Microbiology and Immunology Exam 4 Lecture 7 [Adenoviruses & Papillomaviruses]

Adenoviruses Characteristics

Many serotypes (>50) 1-7 are most common

Virion stucture:

- Non-enveloped

- Icosahedral capside containing dsDNA linear genome

Projecting fiber protein that interacts with the cellular protein Coxsackie Adenovirus receptor (CAR), then the capsid proteins interact with cell surface integrin for internalization

Genome encodes 30-40 genes

Replication in the nucleus using Viral DDDP

Transcription using cellular machinery in nucleus

Adenoviruses: Disease

Infection mainly of epithelial cell on mucous membranes

The target site depends upon virus type which is primarily determined by specificity of virus fiber protein

Clinical syndromes of Adenoviruses

Dependent on virus type

- upper respiratory illness (most common)

- Epidermic Keratoconjunctivitis

- Pharyngoconjunctival fever

- Diarrhea (more common in infants)

- Hemorrhagic cystitis

- Meningitis/Encephalitis (rare)

- Myocarditis (rare)

Common Respiratory infection caused by Adenoviruses: Pharyngitis

Type of Adenovirus

- 1-7

Symptoms

- Redness

- Blistering

Duration:

-3-5 days or longer

Epidemic Keratoconjunctivitis

Type of adenovirus

- 3 and 7

Symptoms

Accompanied by pharynconjunctival fever

Adenovirusues are common cause of Gastroenteritis in

childhood

Types:

- 40,41

Adenoviruses can also cause Hemorrhagic cystitis: Symptoms

Bladder inflammation

bleeding from bladder wall

Hospitalization not uncommon

Types:

- 11 and 21

Treatment and prevention of Adenoviruses

Antiviral:

- None

Immunization:

- Available for military recruits for some serotypes (4 and 7)

Prevention:

- Thorough hand washing helps prevent transmission through fecal-oral route

Papillomaviruses are another virus that infects

Epithelial cells

- cutaneous and mucosal

Mucosal types of papillomaviruses often but not always __________ transmitted

sexually

Cutaneous types of papillomaviruses are trasmitted by

contact

papillomaviruses infection is persistant. Normal clearing after

year or more but can be longer

Infection of papillomaviruses cause ____ and other usually benign proliferations and lesions

warts

Several types of papillomaviruses are associated with and cause ______

cancer

Human Papillomaviruses (HPV) has over ____ types identified

200

HPV risk group: LOW

1,2,3,4

Disease:

Common skin warts

Plantar warts

Benign Oral lesions

HPV risk group: INTERMEDIATE

6, 11

Disease:

Anogenital Warts

Benign Oral lesions

Papillomatosis

HPV risk group: HIGH

16,18,33,39,45

Disease:

Cervical cancer

Vaginal cancer

Other Anogenital cancers

Oral cancers

Clinical manifestations cutaneous warts

Various morphological types

Caused by many HPV serotyeps, usually low-risk types

Long incubation (months)

Difficult to eliminate (cryotherapy, surgery, acid) and can recur

HPV oral Lesions

Depends of HPV type

- Verruca vulgaris

- Condylomas

- Squamous cell papillomas

- Squamous cell carcinoma

HPV Oral Lesions: Verruca vulgaris

HPV-2 and -4 are common cause

Benign

Treated with excision and or cryotherapy

HPV Oral Lesions: Condyloma

Commonly HPV-6 and -11

Usually benign

Treated with excision, cryotherapy, trichloroacetic acid, Imiquimod

Usually sexually transmitted

HPV Oral Lesions: Recurrent Respiratory Papillomatosis (RRP)

Caused by HPV 6 and 11

Usually caused by transmission from mother to baby during birth

Larynx, vocal cords, other areas of respiratory tract

Recurrent, requires constant surgical removal

HPV Oral Lesions: Oral papillomas

Commonly HPV-6 and -11

benign HPV lesions are removed surgically or by cryotherapy

May recur

HPV Oral Lesions: HPV associated head and neck cancer

In som cases oral HPV infection can lead (after many years) to HPV-OSCC (HPV positive Oropharyngeal squamous cell carcinoma)

Associated with the high risk serotypes (mainly HPV-16, sometimes 18)

More common in men than women

HPV related cancers

Cervical cancer is still the second most common cancer for women in the world. greater than 90% of cervical vulvar and anal cancers caused by HPV

Men at greater risk for HPV associated head and neck cancers

75% of the sexually active population have or had

anogenital HPV at some time point with 40% with high risk HPV

At any time point ____ of women are infected

1/4

Papillomavirus Viron Characteristics

Icosahedral shape

Non-enveloped

*L1: major capsid protein

L2: Minor capsid protein

Circular double strained viral DNA genome inside capsid

HPV infects basal cells of epidermis through

tear or wound

- Receptor is probably an integrin

- Maintenance of genome at low level in basal cells. No infectious virions produced in the lower basal layer

NOTE:

- Gets into cell and has to go to nucleus

After the tear or wound heals, the basal cells differentiate into squamous cells as they move up in layers of the skin.

What does the HPV virus due during this

Starts replicating more as the cells are pushed out into the suprabasal layer and they don't start producing infectious virions until they get to the surface

- released either as individual virions or in what are called squames

NOTE:

So the squamous cells are the cells on the surface and that is where the HPV is the most virulent so when those cells are shed the virulent HPV goes with and can infect others (or animals)

HPV infection and viral gene expression dive aberrant cell proliferation (JUST A PICTURE NOT A QUESTION)

An HPV infection results in aberrant proliferation and the development of __________ in outer layers of skin or mucosal surface

koilocytes

Koiloytosis describes the presend of koilocytes in a specimen:

- Nuclear enlargement

- Irregulatiry of the nuclear membrane contour

- Darker than normal staining nucleus

- Clear area around the nucleus

- Sloughed or scraped off koilocytes can be used for identification of low grade HPV lesion by pap smear

How does HPV cause aberant cell proliferation

HPV proteins E6 and E7 drive cells to synthesize DNA and proliferate continuously

Virus uses cellular mechanisms to replicate DNA so wants cells in S phase

NOTE:

- E6 and E7 **** shit up in the cell cycle specifically in the S (synthesis phase)

- P53 is a baller (guardian of the genome)

- E6 ****s up P53 because they hate each other something

- E2F turns on S phase genes = allows for S phase

- Rb hangs onto the E2F transcription factor which prevents cells from moving to the S phase until its ready

- E7 ****ing destroys Rb and thus cell is forced forward to synthesis even when it just wants to hang out in G1

Overall result: Continuous cell cycle = aberrant proliferation

E7's degradation of __ causes release of E2F and stimulation of S phase genes

Rb

E6's degradation of ____ releases cell cycle control

p53

The E6 protein

Causes degradation of the cellular protein p53 through interaction with a ubiquitin ligase called E6-AP

HPVs that do not cause cancer are less able to degrade p53

Other E6 functions:

- Activates hTERT 9telomerase, an enzyme necessary for immortalization of cells) only types that cause cancer do this

- Degradation of other cell components important for controlling cell growth

The E7 Protein

inactivates a cellular tumor suppressor protein called Rb

- Causes release of transcription factor E2F to stimulate DNA synthesis genes

- High risk HPV types are better at doing this than low risk types

Why does HPV do all this bad stuff to you cell

1. Needs to avoid recognition as damage

2. Needs to get those S phase genes going so it can use the resources from the S phase

HPVs infect stratified epithelium--> progression to malignant cancer often associated with viral genome integration

- Leads to unregulated high expression of E6 and E7

- Virus no longer produced after integration

- May stay this way for decades before cancer develops

NOTE:

- Cancer is not something that is on purpose of the virus

- Virus want to make more virus but once its integrated it not longer produces any infectious virus (dead end for replication)

- Dead end for replication of virion but it causes the cell to continue to proliferate

HPV-Associated cervical cancers: Detection and treatment

Caused mainly by:

- 16 18 31

PCR detection now regularly used in clinic

Prolonged or persistent HPV infection is comon

Pap smears can detect early lesion when they are treatable (surgery, cryotherapy)

Later stage lesion (surgery, radiation, chemotherapy)

HPV-associated oral cancers: Detection and Treatment

Dentists are often the first to detect oral cancers

No pap smear type assay available for oral cancer

PCR can be done on biopsy to detect type of HPV

Approximately 50% of oropharyngeal cancers caused by HPV

Treatment of cancer usually through surgery and radiation (HPV oral cancers are more treatable than non-HPV oral cancers)

Development of Prophylactic HPV Vaccine

- HPV L1 protein expressed in yeast or by baculovirus

- Forms L1 pentamer

- Pentamers form virus-like particles that are non-infectious (no genome)

Commercially Available HPV Vaccines

Merck

- Gardasil: L1 like particles from

-- HPV 6 11 16 18

- Gardasil 9 (Nonavalent) recommended

-- HPV 6 11 16 18 31 33 45 52 58

GSK

- Cervarix (Divalent)

-- HPV 16 18

HPV vaccine studies demonstrate high _____ after vaccination

antibody titers

Large scale HPV vaccine studies demonstrate ___-__% efficacy in preventing HPV infections and subsequent HPV associated lesions

97-100%

Since the first HPV vaccine was recommended in 2006 there has been a ____% reduction in vaccine type HPV infections among teen girls in the US

64

HPV vaccine is reducing prevalence of ________ and

Cervical and HPV associated head and neck cancers

Adverse effects of HPV vaccines are typical:

headaches, aches, fevers

Fainting associated with vaccination very rare

Challenges of HPV Vaccination

Prophylactic not curative, millions infected already

Distribution and recommendation of vaccine by health care providers

Cost (insurance pays if you have it)

Multiple types (main types covered by nonavalent vaccine but others could emerge as a problem)

Acceptance of vaccine

- Religious and social concerns

- Misinformation

- Low compliance for boys

Michael Douglas

Had HPV 16 associated oropharyngeal cancer that was successfully treated

- Men are at higher risk of developing oral cancer caused by HPV than are women

- Vaccination recommended for boys

TOPHAT: What is the role of HPV E6 and E7 proteins in HPV infection

A. They act together in a DNA polymerase complex to preferentially synthesize viral DNA over cellular DNA

B. They inhibit the cell cycle checkpoint proteins p53 and Rb and drive DNA synthesis and cell proliferation

C. They enhance entry of the virus into cells

D. They act together as viral RNA polymerase to preferentially transcribe viral genes

B

TOPHAT: Which photo most likely represents a squamous cell carcinoma

- Other side of card-

A

B

C

D

D

TOPHAT: What is untrue about HPV vaccines

A. They are made by using HPV L1 proteins expressed in baculoviruses or yeast

B. They can prevent certain HPV-associated oral lesions and cancers

C. They are effective at treating already-present HPV-associated lesions

D. They are non-infectious

C

TOPHAT: What is untrue about adenoviruses

A. The virion is icosahedral and non-enveloped

B. The target tissue and symptoms depends largely on the adenovirus type

C. The genome is double-stranded DNA

D. They are associated with the development of cancer

D

TOPHAT: Which of the following statements best describes the risk associated with HPV types 16 18 33

A. These types are associated with common skin warts

B. These types are primarily linked to benign oral lesions

C. These types are classified as high-risk associated with cervical cancer

D. These types are commonly known to cause benign oral lesions and anogenital warts

C