Papillomaviruses

Mechanism of transformation

There are two different "types" of E6 and E7 proteins. These two proteins bind to the p53 tumor suppressor protein and block cell cycle control. When expressed at low levels (which occurs during an acute cytopathic infection), they have minimal impacts on the host cell. When E6 and E7 share a promoter and are over expressed (which occurs in high-risk strains) they can lead to transformation of host cells. This transformation is not sufficient by itself but can lead to cancer formation in the host.

Where are immediate early proteins made:

produced in basal cells

What does E6 and E7 do in papillomavirus?

pushes the cell into S phase

Symptoms of warts:

raised, rough, oval growth on the skin; they are not usually painful or itchy; they may be present for long periods of time

What does E1 doin papillomavirus?

recruits cellular DNA polymerase to the origin on the genome; also has helicase activity!

Pap test

test for cervical or vaginal cancer test looks for abnormal cell morphologies associated with cell transformation, while the

HPV screening looks for

the presence of high-risk HPV genotypes.

The mechanism of DNA replication is

theta replication

When E6 and E7 share a promoter and are over expressed (which occurs in high-risk strains)

they can lead to transformation of host cells.

papilloma means

tumor

How can Papillomavirus enter

The virus gains entry to the host through small cuts or wounds on the surface (this includes sexual transmission)

What does E2 do in papillomavirus?

divides up viral genomes at the end of DNA replication

The majority of human papillomavirus strains do not

establish latency and instead are completely cleared from the host. These viruses cause mostly cause subacute or self-resolving infections - like warts.

Mature virions are produced

in the granular layers

Where are early proteins are produced

in the lower spinous layers

desquamation

in which the layers of stratified epithelium closest to the surface are shed into the environment.

The best way to catch cervical cancer early (usually before any symptoms appear) is to ..........

is to get an annual Pap test with HPV screening.

Symptoms (if present) of head and neck cancer by papillomavirus) include

long lasting sore throat, swollen lymph nodes, pain while swallowing and weight loss

Cervical and anal cancers

o High risk types 16 and 18 can (but don't always) integrate into the human genome, which leads to increased E6 and E7 expression. o Just because you are infected with a high-risk HPV strains does not mean that you will 100% get cancer, but your odds go up significantly. What these virus strains do are make genetic changes that contribute to transformation of cells - additional mutations are needed for cancer to occur in the host. o These infections are linked exclusively to sexual transmission; your risk goes up with the number of partners you've had.

Productive phase/vegetative replication

o Increased levels of viral DNA replication take place. o Thousands of copies of the viral DNA are produced. o This phase only takes place in terminally differentiated cells. o Infectious virus is produced. o DNA replication switches to a rolling circle mechanism (maybe more efficient?).

Warts

o Low risk HPV types like 6 and 11 do not integrate into the genome and are not linked with cancer in humans. o This infection can be self-inoculated to other body parts! o Warts are characterized by where they occur on the body: Ø Common warts are found on the hands. Ø Flat warts are found on the face and forehead (mostly in kids). Ø Genital warts are found in the genital area. Ø Plantar warts are found on the soles of the feet. Ø Subungual warts are found under fingernails and toenails! o Treatment Ø These infections will self-resolve without treatment. Ø Chemicals, heat or cold are used to physically remove the warts.

Maintenance phase

o Viral DNA only replicates when cellular DNA replication takes place. o Genomes are present but capsids aren't produced yet. o The virus is causing a "persistent" infection at this point, (1:32)

Papillomaviruses can cause different severity of infections, based........

on whether the virus maintains latency in the host.

How does papillomavirus infect

once enters then the virus infects from the bottom of the epithelial layer (the basal membrane of squamous epithelial cells). This must occur because the virus undergoes different steps in its life cycle as the host cells differentiate and get closer to the surface. · The L1 capsid protein interacts with heparin sulfate proteoglycans. Although a different receptor has yet to be identified, scientists think papillomaviruses probably use a two-step attachment.

HPV is now a leading cause of ________ cancer in the U.S., contributing to about 70% of this type of cancer.

oropharyngeal cancer in the U.S., contributing to about 70% of this type of cancer.

L2 plays a role in

packaging and the final assembly steps.

About _______of men and ______ of women have HPV in their mouths.

10% 4%

____________ of the endosome is required for the uncoating and release of the DNA into the cytoplasm.

Acidification

Papillomavirus proteins involved in DNA replication:

E1 E2 E6/E7

Papillomavirus enter by which endocytosis

The virus enters by clathrin-mediated endocytosis. Actin is somehow (?) a part of the virus entering the cell.

Establishment phase/plasmid replication:

Genome is maintained outside the host chromosome. The viral genome is multiplied to about 100 genomes/cell. The mechanism of DNA replication is theta replication.

What kind of genome does Papillomaviruses

Genome: small, circular dsDNA genome; codes for 8 proteins DNA associates with cellular histones to assist with genome replication

Cervical cancer can be prevented with an_______ This vaccine should be administered before teens are sexually active and infected with HPV strains (usually around 11 or 12). __________has a quadvalent version that protects from infection by 4 high-risk strains, as well as a newer version that includes protection from 9 high-risk strains of HPV. ___________ only protects from high-risk strains 16 and 18. Each of the vaccines are made of _______ that contain empty capsids with L1 proteins from the different strains.

HPV vaccine Gardasil Cervarix virus-like particles (VLPs)

Head/Neck cancers: infect _________ and _________ of throat

In addition to the genital region, HPV can also infect the tonsils and back of the throat. If high-risk HPV genotypes are involved, they can also lead to cellular transformation and contribute to cancer formation in the host. o Oral sex is the main route of transmission for the virus to gain access to the mouth; other transmission routes have not been ruled out. o Symptoms (if present) include long lasting sore throat, swollen lymph nodes, pain while swallowing and weight loss

Head and neck cancer transmission (papillomavirus)

Oral sex is the main route of transmission for the virus to gain access to the mouth; other transmission routes have not been ruled out.

Papillomaviruses has over how many genotypes and how many are linked to cancer (and high risk)

Over 100 genotypes of this virus can infect humans! Only a few of these are concerned "high risk" and linked to cancer.

Papillomaviruses also infect many other

Papillomaviruses also infect many other mammals, birds and reptiles; turtles can get a very nasty infection!

Immune evasion

Papillomaviruses only infect the very outer layers of cells on a human - meaning they don't really need to evade the immune system because they rarely encounter it!

This phase only takes place in terminally differentiated cells.......

Productive phase/vegetative replication

In Papillomavirus the research progressed very________it could not be grown ________ until the discovery of _____________

Research progressed very slowly with this virus because it could not be grown in vitro until the discovery of raft tissue culture (see below) in the late 1980's. In this system, small sections of tissues are floated on liquid, which provides an environment similar to the host.

What kind of shape does Papillomavirus have:

Shape: icosahedral; non- enveloped

Cervical and anal cancers symptoms

Symptoms of this disease appear only after the cancer has progressed and are non-specific - making diagnoses challenging. Symptoms include: abdominal pain, abnormal vaginal bleeding, fatigue, pain during intercourse

What is important about gene expression of Papillomavirus

The important thing to remember about papillomavirus gene expression is that gene expression is coordinated with the differentiation of the host cell!

Treatment for Cervical and anal cancers

Treatment usually consists or surgery, chemotherapy and/or radiation. Newer treatment options (including ongoing clinical trials) specifically target E6 and E7 proteins and have been highly effective.

Papillomavirus uncoats where

Unlike most DNA viruses, papillomaviruses actually (partially) uncoat in the cytoplasm! The L2 capsid protein pokes holes in the endosome so the DNA can escape. L2 then "chaperones" the viral DNA to the nucleus on microtubules. The viral DNA then enters through a nuclear pore complex.

does Papillomavirus have temporal gene expression?

YES!!

Some papillomaviruses are likely to establish latency in the host by ...........

by integrating their genome into the human chromosome (like high-risk strains of HPV) - and these viruses are also more highly linked to the development of cancer.

Papillomaviruses is in what class and type of virus (DNA or RNA)

class 1 virus, double stranded DNA

Assembly/exit of papillomavirus

· The L1 capsid protein can self-assemble into capsids (no energy needed!) in solution - it also does this in the cytoplasm during a virus infection. (This is how they make the HPV vaccine!). The completed capsid then traffics to the nucleus. · The viral DNA is loaded into the capsids inside the nucleus. L2 plays a role in packaging and the final assembly steps. · Release of the virus from the body is tied to desquamation, in which the layers of stratified epithelium closest to the surface are shed into the environment. The viruses can then escape the host cells and survive in the environment (usually still in close proximity to the original host), where they can then infect a new person.

Warts are characterized by where they occur on the body: examples are:

Ø Common warts are found on the hands. Ø Flat warts are found on the face and forehead (mostly in kids). Ø Genital warts are found in the genital area. Ø Plantar warts are found on the soles of the feet. Ø Subungual warts are found under fingernails and toenails!

Treatment of Warts

Ø These infections will self-resolve without treatment. Ø Chemicals, heat or cold are used to physically remove the warts.