Oncogenic Viruses
Prof Dr Ayşe KALKANCI
Terminology
Oncogenic Viruses
Tumor viruses
Human Cancer Viruses
Tenets of viral carcinogenesis
1.Viruses can cause cancer in animals and humans
2. Tumor viruses frequently establish persistent infections in
natural hosts
3. Host factors are important determinants of virus-induced
tumorigenesis
4.Viruses are seldom complete carcinogens
5.Virus infections are more common than virus-related
tumor formation
6. Long latent periods usually elapse between initial virus
infection and tumor appearance.
Tenets of Viral Carcinogenesis
7.Viral strain may differ in oncogenic potantial
8.Viruses may be either direct-or indirect-acting
carcinogenic agents
9. Oncogenic viruses modulate growth control pathways in
cells
10. Animal models may reveal mechanisms of viral
carcinogenesis
11.Viral markers are usually present in tumor cells
12. One virus may be associated with more than one type
of tumor
Multistep carcinogenesis
Normal cell into malignant one
Intermediate stages
Immortalized
Hyperplastic
Preneoplastic
Multistep carcinogenesis
Cellular evolution
Cellular genetic instability
Repeated selection of rare cells
Growth advantage
Mutations
Activation of cellular oncogens
Inactivation of tumor supressor genes
Tumor virus usually acts a
cofactor
Cellular oncogenes
Oncogene is the general term given to genes that are
involved in cancer causation.
Normal versions of these transforming genes are present
in normal cells and have been designated proto-oncogenes.
The discovery of cellular oncogenes came from studies
with actually transforming retroviruses.
Cellular oncogenes
Cellular oncogens are partly responsible for the
molecular basis of human cancer.
Regulating cell proliferation
Differentiation and maintaining the integrity of the
genome.
Incorrect expression of any component might interrupt
regulation.
Results in uncontrolled growth of cells (cancer)
Cellular oncogenes are
Tyrosine-specific protein kinases (srs)
Growth factors (sis)
Human platelet-derived growth factor, a potnent mitogen for
cells of connective tissue origin
Mutated growth factor receptors (erb-B)
Truncated epidermal growth factor receptor
GTP-binding proteins (Ha-ras)
Nuclear transcription factors (myc, jun)
Examples of viral oncogens (DNA viruses)
Virus Viral oncoproteins Cellular targets
Polyomavirus SV40 Large T antigen p53, pRb
Small t antigen PP2A
Human papillomavirus E6 p53, DLG, MAGI-1, MUPP1
E7 pRb
Bovine papillomavirus E5 PDGF beta receptor
Adenovirus E1A pRb
E1B-55K p53
Adenovirus 9 E4ORF1 DLG, MAGI-1,MUPP1
Herpesvirus EBV LMP1 TRAFs
DLG, MAGI-1, MUPP1, members of a family of cellular proteins contain PDZ domains
PDGF, platelet derived growth factor
PP2A, protein phosphatase 2A
TRAF, tumor necrosis factor receptor-associated factor
Tumor supressor genes
The inactivation of functional loss of both allees of such a
gene is required for tumor formation
Prototype of this inhibitory calss of genes is the
retinoblastoma gene (Rb)
The Rb protein inhibits entry of cells into S phase bu
binding to key transcription factors that regulate
expression of S-phase genes.
The function of normal Rb protein is regulated by
phosphorylation.
The loss of Rb gene function is causally related to the
development of retinoblastoma-a rare ocular tumor of
children-and other human tumors.
p53 gene also blocks cell cycle progression
Acts as a transcription factor and regulates the synthesis
of a protein that inhibits the function of certain cell cycle
kinases.
It also causes cells with DNA damage to undergo
apoptosis.
The loss of p53 function allows cells with damaged DNA
to progress through the cell cycle, leading to the eventual
accumulation of genetic mutations.
The p53 gene is mutated in over half of all human
cancers.
Generalization about Viral
Transformation
RNA viruses activate oncogenes
DNA viruses negate tumor suppressors
Virus family Virus Human cancer
Papillomaviridae Human papillomaviruses Genital tumors
Squamous cell carcinoma
Oropharyngeal carcinoma
Herpesviridae Epstein-Barr virus Nasopharyngeal carcinoma
Burkitt lymphoma
Hodgkin diesase
B-cell lymphoma
Human herpesvirus 8 Kaposi sarcoma
Hepadnaviridae Hepatitis B virus Hepatocellular carcinoma
Polyomaviridae Merkel cell virus Merkel cell carcinoma
SV40, BK, JC
Retroviridae Human T-lymphotrophic virüs Adult T-cell leukemia
Human immunodeficiency virus AIDS-related malignancies
Flaviviridae Hepatitis C virus Hepatocellular carcinoma
Medical Microbiology, Lange 2016.
Genome replication
DNA viruses RNA viruses
Interactions of tumor viruses with their
hosts
Tumor viruses establish longterm persistent infections in
humans.
Individual genetic susceptibilities
Host immune responses MAY VARY
AMONG
Levels of virus replication PERSONS
Tissue tropisms
Host immune responses
Avoid and regognition by the immune system
Viral evasion strategies;
Restricted expression of viral genes
Makes infected cells nearly invisibe (EBV in B cells)
Infection in sites relatively inaccessible to immune responses
HPV in epidermis
Mutation of viral antigens that allows escape from antibody and
T-cell recognition
HIV
Host immune responses
Modulation of host major histocompatibility complex class I
molecules in infected cells
Adenovirus, Cytomegalovirus
Inhibition of antigen processing
EBV
Infection and suppression of essential immune cells
HIV
Host immune responses
Host immune mechanisms usually eliminate the rare
neoplastic cells
If the host is immunosuppressed, cancer cells are more
likely to proliferate and escape host immune control.
Organ transplant recipients and HIV-infected individuals
are at increased risk of
EBV-associated lymphomas
HPV-related diseases
Mechanisms of action by human cancer
viruses
DIRECT ACTING
Tumor virus introduces a new «transforming gene» into
the cell
INDIRECT ACTING
Virus alters the expression of a preexisting cellular gene
or genes
Mechanisms of action of human cancer
viruses
The cell loses control of normal regulation of growth
processes
DNA repair pathways are frequently affected
Leading to genetic instability and a mutagenic phenotype
Tumor virus usually acts a
cofactor
Cells become completely transformed
There is no single mode of transformation
Oncogenic mechanisms are very diverse
Cellular transformation: stable, heritable change in the growth control of
cells in culture.
Acquisition of some growth property not exibited by the parental cell
type.
Indirect-acting tumor viruses are not able to transform cells in culture.
RNA tumor viruses
Hepatitis B virus
Hepatitis C virus
Retroviruses
Human T-lymphotrophic virus (HTLV)
HIV
HTLV
HTLV-1 is the causative agent of adult T-cell leukemia-
lymphomas (ATL)
Nervous system degenerative disorder tropical spastic
paraparesis
HTLV-2, HTLV-3 and HTLV-4 have been isolated but have
not been conclusively associated with specific disease.
HTLVs
Pathogenesis and Immunity
HTLV-1 is cell associated and is spread in cells after blood
transfusion, sexual intercourse, or breastfeeding.
The virus enters the bloodstream and infects the CD4
helper T cells.
In addition to blood and lymphatic organs, these T cells
have a tendency to reside in the skin, thus contributing to
the symptoms of ATL.
Neurons also express a receptor for HTLV-1.
HTLV-1
Mother-to-child transmission is estimated at 15-25 %
Early-life infections are associated with the greatest risk
of ATL.
Seropositivity has linked infection with HTLV-1 to a
syndrome called HTLV-1-associated myelopathy/tropical
spastic paraparesis (HAM/TSP)
Uveitis and infective dermatitis are other HTLV-1
associated diseases.
HTLV-1-associated myelopathy/tropical
spastic paraparesis (HAM/TSP)
Development of progressive weakness of the legs and
lower body.
The patients’s mental faculties remain intact.
HAM/TSP is desribed as being of the same magnitude and
importance in the tropics as is multiple sclerosis in
Western contries.
HTLVs
HTLV is competent for replication, with the gag, pol, and env
genes transcribed, translated, and processed as described earlier.
Tax protein transactivates the cellular genes for the T-cell
growth factor IL-2 and its receptor (IL-2R), which activates
growth in the infected cell.
A cellular protein, HBZ, limits Tax activity, promoting cell
survival.
The virus may remain latent or may replicate slowly for many
years but may also induce the clonal outgrowth of particular T-
cell clones.
There is a long latency period (approximately 30 years)
before the onset of leukemia.
Although the virus can induce a polyclonal outgrowth of T
cells, the HTLV-1-induced adult T-cell leukemia is usually
monoclonal.
Antibodies are elicited to the gp46 and other proteins of
HTLV-1.
HTLV-1 infection also causes immunosuppression.
Epidemiology
HTLV-1 is transmitted and acquired by the same routes as
HIV.
It is endemic in southern Japan, the Caribbean, Central
Africa, and among African Americans in the southeastern
United States.
In the endemic regions of
Japan, the children acquire
HTLV-1 in breast milk from
their mothers, whereas the
adults are infected sexually.
The number of seropositive
people in some regions of
Japan may be as high as
35% (Okinawa), with twice
the mortality rate from
leukemia compared to
other regions.
Intravenous drug abuse and blood transfusion are
becoming the most prominent means of transmitting the
virus in the United States, where the high-risk groups for
HTLV-1 infection are the same as those for HIV infection,
and the seroprevalence of HTLV-1 is approaching that of
HIV.
Clinical Syndromes
HTLV infection is usually asymptomatic but can progress
to ATL in approximately 1 in 20 persons over a 30- to 50-
year period.
ATL caused by HTLV-1 is a neoplasia of the CD4 helper T
cells that can be acute or chronic.
The malignant cells have been termed "flower cells"
because they are pleomorphic and contain lobulated
nuclei
ATL is usually fatal within a year of diagnosis, regardless of
treatment.
The 5-year survival rate for patients is less than 5%.
Laboratory Diagnosis
HTLV-1 infection is detected using
ELISA to find virus-specific antigens in blood,
reverse transcriptase polymerase chain reaction (RT-PCR) for
viral RNA,
ELISA to detect specific antiviral antibodies.
Treatment, Prevention, and Control
A combination of AZT and interferon-α has been
effective in some patients with ATL.
However, no particular treatment has been approved for
the management of HTLV-1 infection.
Treatment, Prevention, and Control
The measures used to limit the spread of HTLV-1 are the
same as those used to limit the transmission of HIV.
Sexual precautions, screening of the blood supply, and
increased awareness of the potential risks and diseases all
are ways to prevent transmission of the virus.
Routine screening for HTLV-1, HIV, hepatitis B virus, and
hepatitis C virus are performed to protect the blood
supply.
Maternal infection of children is very difficult to control.
Virus family Virus Human cancer
Papillomaviridae Human papillomaviruses Genital tumors
Squamous cell carcinoma
Oropharyngeal carcinoma
Herpesviridae Epstein-Barr virüs Nasopharyngeal carcinoma
Burkitt lymphoma
Hodgkin diesase
B-cell lymphoma
Human herpesvirus 8 Kaposi sarcoma
Hepadnaviridae Hepatitis B virus Hepatocellular carcinoma
Polyomaviridae Merkel cell virus Merkel cell carcinoma
Retroviridae Human T-lymphotrophic virüs Adult T-cell leukemia
Human immunodeficiency virus AIDS-related malignancies
Flaviviridae Hepatitis C virus Hepatocellular carcinoma
Medical Microbiology, Lange 2016.
Reading & Watching
Symposium - Douglas Lowy: Oncogenic Viruses: Past, Present, and Future
https://www.youtube.com/watch?v=C0aJU-m0XIY
Virology Lectures 2017 #18: Transformation and Oncogenesis
https://www.youtube.com/watch?v=RaHw7sESL8Q
Medical Microbiology, 8e, Murray, Rosenthal, Pfaller.
Medical Microbiology, 27th, Jawetz, Melnick, Adelberg
