25: HPV Flashcards
first evidence of cancer
mediated by viruses
discovery in the early 1900s with chickens developing sarcoma in breast muscle
viruses and cancers in humans
approximately 12% caused by viral infection (more than 80% of cases in the developing world)
1 out of 3 suffer from cancer so 12% caused by viral infection is quite a lot
human viruses associated with cancer
hepatitis b (HBV)
hepatitis c (HCV)
epstein barr virus (EBV)
high-risk human papilloma viruses (HPVs)
human t-lymphotrophic virus-1 (HTLV-1)
kaposi’s sarcoma herpesvirus (KSHV)
why do viruses not want cancer?
typically an accident leading to a dead-end for the virus
are viruses necessary for cancer development?
necessary but not sufficient
- cancer incidence lower than virus prevalence
80% of the population infected with EBV
- vast majority never develop cancer associated with viruses
when are viral cancers likely to appear?
context of persistent infections
- the longer they stay, the more time they have to cause cancer
immunosuppressed have more chances to develop cancer associated with viruses since you can’t control the virus
the immune system can play a deleterious or protective role
inflammation can sometimes be pro-cancer
- inflammation as a major player giving rise to cancers (carcinoma associated with hepatitis)
other human virus-associated cancers increasing with immunosuppression
what is cancer?
uncontrolled growth of abnormal cells in the body
- develops when the body’s normal control mechanism stops working
old cells don’t die but grow out of control forming new/abnormal cells
once cancer is invasive, metastatic is harder to get rid of since cancer is in other parts of the body
types of genes linked to cancer
proto-oncogenes - proteins which normally contribute positively to cell proliferation
- tightly-regulated proteins which push cells to growth when on
- mutations can alter the regulation of proto-oncogenes which prevents them from being turned off
tumour suppressor genes - proteins that prevent the unwanted proliferation of mutant cells
- monitors cells for uncontrolled growth
- mutations render them ineffective
for cancer, you need proto-oncogenes turned on to become oncogenes and tumour suppressors to be turned off
modulation of host cell cycle
viruses subvert cell cycle to their advantage
cell makes nucleotide synthesis which the virus wants since it wants to replicate its own genome and needs energy
target specific steps of the cycle to improve viral replication
- viruses encode oncogenes and tumour suppressor inhibitors
- not because they want it to become a tumour but because they want the cells to be in a phase/stage favourable for viral synthesis
how many species of HPV?
over 100 recognises species which infect humans
HPV infection
asymptomatic (vast majority of HPVs)
cause genital/skin warts
- highly specific for some parts of the body
infection carries a risk of becoming cancerous
- 40 types of HPV affect the genitals and some carry cancers
HPV as the most commonly sexually transmitted infection in the US
> 80% of people infected with at least one type of HPV in their lives
- 40% of these 80% will have symptoms while others are asymptomatic
most infections clear on their own within two years
low-risk HPV
don’t typically cause symptoms
no association with cancer but lead to genital warts
HPV 6 and 11
believed that 1% of people in the US have warts at any given point
high-risk HPV
extensive cervical dysplasia and certain types of cancers
only HPV 16 and 18 which cause the majority of HPV-related cancers (70%)
- leads to pre-cancerous and cancerous lesions
6 types of cancers caused by HPV
vagina
penis
vulva
anus
cervic
oropharynx
initial infection of HPV
sexual interactions where virus is delivered next to the cervix
tiny lesions which happen naturally so the virus can enter layers of basal cells and infect the deepest layer
- replicate, divide and make more cells
virus wants to be in this environment where the cell is replicating and has lots of energy
virus delivers DNA into the cell, circularisation as an episome, maintained in cells expressing oncogenes to push for more replication
- encode E6 and E7
how does HPV turn into cancer?
episomes by accident break once in a while and become linear
- linear pieces integrate with our own genome
no longer gives rise to viruses - dead-end so virus doesn’t want that
virus is dead but proteins normally expressed by the virus are no longer regulated
- proteins will push cells to replicate all the time
some other mutations happening in tumour suppressor genes
- other things happening by chance or lack of chance which means cell can replicate more and evade immune responses
oncogenes E6 and E7
integration is a genetic accident (not part of the viral life cycle)
- dead end
integration results in disregulation of expression of viral E6 and E7 oncogenes
- selective growth advantage for cells promoting oncogenic progression
- E6 and E7 now always on, pushing cells to oncogenic progression towards cancer
HPV infection leads to cervical cancer as well as others
risk that HPV infection can become chronic with pre-cancerous lesions progressing to invasive cervical cancer
15-20 years for cervical cancer to develop in women with normal immune systems
5-10 years in women with weakened immune systems (untreated HIV infection)
other cancers include oral, anal, vulvar, vaginal and penile cancers
HPV prevention
safe sex practices (not 100% effective)
pap and HPV tests
- detects abnormal cell proliferation in the cervix
vaccination
HPV vaccine
made of the L1 protein which naturally assembles to form empty virions
- essentially a subunit vaccine where it forms the virus itself
- over expressing L1 which means the virus assembles but is empty
first generation vaccines (2006-2007)
- cervarix against HPV 16 and 18
- gardasil against HPV 16, 18, 6, 11
second generation vaccine (2019)
- gardasil 9 against many more
getting vaccinated as a teenager
receiving the vaccine between 12-13 lowers rates of cervical cancer by 87%
cancer rate 62% lower when shots were given between 14-16
34% when shots given between 16-18
