Hepatitis B and C viruses are responsible for 70-80% of hepatocellular carcinoma cases worldwide. Chronic infection leads to cell damage and regeneration, accumulating DNA mutations over decades and potentially causing cancer. While HBV DNA integrates into liver cells, the exact mechanism of HBV and HCV carcinogenesis is unclear. HTLV-1 causes adult T-cell leukemia through multiple factors, notably the viral oncoproteins TAX and REX which deregulate host cell genes and activate proliferation pathways in infected T-cells over many years.

2. HEPATITIS VIRUS
• Hepatitis viruses that cause human cancer are:
i. Hepatitis-B virus (DNA virus)- A member of hepacnapiritae
family
ii. Hepatitis- B virus ( RNA virus) – A member of flapiritae family
• Epidemiologic data firmly support that two hepatropic
viruses, HBC and HCV, are currently involved in etiology
of 70-80% cases of hepatocellular carcinoma worldwide.
• There is strong epidemiological evidence linking HBV
infection to development of hepatocellular carcinoma as
observed from the following:

3. a. The geographic distribution in the incidence of hepatocellular
carcinoma closely matches the variation in prevalence of HBV
infection, . E.g. high incidence in Far-East and Africa.
b. Epidemiological studies in high –prevalence regions indicate about
200- times higher risk of developing hepatocellular carcinoma in
HBV-infected cases as compared to uninfected population in the
same area.
• Unlike HBV which is a DNA virus, an RNA hepatotropic
virus, hepatitis C virus (HCV), in also implicated in
etiology of hepatocellular carcinoma. HCV is involved in
about half the cases of hepatocellular carcinoma

4. HEPATITIS VIRUS ONCOGENESIS
• Although HBV DNA has been found integrated in the
genome of human hepatocytes in many cases of liver
cancer which causes mutational changes, but a definite
pattern is lacking.
• Thus , exact molecular mechanism as to how HBV (as
also HCV) cause hepatocelluar carcinoma is yet not
quite clear
• Probably, multiple factors are involved:
– Chronic and persistent viral infection with HBV (or HCV)
incites repetitive cycles of inflammation, immune
response, cell degeneration/cell death, and regeneration
of the hepatocytes which leads to DNA damage of host
liver cells.

5. • It is possible that immune response by the host to persistent
and unresolved infection with these hepatitis viruses becomes
defective which promotes tumour development
• On regeneration, proliferation of hepatocytes is stimulated by
several growth factors and cytokines elaborated by activated
immune cells which contribute to tumour development, e.g.
factors for angiogenesis, cell survival etc.
• Activated immune cells produce nuclear factor kB(NF-kB) that
inhibits apoptosis, thus allowing cell survival and growth.
• HBV genome contains a gene HBx which activates growth
signalling pathway.
• HBV and HCV do not encode for any specific viral
oncoproteins.

6. Human T-Cell Leukemia Virus Type 1
(HTLV-1)
• HTLV-1 causes adult T-cell leukemia/lymphoma(ATLL),
a tumour that is endemic in certain parts of Japan, the
Caribbean basin, South America, and Africa and found
sporadically elsewhere, including the United States.
• Worldwide, it is estimated that 15 to 20 million people
are infected with HTLV-1.
• Similar to human immunodeficiency virus (HIV), which
causes AIDS, HTLV-1 has tropism for CD4+ T cells, and
hence this subset of T cells is the major target for
neoplastic transformation.

7. • Human infection requires transmission of
infected T cells via sexual intercourse, blood
products, or breastfeeding.
• Leukemia develops in only 3% to 5% of the
infected individuals, typically after a long
latent period of 40 to 60 years.

8. HTLV-1 ONCOGENEIS
• The molecular mechanism of ATLL leukaemogenesis by
HTLV-1 infection of CD4+ T lymphocytes is not clear.
• Neoplastic transformation by HTLV-1 infection differs from
acute-transforming viruses because it does not contain v-
onc, and from other slow- transforming viruses because it
does not have consistent site of insertion of mutations, nor
does it contain an oncogene.
• Probably, the process is multifactorial:
i. HTLV-1 genome has unique region called pX distinct from
other retroviruses, which encodes two essential viral
oncoproteins- TAX and REX. TAX protein up- regulates the
expression of cellular genes controlling T-cell replication ,
which REX gene product regulates viral protein production by
affecting mRNA expression.

9. ii. TAX viral protein interacts with transcription factor, NF-
kB, which stimulates genes for cytokines (interleukins)
and their receptors in infected T-cells which activates
proliferation of T-cells by autocrine pathway.
iii. The inappropriate gene expression activates pathway of
the cell proliferation by activation of cyclins and
inactivation of tumour-suppressor genes CDKN2A/p16
and TP53, stimulating cell cycle.
iv. Initially, proliferation of infected T-cells is polyclonal but
subsequently several mutations appear due to TAX-based
genomic changes in the host cell and monoclonal
proliferation of leukaemia occurs.