GMS MOD 16 Papillomaviruses

What is papillomaviruses genome?

naked icosahedral capsid

circular dsDNA

two capsid protiens by 5 L1 and 1 L2

What is the clinical relevance of papillomaviruses?

Benign warts and other skin lesions and cancer (100% cervical cancer)

why do people think jackalope exists?

Due to warts being able to pile up to appear like horns on rabbits

When was the first link of virus with human cervical carcinoma?

1976

How did they show the link?

Took cervical scrapings and see open koilocytes cells on epithelial cells which caused proceeded the development of tumors

True or False: Papilloma is very widespread in nature infecting many vertebrates

true

Why is it a problem when trying to study papilloma?

They are highly species specific , can't take human virus and place it in animals

how many HPV are there?

around 15+ based on nucleic acid homology

How many strains are high risk and why?

15 HPV because they associate at a much higher rate with cancers

Which two HPV cause the vast majority of cervical cancers

HPV-16 and HPV-18

T or F HPV is the most common sexually transmitted infection

true

____% of women have genital HPV infections whereas _____% of adults have oral HPV infections

43%; 7%

Skin HPVs

Transmitted via direct contact with an infected individual or a virus contaminated surface

Genital tract HPVs

Transmitted via direct sexual contact where the mesoscale epithial cells serve as reservoirs

HPV transmission

HPV strains show tissue specificity

T or F HPV strains only infect skin

False, they infect either skin or mucosa (genital tract, oral, nasal)

Which two HPV strains cause 90% of all genital warts that are low risk

HPV-6 and HPV-11 (still low risk due to no cancer formation)

Which HPV only cause planter warts on feet?

HPV-1

In the 72 Capsomere, which is better to vaccinate against? L1 or L2

L2 due to its make up of vast majority of capsid

Which HPV is a prototype pv?

HPV-16

How many genes does HPV-16 have?

8 genes, 6 early (controlling transcriptions and replication ) and 2 late( capsid proteins) genes

LCR

contains replication origin and cis acting signals

How many promoters are in HPV-16

2, Early (E1-6 ) and late ( L1 and L2)

Papillomavirus life cycle

-Unusual life cycle: life cycle is tied closely to cell differentiation in skin

-In order for the virus to infect an animal, there has to be some micro trauma in the skin

-Viruses get through the micro trauma into the basal layer, and infect themselves in the basal layer

-During the infection of basal layer, only a portion of virus genes is expressed. The other viral genes not expressed (including structural genes)

-Basal cells multiply and they move up, and as they move up they differentiate into different layers of the skin before they eventually die and get sloughed off

-As they differentiate, the virus starts expressing other genes. So the virus expresses more genes as the skin cells move up and mature

-Basically virus replication is so tightly linked with skin cell maturity, you cannot replicate the virus in a cell culture

Basal cells

early gene expression and plasmid DNA replication ~50 copies

Keratinocytes

Vegetative replication ~1000s copies per cells, late gene expression which assembly of virus particles

how do cells at the very end get out?

they die and release the virus out into lumen

If cells don't have nuclei what does the virus do?

The virus has to hijack the host cell machinery by keeping the cell undergoing cell cycle keeping nuclei around.

Hyperkeratosis

Thickening of the skin caused by a mass of keratinocytes

Early vs late genes

Early is for DNA replicaiton and Late is for Capsid proteins

How does E7 activate the cell cycle progression?

By binding to RB because its a tumor suppressor protein and pulls it away from E2F which activates the cell cycle and activates a protein p53

Which cell activates transcription of cell cycle genes?

E2F

How does E6 block apoptosis from p53 ?

It induces p53 degradation by using E6AP which binds to p53 and breaks it down

what does activated p53 do?

it induces cell cycle arrest and apoptosis

E7 and E6 leads to what?

Oncogenesis due to uncontrolled proliferation and loss of the ability of the cell to kill itself

Is making oncogenesis and objective for HPV?

no, its a normal feature of HPV and the virus has to transform in order to induce the cell cycle so that it can replicate

which wart can have malignant potential?

Flat warts HPV-10

Pathogenesis of cervical cancer

molecular disruptions causing dysplastic changes in the epithelium

HPV declines overtime due to settling into mono relationships

T or F Cervical cancer is very high in women under age of 25

False its low due to to the interval of accusation and transformation is 10-15 years. Over age of 25 and 30 is a higher risk

if we have 10 mill cases of HPV infection how many become cancer

about 11K due to overtime HPV16 and 17 about 70% causing cancer

Where does cervial cancer show?

In the internal OS and External OS starting at lowgrade CIN to highgrade CIN to cancer with bumps

Progression from benign to invasive

once HPV infection production starts causes mild dysplasia , at later stages with moderate and severe dysplasia, the virus production stops but high E7 and E6 and integration of viral DNA into hostcells

How does progression to cancer correlates with HPV integration?

Cancer was always associated with integration of the genome into host cells due to DNA replication and breakage of DS genome around the E2 gene. When it breaks it become a deletion of the E2 proton since its a - regulator shutting down E6 and E7. So without E2, they increase causing cancer etc

Integration disrupts______

E2 function

Disrupting E2 causes what?

Reducing ability to repress the transcription fo E6 and E7 which causes unregulated expression of HPV E6 and E7

Can you treat squamous cell carcionma?

No, unfortunately at that stage its too late to do something

Pap smear

Basic and easy way to diagnose HPV infection

Pathology , cytology

What do they use to identify strain?

PCR, and will monitor what strain so they can actively treat it

Where is the burden of cervical cancer is the greatest?

Highest in developing countries due to lack of access

Prevention and treatment

Pap smears

Recombinant virus like vaccines

Therapeutic options

Which two FDA approved vaccines used for HPV-16 and 18

Gardasil and Cervarix vaccinated young means lifetime drop of cervic cancer