Lec 13 Papilloma Viruses Flashcards
Clinical presentation of papillomavirus infections
dsDNA, small DNA viruses
Papillomaviruses can infect humans and a wide spectrum of animal species
TUMOR VIRAL INDUCED PAPILLOMA are usually RARE. Seen in horses and rabit.
Target outer skin epithelial cells only, specifically the BASAL KERATINOCYTES, the ACTIVELY DIVIDING CELLS!
Low-risk human papillomaviruses can cause low-grade squamous intraepithelial lesions (SIL), like skin warts and anogenital warts
Wart: Any part of the body in humans, infected by a papilloma virus
The location of the wart is detrimental to bad side effects, especially in foot and genetalia
In general
dsDNA, small DNA viruses
What 2 things do they have in common?
All non-enveloped
Circular or linear dsDNA surrounded by capsid proteins
Other tumor viruses: retroviruses, hepatitis B and C, Herpesvirus, adenovirus
HIV is NOT a tumor virus
High risk human papillomaviruses
HIGH-RISK human papillomaviruses can cause GENITAL and ANAL CARCINOMAS as well as HEAD and NECK CANCER
CERVICAL cancer is the 2nd leading cause of CANCER-related DEATHS in WOMEN, Cervical cancers are very associated w/ papilloma viruses. Men have symptoms too!
Genotypes HPV16 and HPV18 are responsible for 70% of cervical cancer cases
High Risk HPV infection can be prevented by vaccination, very effective in both genders.
Infection is life long, vaccinations cannot do anything after the virus is infected, do not decrease cancer risk once infected
Pap smear and other screening are reliable in looking at development
What is the difference between a tumor/cancer and hyperplasia?
What is transformation or a transformed cell?
Hyperplasia: proliferation of cells (e.g. a wart)?
Tumor cells have acquired mutations in genome
Note: Not all tumors are metastatic!
Hyperplasia cell do not have necessarily acquired mutations in genomes!
Transformed cell looks like a tumor but has not acquired a mutation eg. wart
Papilloma viruses general
VLPs
Family: Papillomaviridae
B/c of diversity there is not much cross reactivity in-between strains (> 120 genotypes) so vaccines
include > 1 strain of HPV
non-enveloped
icosahedral capsids
capsids are composed of the major capsid protein L1 and minor capsid protein L2
capsid architecture solely made by L1 protein, which is assembled into pentamers
Very densely packed, sturdy structure. Also resemble VLPs: the capsid w/o a genome inside. A virion that is not replicatively competent.
The VLPs represent current HPV vaccines. Express genes in yeast and bacteria, virus forms spontaneously.
The outer structure is identical to the authentic viral epitopes, induces proper Ab production.
HPV Transmission
HPV transmission occurs via contact with infected tissue or surfaces
Genital HPV types transmitted mainly by the sexual route
at least 50% of sexually active men and women have been infected at some point
mother to newborn transmission is possible (very rarely)
Mother is more sensitive during partuition (less IS response…)
HPV Prevention
having a mutually monogamous relationship decreases the risk of HPV infection
HPV vaccine
Papanicolaou test (Pap smear test) as cervical cancer screening tool
HPV Therapy
WARTS CAN BE REMOVED by cryotherapy, electrocautery or chemically if necessary
in case of cervical changes: cryosurgery, laser ablation, cone biopsy or loop electro surgical excision procedure (LEEP)
Usually all warts go away b/c immune system is able to fight these infections given enough time
Papillomavirus genome
unsegmented. circular dsDNA
histone-associated viral DNA
8 ORFs
genes are partly overlapping
upstream regulatory region (URR) with origin of replication
2 polyadenylation signals
Genome organization is highly conserved among human and animal papillomaviruses
multiple promoters
3 major + several minor promoters
promoter activity depends on the host cell’s differentiation state
generation of many different polycistronic mRNAs, which get extensively spliced
HPV Life cycle: Entry
- Infection of basal cells
- Receptor binding (L1)
- Uncoating (L2)
- Nuclear transport
Entry
papillomaviruses only replicate in keratinocytes
- Infection of basal cells
- through micro wounds
- Receptor binding (L1)
- cell surface heparin sulfate proteoglycans
- Uncoating (L2)
- forms pores into endosomal membrane
- Nuclear transport
- of viral DNA via L2
- viral DNA as episome
The skin is one of the best immunological systems. Highly sensitive to invaders. The virus is not detected b/c the infected cells usually present antigens to IS. Skin transplants are not infected too much
HPV Life cycle: Past entry
- Early transcription
- ‘Establishment phase’
- Basal cell division
Past Entry
basal keratinocytes are the only
actively dividing cells of the stratified epithelium
- Early transcription
- expression of early genes
- no L1 or L2 synthesis
- no virion generation
- ‘Establishment phase’
- genome replication up to 50-100 copies/cell
- Basal cell division
- production of two cells with viral episome
- one cell stays behind as basal cell
- the other cell migrates and differentiates
HPV Life cycle: Virion production
- Productive Phase
- Late transcription
- Release
Virion production
virion production occurs only in terminally differentiated keratinocytes
- Productive phase
- high levels of viral DNA replication (midzone) - Late transcription
- expression of E4 and capsid proteins
- depends on upregulation of late promoter,
late stage specific poly-A and splicing sites - Release
- facilitated by changes in the cornified keratinocyte cell envelope
- NON-CYTOLYTIC
Virus epithelial lining progression
Life cycle duration?
Which layer does replication happen?
Once virus enters SUPERFICIAL ZONE the STRUCTURAL PROTEINS ARE EXPRESSED and INFECTIOUS VIRUSES are made.
Whole cycle takes 3 weeks
Follows very closely w/ the host cell.
Most of the time the virus cannot be recognied by IS, only seen when capsid proteins are seen and are killed by vaccine antibodies
HPV Life cycle: Viral persistence and latency
Viral persistence and latency
maintenance of viral genome in basal keratinocytes: ‘Maintenance phase’
viral genome replicates in synchrony with the host cellular DNA, cell cycle dependent
viral GENOME IS TETHERED to MITOTIC CHROMOSOMES through viral E2 and cellular proteins
HPV Oncogenesis
Persistent infection
Oncogenesis
cancer development can take up to several decades after initial infection
-> PERSISTENT INFECTION = major risk factor
transformation of HOST CELLS INTO INFINITELY PROLIFERATING CELLS
