Viral carcinogens

1. VIRAL CARCINOGENESIS
&
CLINICAL TARGETS

2. Introduction
• > 15% of all human cancers are thought to have a viral etiology
• A hallmark of virally induced cancers = associated with persistent viral
infections
• Human cancer having a viral etiology has substantive consequences
• Viral genes expressed in associated cancers represent targets for
therapeutic vaccines and viral-specific anticancer drugs.

3. Example
• Can look forward to the elimination of most cases of primary
hepatocellular carcinoma (HCC) and cervical carcinoma .
• Development of vaccines against, hepatitis B virus (HBV) and most
tumorigenic strains of human papillomaviruses (HPVs)
• Potent antiviral drugs active against hepatitis C virus (HCV).

4. Obstacles
• Known human tumor viruses, however, usually do not induce cancers
rapidly
• Often 15 to 50 years will elapse between the primary infection and
tumor development
• Human tumor viruses do not express cellularly derived oncogenes
• Some of them can inhibit cellular tumor suppressor genes

5. A virus capable of establishing a durable productive infection
would not benefit from inducing a disease that kills the host
• Viruses establish durable, long-term infections
• Cause cancer only in a minority of persistently infected individuals
• Slow course of cancer induction suggests that viral infection alone is
rarely sufficient to cause malignancy
• Cancers arise only after additional oncogenic “hits” have accumulated

6. Mechanisms – Direct & Indirect
Direct mechanisms
• Viral oncogene expression
• Genotoxic effects of viral gene products
• Example of oncogenic effects - inactivation of tumor suppressor
proteins p53 , retinoblastoma protein (pRB)

7. Indirect oncogenic mechanisms
• cells that give rise to the malignant tumor have never been infected
by the virus
• viral infection is thought to lead to cancer by attracting inflammatory
immune responses
• leads to accelerated cycles of tissue damage and regeneration of
noninfected cells
• virally infected cells may secrete paracrine signals
• These signals drive the proliferation of uninfected cells

11. PAPILLOMAVIRUSES
• Papillomaviridae is named or the benign skin warts (papillomas) that
some members of the family cause
• Animal trials showed papillomavirus-induced lesions can progress to
malignant skin cancer
• early 1980s suggested the possibility of a hit-and-run carcinogenic
role for herpes simplex viruses in cervical cancer
• Now there is overwhelming evidence that a sexually transmitted HPV
types, including HPV16 and HPV18, play a causal role in cervical
cancer

12. • papillomaviruses can achieve infectious entry into a wide variety of
cell types
• Viral replication occurs at late phase of the viral life cycle
• Strictly dependent on host cell factors found only in differentiating
keratinocytes near the surface of the skin or mucosa
• majority of HPV-induced cancers appear to arise primarily at zones of
transition(squamo-columnar)

13. • more than 300 known HPV types each with distinct serotype
• antibodies that neutralize one HPV type do not robustly neutralize
other HPV types
• transient infections are cleared over the course of months
• stable infections where virions are chronically shed from the infected
skin surface for the lifetime of the host
• High-risk HPV types usually establish only transient infections
• Individuals who fail to clear their infection are at much greater risk of
developing cancer

14. Gene Functions
• strict tissue-differentiation specificity of the papillomavirus life cycle
• Late half of the viral genome, which encodes the L1 and L2 capsid
proteins
• HPVs encode six key early region genes: E1, E2, E4, E5, E6, and E7
E2 serves as a transcriptional repressor- loss of E2 expression results
in the upregulation of early viral gene expression
E6 protein - triggers the destruction of p53 (High risk HPV)
E7 proteins- mediates interaction with pRB
disrupts the formation of a complex between pRB and transcription
factors, thereby blocking the ability of pRB to trigger cell cycle arrest

15. • E5 oncogene- agonist for cell surface growth factor receptors (PDGF-
β, EGF) causes viral immune evasion in precancerous lesions

16. Human Papillomavirus Vaccines
• Gardasil 9 (Merck) and Cervarix (GSK)
• contain recombinant L1 capsid proteins based on HPV16 and HPV18
• these are assembled in vitro into virus-like particles (VLPs).
• VLPs are highly immunogenic in humans
• Elicit serum antibody responses against L1
• Are capable of neutralizing the infectivity of the HPV types
• Gardasil 9 also includes VLPs based on an additional five HPV types
that cause about 90% of all genital warts

17. • next-generation HPV vaccines are currently in human clinical trials
• targets the papillomavirus minor capsid protein L2
• L2 is required for key steps of the infectious entry process
• Another category of vaccines elicit T-cell-mediated immune responses
against the E6 and E7 oncoproteins

18. POLYOMAVIRUSES
• naturally human-tropic polyomaviruses, BK virus (BKV) and JC virus
(JCV)
• known to cause kidney disease and progressive multifocal
leukoencephalopathy respectively, in immunosuppressed individuals
• BKV plays a persistent directly carcinogenic role in a small percentage
of bladder cancer and few cancers of the urinary epithelium
• Merkel cell carcinoma fast-growing lesion on sun-exposed skin
surfaces
• Dramatically higher in immunosuppressed

19. • majority of healthy adults have serum antibodies specific for the MCV
major capsid protein VP1
• unusually high serologic titers against MCV VP1 often precede the
development of MCC by many years
• LT proteins of polyomavirus have functions similar to the E7 proteins
of high-risk HPVs
• mediates inactivation of pRB function
• MCC tumors are “addicted” to the expression of MCV T antigens
• Immunomodulatory therapies shown clinical responses in 30% to 50%
of patients

20. EPSTEIN-BARR VIRUS
• initial EBV infection occurs asymptomatically in early childhood
• transmitted through the saliva
• Virus replicates in the oropharyngeal epithelium.
• EBV envelope glycoprotein gp350 binds with high affinity to the B-
cell–specific CD21 complement receptor
• mediates virus attachment to B lymphocytes followed by virus entry
• establishment of long-term nonproductive infection
• EBV persists in the host by establishing latency in a small number of
resting B cells

21. • Three forms of EBV latency
latency I - EBV nuclear antigen-1 (EBNA1), required for maintenance
of viral DNA
latency III - expression of EBNA1–6, several latent membrane proteins
(LMP1, LMP2A, and LMP2B),etc
• Primary and chronic EBV infection is controlled by immunological
reactions directed at various latency proteins

22. • hallmark of all types of Burkitt lymphomas is deregulation of the
cellular Myc protooncogene
• Burkitt lymphoma tumors lack detectable EBV DNA
• Carries multiple additional mutations in host cell genes
• EBV is associated post-transplant lymphoproliferative disease (PTLD),
mixed cellularity and lymphocyte-depletion subsets of Hodgkin and
other lymphomas, nasopharyngeal carcinoma , gastric
lymphoepithelioma-like carcinomas

23. • Ganciclovir reduce EBV replication by inhibiting viral DNA polymerase
• EBV-associated lymphoid cancers express the B-cell marker CD20 -
rituximab (an anti- CD20 mAb) effective adjunct therapy

24. HEPATITIS VIRUSES
• HBV and HCV are the leading cause of liver cancer in the world (80%)
• 60% of HCC is associated with HBV, 20% is related to HCV, remainder
by alcoholism, aflatoxin.
• HBV is transmitted primarily through exposure to infected blood,
semen, and other body fluids
• HCV is transmitted primarily by blood or sexual contact

25. Hepatitis B Virus
• enveloped double-stranded DNA virus
• member of the viral family Hepadnaviridae
• Strong preference for infecting hepatocytes.
• Presurface–surface (preS-S) region encodes - S (HBsAg), M (or pre-S2),
and L (or pre-S1) proteins
• L protein is responsible for receptor binding and virion assembly
• precore–core (preC-C) region encodes the HBcAg and HBeAg.
• P region encodes the viral polymerase
• X (HBx) protein modulates host-cell signal transduction

26. • Viral cores are enveloped with intracellular membranes and viral L, M,
and S surface antigens
• HBV replication is not cytotoxic
• liver injury is due to the host immune response
• Chronic HBV carriers exhibit an attenuated virus-specific T-cell
response
• resolution of infection, is associated with declining viral DNA titers
• However, even subjects who have resolved the infection continue to
have very low levels of viral DNA

27. • Nucleoside/nucleotide analogs, such as lamivudine,entecavir,
adefovir, and tenofovir, inhibit HBV reverse transcriptase

28. Hepatitis C Virus
• enveloped single-stranded RNA virus of the Flaviviridae family
• viral RNA encodes a single polyprotein, processed into structural and
nonstructural proteins
• envelope glycoproteins E1 and E2 mediate infectious entry into
hepatocytes and B lymphocytes
• HCV nonstructural proteins(NS2, NS3, NS4A, NS4B, NS5A, NS5B)
required for virus replication and assembly
• Older treatments 24 to 48 weeks of pegylated IFN-α and ribavirin
• Newer NS5B polymerase inhibitor sofosbuvir

29. Clinical Characteristics and Treatment of
Hepatitis Virus–Associated Malignancies
• Recombivax HB utilizes a recombinant HBsAg ,available for HBV
prevention
• The vaccine is recommended for infants, adolescents aged 11 to 15
years, and adults with potential risk of HBV exposure
• A newer combination vaccine, Twinrix, offers protection against both
hepatitis A virus and HBV.
• Hepatitis B immune globulin recommended for reinfection
prophylaxis in the posttransplant period for HBV-infected individuals
• Antiviral therapy is recommended for HCV-infected patients
undergoing liver transplantation.

30. CONCLUSION
• Oncogenic viruses are important causes of cancer
• especially in less industrialized countries and in immunosuppressed
individuals.
• Vaccines and antiviral agents have begun playing an important role in
the 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.