Oncogenic Viruses

Christopher B. Buck, Lee Ratner, and Giovanna Tosato

Wahyu Haris Prabowo
Tahap III Stase Bedah Onkologi
Principles of Tumor Virology

Viral infection
Viral infection Majority of alone is rarely
Oncogenic virus
play a causal cases (>85%) sufficient to
in human 
role in 10% of occurs in induce
comes from 6
cancer developing malignancy 
viral families
diagnosis countries need additional
oncogenic “hits”
Viral Oncogenic Mechanism
Direct
• Hit and run mechanism
• Viral gene product preserve
cellular viability and promote
cell growth  accumulation
of precancerous cell 
additional genetic hits 
malignancy
Indirect
• Viral infection cause
inflammatory immune
response  accelerated
tissue damage and
regeneration  proliferation
of unaffected cell
 By development of
Can be use as vaccine or antiviral agent
Virus-induced cancer
therapeutic approach to prevent, attenuate or
eradicate viral infection
Oncogenic Virus Families

Epstein-Barr
Papillomaviruses Polyomaviruses
virus

Kaposi Sarcoma
Retrovirus Hepatitis virus
Herpesvirus
Papillomaviruses
History

Mid 19th century

First
 uterine cervix Harald zur Husen
demonstrated
Named for the cancer is related  found HPV16
causing cancer in
benign skin warts to sexual behavior and HPV18 in
rabit by Richard
(papillomas) after observing its various cervical
Edwin shope
incidence in nun cancer cell line
(1930)
and prostitute
Tissue Tropism
Papillomaviruses can enter
various cell, but its cycle is
dependent on host cell factor
found in keratinocyte
HPV-induced cancers arise
primarily at transition zones of
the endocervix, the inner surface
of the anus, and tonsillar crypts.

There are more than 300 known

HPV types  each has distinct
serotype and highly species
restricted
Gene Function
Genome

• 8 kb, double-stranded, closed-circular DNA molecules (plasmid)

• Normal viral cycle  the genome neither transform into linear form nor
integrate to host chromosome

Oncogenesis

• Loss of E2 expression due to DNA host integration  upregulation of early

gene expression (E1, E2, E4, E5, E6, and E7)
• E6 protein triggers p53 destruction and activation of cellular telomerase
• E7 protein interact with pRB  disturb cycle cell arrest mechanism
• E5 (only expressed in several papilloma)  disturb cell surface growth
factor receptors  immune evasion
HPV Vaccine
• Trade name  Gardasil 9 (Merck) and Cervarix (GSK)
• Contain recombinant L1 capsid proteins based on HPV16 and HPV18 that
are assembled in vitro into virus-like particles (VLPs).
• Gardasil 9 also includes VLPs of other five HPV types associated with
cervical cancer
• The vaccines effectively prevent the development of cervical
intraepithelial neoplasia without increased risk of adverse events
• Current HPV vaccines cannot eradicate existing infections due to L1
protein are not expressed at latent phase
• Next-generation HPV vaccines (target L2 protein) are currently in human
clinical trials
Nonmelanoma Skin Cancer

Epidermodysplasia verruciformis is a rare immunodeficiency 

characterized by the appearance of numerous wart-like lesions
across wide areas of skin

The lesions typically contain papillomaviruses from genus Beta,

such as HPV5 or HPV8.
Bladder Cancer

Etiology (human, a few

Etiology (cattle)  cases)  HPV 16 and
bovine papillomavirus 18  characterized by
type 2 HPV-induced histologic
pattern (koilocytosis)
Polyomaviruses
History

1960  Bernice
1950  Ludwig et et al reported
Bernice and Sarah Polyomaviruses in
al found filterable discovery of
 found murine human  BK virus
infection that simian vacuolating
polyoma virus can and JC virus
induce salivary virus 40 (SMV40)
cause many (HPyV1 and
gland cancer in  polyoma virus
different cancer HPyV2)
mice contamination in
poliovirus vaccine
BK Polyomavirus

BKV LT expression
frequently
It also found in observed in the
several dozen inflammatory
cases of urinary precursor lesions
Latter called by Found in bladder
carcinomas of prostate,
HpY viruses carcinoma
affecting although no
transplant evidence support
recipients. persistent
infection with
prostate cancer
Merkel Cell Polyomavirus
Typically present as fast-
Discovered in 2008 by
Rare but lethal form of growing violaceous
yuan chen and Patrick
cancer lesion on sun-exposed
moore
skin surfaces

High levels of MCV DNA,

Risk factors: HIV/AIDS stronger T-antigen
patients and organ expression, and tumor
transplant patients CD8+ T cells infiltration
 better prognoses
Merkel Cell Polyomavirus
Other Polyomavirus

HPyV6 and HPyV7 may

HPyV (trichodysplasia play a causal role in
HPyV7 DNA and T-
spinulosa polyomavirus) pruritic skin rashes with a
antigen expression can
 ascociated with distinctive “peacock tail”
often be detected in
abnormal spiny growths histology in patients with
thymic tumors
on the facial skin various forms of
immunosuppression
Epstein-Barr Virus
History

Michael Epstein In Burkitt’s

1958  Denis
and Yvonne Barr  lymphoma 
Burkitt described
examine Dr Burkitt EBV tumorigenesis malaria weakened
an unusual B-cell–
tumor samples  mechanism is still B cell proliferation
derived tumor in
found viral particles under  increase the
jawbones of
similar morphology investigations likelihood of
equatorial Africa
to herpes simplex oncogenic c-myc
children
viruses translocation
Ebstein-Barr Virus Lifecycle
Persistent (latent)
Infection in Infect tonsillar infection in
childhood by saliva crypts oropharyngeal
epithelium

Other stimulus
Viral multiplication “weakened” the
virus
Lymphomas

EBV also associated with

posttransplant
Nearly all cases of
lymphoproliferative
endemic Burkitt lymphoma
Main pathophysiology  disease (PTLD), mixed
are EBV-positive  20%
cellular Myc cellularity and lymphocyte-
in sporadic cases in
protooncogene depletion subsets of
immunocompetent
deregulation Hodgkin and other
individuals outside of
lymphomas and natural
malaria-prone regions
killer (NK)/T-cell
lymphoma
Carcinomas

EBV is also present in a

EBV associated with small percentage (5% to
nasopharyngeal 15%) of gastric
carcinoma in both adenocarcinomas and
endemic (China) and over 90% of gastric
non endemic cases lymphoepithelioma-like
carcinomas
Prevention and Treatment
Prevention

• Reduction immunosuprrsive drug consumption

• HIV infection control
• Prophylactic vaccine  dicfficult

Treatment

• Ganciclovir  could reduce EBV replication

• Most EBV  express CD20  rituximab maybe become a potential
therapy
Kaposi Sarcoma
Herpesvirus
History and Epidemology
Late 19th century 
Moritz Kaposi describe Aggressive form of KS  1994  Moore, Chang et
rare sarcoma in older more prevalent in AIDS al  found herpesvirus in
men  Kaposi sarcoma pandemic KS tumor
(KS)

Seroprevalence  1-7%
in general population and
Increased incident in HIV
25-60% in gay men, and
patient
up to 30% in Uganda
pediatric population
Clinical and Histologic Presentation
Lymphoproliferative Disorders
KSHV

Cause two form B-cell

proliferative disorder

multicentric Castleman Primary effusion

disease (MCD) lymphoma (PEL)
Lymphoproliferative Disorders
MCD PEL

• Predominantly in AIDS patient  • Prevalence  4% in HIV associated

majority have KSHV infection Hodgkin lymphomas
• Also occur in HIV negative patient  • Present as liquid malignancy in body
40-50% cases are KSHV negative cavity effusion
• Systemic symptoms • All tumor cell infected with KSHV with
• Diagnosis based on histologic finding of 80% EBV coinfection
LANA-positive plasmablasts in mantle • Symptoms  effusion and
region of affected lymph nodes inflammatory symptoms
• Median survival  2 years
Retroviruses
Animal and Human Retroviruses
Retroviruses are positive
single-strand RNA viruses
that utilize transcription of
their RNA genome into a
DNA intermediate during
virus replication
Chronic transforming
Infect a wide range of retroviruses integrate
animal species and are almost randomly in the
distantly related to genome and can disrupt
repetitive elements in the the regulation of nearby
human genome, known as genes and induce cell
retrotransposons proliferation or resistance
to apoptosis  malignancy
Human T-cell Leukemia Virus (HTLV)

HTLV-1 is
HTLV-1 prevalence
transmitted
 15-20 million
HTLV-2, HTLV-3 sexually, by blood
Four types  people
and HTLV-4  not products
HTLV-1. HTLV-2, worldwide, most
known to be contamination,
HTLV-3 and HTLV- commonly in
associated with and breastfeeding
4 Caribbean Island;
disease in humans  only 2-5% of
South America;
infected individual
southern Japan
develop disease
Human T-cell Leukemia Virus (HTLV)
Human T-cell Leukemia Virus (HTLV)
Human T-cell Leukemia Virus (HTLV)

Adult T-Cell
Leukemia/Lymphoma (ATLL)

Lymphoma
Smoldering Chronic Acute
type
Clinical Manifestation
Hepatitis Viruses
Hepatitis Viruses
WHO  257 million people
are currently living with HBV
infection and 71 million
people have chronic HCV
infection
Mortality rate  880,000
HBV is transmitted primarily
deaths per year are for HBV-
through exposure to infected
induced liver disease and
blood, semen, and other
350,000 to 500,000 deaths
body fluids
for HCV-related liver disease

Acute HCV infection could

cause mild and vague
HCV is transmitted primarily
symptoms and can resolves
by blood or sexual contact.
spontaneously in 10% to 50%
of cases
Cirrhosis Risk Factors
• Coinfection with both • HIV
hepatitis viruses • Alcoholism
• Persistently high levels of • Male gender
HBV or HCV viremia • Advanced age at the time
• HBsAg of infection
• Certain viral genotypes • Diabetes
• Schistosomiasis • Obesity
Hepatitis B Virus
HBV replication is not
Enveloped DNA virus HBV is not associated
cytotoxic  liver injury
and member of with extrahepatic
is due to the host
Hepadnaviridae family disease
immune response

Chronic HBV infection Current guidelines Treatment is continued

can be managed with recommended therapy for 6 to 12 months after
alpha interferon  only only when liver disease clearance of HBeAg or
cure 3-15% patient is clinically apparent HBsAg.
Hepatitis C Virus

Current treatment
Older treatments using NS5B
Seven types of
Enveloped single- for HCV infection polymerase
genome 
stranded RNA utilized 24 to 48 inhibitor
majority of cases
virus of the weeks of sofosbuvir and
are due to
Flaviviridae family pegylated IFN-α newer direct-
genotype 1
and ribavirin acting antiviral
therapies
Pathogenesis
Management
Diagnosed by serologic
HBV vaccine  HCC  early diagnosis
assays and/or antigen
Recombivax HB is the key factor
assays

Therapeutic option for HCV reactivation can

HCC depends on number occur with chemotherapy
and size of HCC nodule, or monoclonal antibody–
vascular invasion, based
metastasis, liver function immunosuppressive
and portal hypertension therapies
Conclusion
Conclusion
• Oncogenic viruses  important causes of cancer, especially in
less industrialized countries and in immunosuppressed
individuals.
• Oncologic virus are common causes of anogenital cancers,
lymphomas, and oral and hepatocellular carcinomas.
• Vaccines and antiviral agents have important role in
prevention of virus-induced cancers.
• Studies of viral pathogenesis will continue to establish
paradigms that are critical to our understanding of the
regulation of cell growth and cancer etiology.
Thank You