cervicovaginal secretions & serum are
strongly correlated
efficacy against combined endpoint of CIN1, CIN2/3 due to HPV 6, 11, 16, or 18
of 96% or + efficacy (up to 3.7 yrs after vaccination for F 15-26) … similar efficacy for bivalent vaccine in HPV 16 & 18
australian surveillance cohort
funded HPV vaccination for 12-13, catch up programs for 13-26 girls, women & men showed decr in genital warts … cervical cancer vaccine may eradicate disease
new 9 valent vaccine found to be
equivalent/non-inferior to quadrivalent HPV vaccine (but covers more serotypes)
HPV seropositivity rises a lot as
15-21 ppl become sexually active
most HPV infections are
asymptomatic, cleared by immune system.
small proportion of HPV infections can
progress to cerv cancer
development of cancer linked to
ability of virus to disrupt normal cell cycle control, promote uncontrolled cell div & accum genetic damage
hpv genotypes divided into
diff risk groups, stratified according to oncolytic properties
hpv vaccine elicits
IgG immune response
evidence of hpv efficacity >95%
clin trial data & post vaccine surveillance cohorts, australia
