10. The Pathogenicity of Viruses - Papillomavirus Flashcards
What conditions are caused by the human papillomavirus?
Warts and some subtypes can cause cancer.
What cancers have been associated with papilloma virus?
- Cervical cancer
- Tumours of the urogenital tract
- Upper airway cancers
How is the papillomavirus transmited?
Direct contact
Sexual contact
During birth from mother to child
Describe the genome of the Papilloma virus.
Non-enveloped circular double stranded DNA, about 8000 bp in length enclosed by a capsid containing 8 different genes.
Name the 8 Genes of HPV.
- E4
- E5
- L2
- L1
- E6
- E7
- E1
- E2
E1, E2, E4, E5, E6, E7, L1, L2
How many types of papillomavirus are known?
Over 100
What cell types or tissues structures does the papillomavirus infect?
Squamous epithelial cells of skin (keratinocytes) or mucous membranes.
How does papillomavirus facilitate attachment to their target cells?
- Initially papilloma virus binds to heparan sulfate proteoglycans (HSPGs) on the basement membrane exposed due to epithelial trauma or permeabilization.
- This binding causes a conformational change in the capsid to expose an N-terminal L2 peptide motif.
- This exposed L2 peptide motif is cleaved by furin or proprotein convertase 5/6.
- Cleavage induces a conformational change that exposes a binding site on the capsid to be exposed to an unidentified host cell receptor.
Describe the process of entry of the HPV once attachment has occured.
Internalisation of the PV occurs by endocytosis. It is thought to occur via clathrin-dependent and clathrin-independent endocytosis however recent studies have also implication caveolin-dependent uptake.
What is particularly remarkable about the internalisation process of HPV?
It takes a significantly longer time than most other viruses, approximately 2-4 hours with some capsids never being internalised.
How does the HPV genome escape the endosome after internalisation?
The capsid shedding occurs in the endosome.
The process of vDNA release is not very well understood however studies have shown the requirement of the protease ‘gamma-secretase’ for HPV infectivity and therefore it is suspected to play a part in endosomolysis.
Once internalised where does the HPV migrate to?
The nucleus
How is HPV trafficked to the nucleus?
It is not certain however theories suggest via microtubules facilitated by the motor protein dynein.
It is also suggested that nuclear entry requires nuclear envelope breakdown due to the requirement of cell division for infection to occur.
How long does it take for HPV DNA to enter the nucleus?
~24 hours
Once within the nucleus, where does the HPV DNA localise ?
Specific nuclear structures known as N10 bodies
What is the effect of HPV localisation to N10 bodies?
The initiation of transcription.
What genes are first expressed during transcription?
E6 and E7
What is the role of E6 and E7?
E6 and E7 protein products result in non-scheduled cellular replication by reacting with the cell cycle control proteins p53 and pRB respectively.
E6-p53
E7-pRB
What is the role of E1 protein?
E1 is a phosphoprotein which binds specifically to the origin of replication and aids in the initiation and elongation of viral DNA synthesis during the process of replication.
What is the purpose of E2 transcription?
E2 protein regulates transcription by binding to E2 binding sites and initiating their transcription.
Also contributes to replication by binding to E1 and enhancing its ability to bind to the origin of replication.
Which genes are associated with the HPV viral capsid?
L1, L2 and E4 genes.
What occurs to HPV when unscheduled host cell replication occurs?
Replication of the HPV genome to form more viral particles which are past onto daughter cells.
Describe the process of virion assembly
L1 and L2 proteins enter the nucleus mediated by karyopherins where the capsid is formed around copies of the genome.
Describe the process of virion release.
Virions remain in the dividing cells until the host epithelial cell completes is differentiation into terminally differentiated squamous epithelium.
HPV virions are not thought to be lytic in nature and therefore release of the virion is suspected to occur as a result of normal loss of nuclear and cytoplasmic membrane integrity custom of terminally differentiated squamous cells, releasing virions into the environment.
Which HPV genes are associated with oncogenesis?
E5, E6 and E7
How does HPV alleviate the immune response?
Most forms of HPV exert no pathogenic consequence and so avoid an immune response to its presence.
Virion proteins are not expressed on the surface of living cells preventing infected cell detection.
Cancerous HPV infected cells are genetically unstable and rapidly evolve to evade immune recognition. Defects in MHC class I proteins are also common in these cells preventing their detection by cytotoxic t cells.
