GENERAL VIROLOGY 5

Introduction to Oncoviruses

By:

Prof. Dr. Ghada Fahmy Helaly

Microbiology & Immunology Department
Faculty of Medicine
Mu’tah University
 Oncoviruses
• An oncovirus is a virus that can cause cancer. This term originated from
studies of acutely transforming retroviruses in the 1950–60s, often called
oncornaviruses to denote their RNA virus origin.

• Now refers to any virus with a DNA or RNA genome causing cancer and is
synonymous with "tumor virus" or "cancer virus".

• The importance of this is that these cancers might be easily prevented through
vaccination (e.g., papillomavirus vaccines), diagnosed with simple blood tests,
and treated with less-toxic antiviral compounds.

Prof. Dr. Ghada Fahmy Helaly

 Oncogenesis: An abnormal growth of tissue resulting from uncontrolled,
progressive multiplication of cells and serving no physiological function, as a result
of genetic changes that alter the expression or function of proteins that play critical
roles in the control of cell growth and division.

 Proto-oncogenes: normal (pre-mutation)genes.

 present in normal cells.
 conserved in their genomes.
 code for proteins which regulate cell growth & differentiation.

 Oncogenes: mutated versions of proto-oncogenes.

 contribute to cancer development by disrupting cell's ability to control
its own growth.

Prof. Dr. Ghada Fahmy Helaly

Cancer arises from a combination of dominant gain of function mutations
in proto- oncogenes and recessive loss of function mutations in tumor
suppressor genes (such as P53 gene and Retinoblastoma (Rb) gene)

Prof. Dr. Ghada Fahmy Helaly

 CANCER CELLS AND NORMAL CELLS
CANCER CELLS NORMAL CELLS
Frequent
mitoses
Normal
cell

Nucleus Few
mitoses
Blood vessel

Abnormal
heterogeneous cells

Loss of contact inhibition.

Increase in growth factor secretion Intermittent growth factor secretion.

Increase in oncogene expression. Oncogene expression is rare.

Loss of tumor suppressor genes. Presence of tumor suppressor genes.

Prof. Dr. Ghada Fahmy Helaly

HOW VIRUSES CAUSE CANCER:
DIRECT ACTING INDIRECT ACTING
 Viral Oncoproteins:
- virus – encoded non structural proteins.
- target tumour suppressor proteins of host cell.
Loss of normal growth
regulation processes
 Acquisition of proto-oncogene:
- alteration of expression of proto- oncogene  oncogene.
- usually mutated in the process.
- transformation of target cell. Mutagenic phenotype

 Proviral Insertion:
- activate cellular proto-oncogene.
- introduction of new ‘Transforming gene’ into the cell.
- replication intact.
- induce tumours after long latent periods.
Prof. Dr. Ghada Fahmy Helaly
CELLULAR ONCOGENES VIRAL ONCOGENES
 Present in cancer cells.  Present in viruses.

 Contains introns characteristic of  Do not possess introns.

eukaryotic cells.  Also called ‘cancer genes’

 Encodes proteins triggering  Encodes proteins triggering
transformation of normal cells. transformation of normal cells into
cancer cells.

Features of viral Oncogenesis:

 Cause cancer in humans & animals.
 Long latency between viral infection and tumorigenesis.
 Modulate growth control pathways in cells.
 Viral markers are present in tumour cells.
Prof. Dr. Ghada Fahmy Helaly
Interaction between host & oncogenic virus:

(1) PERSISTENT INFECTIONS:

Chronicity of the infections modulate growth control mechanisms.

(2) LATENCY OF VIRAL GENOME:

Episomal copies of viral genome are maintained in transformed cells.
 Viral genome is incorporated into host cell genome.
Tumorigenesis after latent period.

(3) EVASION OF HOST IMMUNE RESPONSE:

 Restricted expression of viral genome (EBV).
 Infection of sites inaccessible to immune response(HPV).
 Mutation of viral antigens (EBV).

Prof. Dr. Ghada Fahmy Helaly

VIRUSES CAUSING HUMAN CANCERS:
DNA oncogenic viruses
Oncoviruses
RNA oncogenic viruses
VIRUS FAMILY VIRUS HUMAN CANCER
Papillomaviridae Human Papilloma virus Genital tumors
Squamous cell carcinoma
Oropharyngeal carcinoma
Herpesviridae Epstein –Barr virus Nasopharyngeal carcinoma
Burkitt’s lymphoma
Hodgkin disease
B cell lymphoma
Human Herpes virus 8 Kaposi sarcoma
Hepadnaviridae Hepatitis B virus Hepatocellular carcinoma
Flaviviridae Hepatitis C virus Hepatocellular carcinoma

Retroviridae Human T cell lymphoma virus Adult T cell lymphoma

Human immunodeficiency virus AIDS related malignancies

Prof. Dr. Ghada Fahmy Helaly

 Prof. Dr. Ghada Fahmy Helaly

RNA VIRUSES
 RETROVIRUS

 Virion – Enveloped, 2 copies of single stranded RNA

 Possess reverse transcriptase (RNA dependent DNA
polymerase)


Accessory protein Tat:
- interferes with DNA repair mechanisms.
- interfere with Rb gene mediated growth regulation
pathway.

Prof. Dr. Ghada Fahmy Helaly

 Hepatitis C Virus ( HCV)
 Flaviviridae. Single stranded RNA.
 Over 170 million chronic carriers.
 Hepatocellular carcinoma.
 Mechanism- inflammation cirrhosis
• HCV core protein interferes with p53 (tumor
suppressor gene)

Prof. Dr. Ghada Fahmy Helaly

Human T- Lymphotropic Virus 1 ( HTLV-1)

 Associated with leukemia and

lymphoma.
 Has special 2 genes tax and rex play
role in oncogenesis by regulating mRNA
transcription and translation.

Prof. Dr. Ghada Fahmy Helaly

 Prof. Dr. Ghada Fahmy Helaly

DNA VIRUSES
Human Papillomavirus (HPV)
• HPV induced cervical cancer, specially type16 and 18.
• Associated with oropharyngeal cancers, as well as anal
and genital cancers.
• Types 6 and 11 are associated with genital warts.

• Episomal HPV DNA – in premalignant lesions.

• Integrated HPV DNA – in cervical cancer cells.
• Oncogeneticity: Transforming Oncoproteins (E6 and E7)
interacting with tumour suppressors(p53, Rb )

Prof. Dr. Ghada Fahmy Helaly

 Hepatitis B Virus
• Hepadnaviridae
• Genome – circular, ds DNA
• Hepatocellular carcinoma
• HBV integration: The insertion of HBV
genome in cellular genes frequently targets
genes that regulate key cellular pathways.
• In HCC cells, overexpression of HBx and
the oncogene c-myc each increased rRNA
levels cell division was observed .

Prof. Dr. Ghada Fahmy Helaly

 HERPES VIRUS
 Epstein-Barr virus (HHV-4).
 Kaposi sarcoma herpes virus (HHV-8).
 Properties
 Large viruses.
 Genome – linear double stranded DNA.
 Icosahedral capsid with lipid containing envelope.
 Acute infection followed by latency (Latency genes).
 Recurrence from latent infection.

Prof. Dr. Ghada Fahmy Helaly

Epstein-Barr Virus (EBV):
 Transmitted by transfer of saliva/genital secretions.
 Infects B cells and epithelial cells.
 Can establish latency.

 Infectious mononucleosis.
 Burkitt’s lymphoma.
 Nasopharyngeal carcinoma.
 Non Hodgkin’s lymphoma.

Tumours contain integrated & episomal forms of viral DNA.

Prof. Dr. Ghada Fahmy Helaly

Oncoproteins of EBV:

 LMP1(latent membrane protein 1) stimulation of transcription factors

for anti-apoptotic proteins.

 Epstein-Barr nuclear antigen (EBNA): EBNA3C binds Rb and

promotes cell cycle progression. EBNA1 Inhibits p53 induced

apoptosis

Prof. Dr. Ghada Fahmy Helaly

Kaposi’s sarcoma-associated herpesvirus (HHV-8):
• Angioproliferative tumor that can involve skin (most often),
lymph nodes, or viscera, establishes latency.
• Sexually transmitted.
• Causes disease in immunosuppressed patients; asymptomatic
in healthy people.
• Inflammation or some other stimulus ignites the lytic cycle to
infect surrounding cells.

ONCOPROTEINS: Latency Associated Nuclear Antigen (LANA1)

bind to p53 and inhibit p53-dependent apoptosis

Prof. Dr. Ghada Fahmy Helaly

SLOW VIRUSES AND PRIONS:
 Subacute sclerosing panencephalitis  Measles virus.
 JC virus immunosuppressed progressive multifocal
leukoencephalopathy.
 Retroviruses.
 Prions: proteinaceous material lacking nucleic acid  spongiform
encephalopathies. Clinical diseases: kuru and Creutzfeldt-Jakob disease
of humans, scrapie of sheep, bovine spongiform encephalopathy (or mad
cow disease).
Prof. Dr. Ghada Fahmy Helaly
Prof. Dr. Ghada Fahmy Helaly