Papillomaviruses
DNA tumor viruses
disease association (i.e. cervical cancer is the leading lethal malignancy in the world)
good model system for study of GF, transc. factors, etc.
good model to study the development of cancer (tumor virus oncogenes are very similar to human oncogenes)
history:
functional definition: viruses are disease-causing agents which pass through a filter that catches bacteria
1907: papilloma virus discovered in hand wart (first human virus discovered)
1930s: viruses isolated from rabbit tumors Þ used to infect other rabbits Þ tumors in new rabbits, but no virus
- conclusion: viruses can cause cancer but may not be present in the tumor cells
1950s: inject virus into host where it can’t replicate (i.e. human virus into mouse) Þ cancer, no virus production
- inject virus into susceptible host Þ virus production but no cancer
mechanism of carcinogenesis
RNA viruses have it easy: host cell has all the machinery to translate viral RNA (and assemble virus)
DNA tumor viruses typically infect cells that are committed not to enter the cell cycle, so they must somehow acvate the host cell into S phase in order to activate host DNA replication machinery
- viruses are able to do this by expressing oncogenes that turn on the cell replication cycle
- in a normal viral infection the end result is cell death, so viral oncogenes are not a problem
- in some host cells the virus is unable to replicate, but the viral oncogenes cause continued host replication
Papillomavirus
over 80 different types; very specific for different epithelia (i.e. one type causes warts on hand but not feet)
EV: Epidermodysplasia verruciformis
- HPV enters epithelial basal cells via injury and replicates to ~ 100 DNA copies
Þ basal latency
as the basal cells divide normally, they eventually reach the spinous layer where there is rapid replication of viral DNA Þ vegitative amplification
late gene transcription and virus assembly occurs in the cornified layer
genome: 8 kb; 8 early region orfs, 2 late region orfs (capsid genes)
- early gene region transcribed from tissue specific promoters
- late gene region from tissue and differentiation specific promoters (only active in teminally differentiated epithelial cells)
early region gene products (late region genes encode capsid proteins)
- E1: essential DNA replication factor; forms complex with E2
Þ promotes replication, inhibits transc.
E2: transcription factor; represses early HPV promoter in genital HPV
Þ enhances replication, may repress early gene trancription
disruption of E1 or E2 Þ increased viral oncogene transcription (de-repression of promoter)
E5: smallest known oncogene; activates growth factor receptors (PDGF, EGF)
E6: degradation of p53 (through interaction with E3 ubiquitin ligase)
E7: binds Rb Þ release of transcription factor E2F Þ provides signals for S phase DNA synth
Clinical Syndromes
cutaneous warts: two types
- common wart
- EV: inherited disease; patients get lots of warts from many different HPV strains; these strains are also found in normal people, but only cause warts in EV or immunosuppressed patients
respiratory: nasal polyps; benign respiratory lesions; juvenile respiratory papalomatosis (warts on vocal cords)
cervical and anogenital cancer:
- 85% of cervical and anogenital cancers contain HPV
- HPV 6, 11 cause benign genital warts (only knock out p53)
- HPV 16, 18, 31, 33 cause malignant lesions (take out pRb and p53)
- difference between benign and malignant is probably in the specific cell type they infect
- koilocytes: cells that contain lots of HPV can be seen in a pap smear
viral genome integration:
- in benign and preneoplastic lesions, the viral genome is separate from the host genome
- integration of the viral genome is random (usually unstable), but in malignant lesions, a pattern is seen:
- the viral DNA is interupted in the open reading frame of E1/E2
Þ loss of promotor repression Þ overexpression of E6 and E7