Oncoviruses By Bhuvanesh Kalal

Oncovirus cancerous agent

[email protected] or [email protected]

the

Table of contents 1. 2. 3. 4. 5. 6. 7. 8.

Definition History Classification Key words Transformation Oncogene Replication Example– DNA Oncovirus (HPV) RNA Oncovirus (HTLV)

Defination: *viral agents causing cancer in eukaryotic animals by integrating in host genome *A virus associated with malignancies in natural host, experimental animals or cell cultures. *viruses which modified proto-oncogene, obligatory host specific, with the ability immortalization, possess genes which stimulate growth and cause cancer.

Research History In 1908, Ellerman & Bang first discovered virus, producing leukemia in chicken. In 1911 Peyton Rous 1st shows the presence of filterable sarcoma material that induce the CANCER.

Classification Oncovirus

DNA oncogenic viruses

RNA oncogenic viruses

DNA Oncov iruses Virus Family

Papovaviridae

Herpesviridae

Virus

Associated tumours

Papilloma *

Genital (Cervical, vulvar, penile) warts, may progress to .carcinoma

Polyoma *

Various carcinomas and sarcomas

SV40

( Sarcoma(in Rodents

BK & JC *

Polyoma in man, tumours in rodents

( Hepatitis simplex type (1 & 2

•

Cervical carcinoma

Cytomegalovirus *

Koposo's sarcoma, cervical neoplasia

Epstein Barr virus *

,Nasopharyngeal carcinoma Burkitt's lymphoma, B Cell lymphoma

Hepatitis viruses

Hepatitis B viruses *

Primary hepatocelular carcinoma

Pox virus

Molluscum

Nodular epidermal hyperplasia

Adenoviridae

contagiosum *

Shope fibroma *

Fibroma

Yabavirus

Nodular fibromatous hyperplasia

Type 2, 5, 12

None in man, sarcomas in hemsters

RN A Oncovir use s Retroviridae Avian sarcoma leucosis virus (ALV) complex

Various sarcomas, lymphomas and .lekaemia (natural tumours) in birds

Mouse leukaemia and (sercoma (MLV

. Various sarcomas, leukaemias

(Feline leukaemis (Fel V

Various sarcomas, lymphomas in mice and lekaemias

Bovine leukaemia

Lymphosarcoma (B cells) in cattle

Human T Cell leukaemia * ((HTLA-1, 2

T-cell leukaemis/lymphoma in man

Flaviridae Hepatitis C virus *

Primary hepatocellular carcinoma

Oncogenic Viruses associated with human cancer Virus family

virus

Type of malignancy

DNA VIRUS Papovaviridae

Herpesviridae

Human papilloma virus

Cervical, Valvular, Penile cancers of squamous cell type polyma

BK virus and JC virus

Polyoma

EB virus

Burkitt's lymphoma, cervical carcinoma

HSP type 2

B-Cell lymphoma, Cevical carcinoma

Hepatitis C virus

Hepatocellular carcinoma

HTLV

Adult T-Cell leukaemia

RNA VIRUS Flaviridae Retroviridae

Key Words Immortalization : ability of virus to establish persistent

infection that can also stimulate uncontrolled cell growth indefinitely provided that adequate nutrients are available. Neoplasia: property of cell to undergo rapid, abnormal and uncontrolled growth at the cost of remaining cells.

Permissive and Non-permissive cell Malignancy HeLa cell Episomes Transformation: Ability of virus infected cell, to Change in the biological functions of a cell by the regulation of viral genes to cause malignant growth result in NEOPLASIA. these change often (but not always) result from integration of the viral genome into host cell genome.

Transformation of Normal cell to cancer cell

Characteristics of Transformed cells: ► Possession

of viral genome: ► Morphologic changes: ► Loss of cell-contact inhibition of growth: ► Increased efficiency of clone formation ► Decreased growth factor requirements: ► Change in membrane transport properties: ► Expression of tumour-associated antigen: ► Change in plasma membrane composition: ► Chromosomal alteration:

Oncogene ► ► ► ► 5. 6. 7.

gene which encode for protein were first discovered in retroviruses proto-oncogenes exist naturally in the human genome Functions:INDUCTION OF CELLULAR PROLIFERATION INHIBITION OF CELLULAR PROLIFERATION REGULATION OF PROGRAMMED CELL DEATH

Type of Oncoviral infection 1. Productive : Synthesis and Release of progeny virus. a) Lytic—Host cell Killed e.g. DNA virus b) Nonlytic—No noticeable cytopatic effect on host cell e.g.. RNA virus 2. Non Productive : Progeny virus nor produced a) Abortive—loss of viral genome after infection b) Defective—viral genome incomplete c) Non permissive—Host cell lack certain factor

Multiplication of oncoviruses ► DNA

Oncovirus:

► RNA

Oncovirus:

In case of oncogenic DNA viruses: ► integrated with the host cell genome as prophage ► encoded proteins which bind and inactivate the growth-regulatory proteins of the cell ► such as the retinoblastoma (RB) or p53 gene product ► cells bcl-2 oncogene prevents (apoptosis). ► defective or incomplete, no infections virus is produced

Multiplication of a RNA oncovirus Capsid Reverse transcriptase

Envelope Two identical strands of RNA

Virus

1 Retrovirus penetrates host cell.

Host cell

DNA of one of the host cell’s chromosomes

5 Mature

retrovirus leaves host cell, acquiring an envelope as it buds out.

Identical strands of RNA Viral proteins RNA

Reverse transcriptase Viral RNA

4 Transcription of the

provirus may also occur, producing RNA for new retrovirus genomes and RNA that codes for the retrovirus capsid and envelope proteins.

Provirus

2

Its RNA is uncoated; reverse transcription takes place.

3 The new viral DNA is

tranported into the host cell’s nucleus and integrated as a provirus. The provirus may divide indefinitely with the host cell DNA. Figure 13.19

► Examples

CLASSIFICATION ► Phylum:

Vira ► Sub Phylum: Deoxyvira ► Class: Deoxycubica ► Order: Haplovirales ► Group: Group I (dsDNA) ► Family: Papovaviridae ► Genus: Papillomavirus ► Strain : Human papillomavirus

► Papillomaviruses

are a diverse group of DNA-based viruses that infect the skin and mucous membranes of humans and a variety of animals

► Richard

Shope

TYPES ► More

than 100 types of human papilloma viruses (HPVs) ► HPVs 16, 18, 31, 33, 35, 39, 45, 50, 51,53, 55, 56, 58, 59, 64 and 68 are considered “high risk” types ► HPV 16 and 18 are the most closely associated with cervical carcinoma

► Some

sexually transmitted HPVs -- types 6, 11, may cause genital warts

Structure ► small ► non-enveloped ► (~52-55nm

diameter ) ► A single viral protein (L1 ) necessary and sufficient for formation of a 60 nm capsid composed of 72 star-shaped

GENOME

GENE ORGANIZATION ► typically

contains around 8000 bp [7904 bp forHPV16 (GenBank® accession number NC 001526)] ► organized in three regions: • the early gene (E1 to E7) • the late gene (L1 and L2) • the upper regulatory region (URR)

► E1

: encode proteins that are vital for extra chromosomal DNA replication and the completion of the viral life cycle ► E2 : encodes two proteins - one, which inhibits transcription of the early region; and the other, which increases the transcription of the early region ► E4 : Maturation, induces the collapse of the cytoplasmic cytokeratin network in human keratinocytes, stimulate releasing ►

► E5

: interacts with various transmembrane proteins like the receptors of the epidermal growth factor, platelet-derived growth factor, and colony stimulating factor-1 ► E6 and E7 :encode for oncoproteins that allow replication of the virus and the immortalization and transformation of the cell that hosts the HPV DNA. ► L1 and L2 : encode for viral capsid proteins during the late stages of virion assembly

Regulation Mechanism ► E7

associates with pRb and disrupts the association between pRb and the E2F ► .E7 also associates with histone deacetylases, components of the AP1 transcription complex and the cyclindependent kinase inhibitors p21 and p27. ► in the high-risk HPV types, both E6 and E7 proteins are expressed together from a single polycistronic mRNA species.

► E7

block ARF (ADPribosylation factor) pathway ► E6 PDZbinding can mediate suprabasal cell proliferation and may contribute to the development of metastatic tumours by disrupting normal cell adhesion

Transmission ► By

skin-to-skin or mucosa-to-mucosa contact ► By sexual contact ► By mother to child during birth

Major steps in the development of

HOW IT GIVES THE SYMPTOMS OF CANCER

► “low

risk” HPV gives warts on the anus, vagina, vulva, penis and thighs. ► “intermediate risk” give lesion. ► “high risk” gives pre-cancerous lesions and can lead to cancer of the cervix, anus and other genital areas.

DIAGNOSIS 1) Pap (Papanicolou) test : to detect celular change. *cells collected from the cervix (the lower, narrow end of the uterus) to detect cancer or abnormal cells that may lead to cancer 2) Colloscopy : 3) DNA test :

Prevention • • • •

Absolutely no skin-to-skin sexual contact The more sexual partners, the higher the chance of contracting HPV. contraception Vaccination is now available to prevent certain low risk types that cause genital warts certain high risk types that cause cancer.

Treatment ► Cryotherapy

– liq. N2 ► Cautery – electrical current, laser therapy ► Chemical treatments - drugs ► Surgery – removal ► Vaccination

Production of prophylactic HPV virus-like particle (VLP) vaccines The vaccine mimics the virus shell

(Atomic force microscopy image of a single VLP)

L1 capsomere L1

L1 protein

5 x L1

Virus-Like Particle (VLP)

72 capsomeres

Atomic force microscopy image of a single VLP

5 x L1

L1-external protein

Expression and self assembly in a recombinant eukaryotic vector

Adapted from Syrjänen & Syrjänen. Papillomavirus infections in human pathology. Wiley & Sons, Chichester; 2000. pp 11–46.

HPV 16 VLP composed of 72 capsomere subunits of L1 protein

Major Pharma developing HPV VLP vaccines Sanofi Pasteur MSD - Gardasil  a quadrivalent HPV 6, 11, 16, 18 L1 VLP vaccine; alum adjuvanted  licensed in UK October 2006  awaiting guidance from Joint Committee on Vaccination and Immunisation (JCVI) regarding policy for vaccination in the UK GlaxoSmithKline - Cervarix  a bivalent HPV 16, 18 L1 VLP vaccine; AS04 adjuvanted  submitted to European Agency for the Evaluation of Medicines (EMEA) March 2006

BREIF DISCRIPTION OF RNA VIRUS ► RNA

oncovirus also calles as oncornaviruses.

Classification ► Phylum:

Vira ► Sub Phylum: Ribovira ► Class: Ribocubica ► Order: Gymnovirales ► Group: RNA ► Family: Retroviridae ► Subfamily:

Orthoretrovirinae ► Genus: Deltaretrovirus ► Strain

: Human T-cell leukemia virus ► Type : HTLV 1 & 2

► Infection

in T-cells ► Transmission ► Gives Adult T-cell leukemia (ATL) ► Composed of 2 copies of ssRNA

References

► www.wikipedia.com ► www.iarc.uk

► www.cancerresearchuk.org ► www.cancer.gov ► https://cissecure.nci.nih.gov/

www.nature.com ► Research paper by john Doorbar ► www.hpvinfo.com ► Online Microbiology and immunology books ►

►

Research paper By Brandon Stott and Michelle Wyse

► http://www.jem.org/cgi/

CONCLUSION

DISCUSSION

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