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PAPILLOMA VIRUSES
Papilloma Viruses
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Characteristics
dsDNA viruses (circular)
Genone 8 kbp
Genome associated with cellular histones
Naked capsid
Widespread in humans and other animals
They cause ‘warts’
Some strains 16,18 and 31 associated with high risk of
cervical cancer
– Over 100 types of HVP found so far
Papilloma Viruses
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Different types infect different anatomical sites
HPV-1 target feet
HPV-2, 4, 7 hands
Virus targets mucosa (oral, nasal, genital) OR skin
Transmission of genital tract HPV thru sexual contact
Transmission of skin HPV thru touching, or
contaminated surface
• HPV that infect genital tract mucosal can cause
– cervical warts referred to as ‘condylomas’ (benign
rarely progress to cancer)
– Strains 16,18 and 31 associated with high risk of
cervical cancer such as Squamous Cell Carcinoma
• Referred to as Oncogenic HPVs
• Genital tract infections are transient in many cases
cause no symptoms
• Lack of symptoms allows for easier spreading
HPV 16
• HPV 16 is of interest due to oncogenic properties
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6 Early genes (E1, E2, E4, E5, E6 and E7)
2 Late genes (L1 and L2)
Genome has multiple ORFs
Variable Splicing of mRNA transcripts yields variety of
mRNAs with multiple ORFs
– Virus targets mucosa (oral, nasal, genital) OR skin
• Transmission of genital tract HPV thru sexual contact
• Transmission of skin HPV thru touching, or
contaminated surface
Infectious Cycle
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Infection requires entry to NON-DIFFERENTIATED basal cells
Virus binds to heparin and 6-integrin
Virions are taken in by endocytosis
Genome ends up inside nucleus
– Stays as circular DNA
– Does not incorporate itself into host genome
• Replication of genome occurs generating 50-100 copies
– Every cell division genome is duplicated and split equally between parent
and daughter cell
– This type of division is referred to as ‘plasmid replication’
• When Basal Cells become Keratinocytes burst of viral replication
occurs
– This burst is called vegetative replication
– During this same period L1 and L2 genes are expressed producing capsids
– Release of assembled virions occurs during cell death
HPV 16, 31 Genome Structure
 In undifferentiated basal cells Pearly transcribes all six E genes
 Transcript terminates at Poly(A)early
 Poly(A)early immediately after E genes resulting in no expression
of Late genes
mRNAs generated have multiple ORFs, unclear how ribosomes
translate them
HPV 16, 31 Genome Structure
 Late promoter (Plate) active in Keratinocytes
 When E1 and E2 levels increase a shift occurs towards
vegetative DNA replication
 Transcripts from Plate terminate to Poly(A)late
Giving rise to L1 and L2
Alternative splicing is responsible for the shift in E1 and E2
and ultimately increase in L1 and L2
L1 and L2 encode for capsid proteins which leads to an
increase in virion production
Splicing of Plate-Poly(A)late transcript results in removal of E
genes and expression of only L1 and L2 genes
Functions of HPV Proteins
 E1 is a DNA helicase, binds replication origin and initiates
DNA replication. By unwinding genome cellular DNA
polymerases can replicate viral genome
 E2 enhances binding of E1 onto replication origin
 E6 enhances degradation of p53 protein which is a major
cell cycle control protein
E7 binds Rb protein increasing cell cycling
L1 major capsid protein
Splicing of Plate-Poly(A)late transcript results in removal of E
genes and expression of only L1 and L2 genes
Some cellular transcription factors known to bind regulatory
sequences of PV genome are: NF-1, SP1 and AP1
Viral Replication Surges in Keratinocytes
 Replication surge is unusual given the fact that keratinocytes are terminally differentiated
and do not carry any significant DNA replication
 E7 is responsible for this peculiarity, binds Rb resulting in release of E2F transcription
factor
E2F then participates in expression of a variety of genes involved in cell cycle
E7 binds Rb protein increasing cell cycling, essentially convincing keratinocytes to divide
Rb is a major tumor suppressor protein. Many retinoblastoma cancers are due to mutated Rb
E6 Eliminates p53
 p53 normally induces apoptosis of cells that should not
be dividing such as Keratinocytes
 p53 neutralization is achieved by ubiquitination which
leads to proteasome degradation
 similar to Rb, p53 mutations are observed in a variety
of cancers
p53 Function
 p53 normally is in low levels in the cytosol and inactive
 In stress conditions:
• increase in phosphorylation occurs making it more
stable
•Increase in p53 expression also occurs
 p53 activation can stop cell cycling at G1 for repair
OR cause apoptosis
In many cancers p53 is mutated, in HPV is NORMAL!!
No reason to mutate, simply eliminate by ubiquitination
Cervical Cancer Cell Lines Induced by HPV
 Surprisingly do not produce HPV virions!
 In these cell lines genome is inserted into host genome
Normal HPV infected cells do not incorporate HPV genome into
their own genome
E6 and E7 are the only genes being expressed in HPV related
cancers
No surprise E6 and E7 target p53 and Rb respectively
Viral integration into host cellular genome has no advantage
 Expression of E7 allows neutralization of Rb, release of E2F and
expression of cell cycling genes
Normally p53 would eliminate them but p53 itself is eliminated
through E6
Cervical Cancer Diagnosis and Prevention
 Pap test has been the main diagnostic tool for cervical cancer for
decades.
 The discoverer is George Papanicolaou
Significantly reduces mortality rates of cervical cancer
Cervical warts are pre-malignant tumors and often removed surgically
or freeze killed with liquid nitrogen
HVP vaccines are now available that raise immunity against L1 protein
of HPV strains 16, 18 (Guardasil includes L1 from stains 6, 11, 16 and
18)
L2 is considered in vaccination trials, could provide immunity against
wider range of HPV types
Vaccination is recommended at young age before encounter with virus
i.e ages 11-12