Oncogenic Viruses

The association of viruses with malignancy dates from the observation by Ellerman and Bang (1908) that
the mode of transmission in leukemia in fowls resembled that of an infectious disease. Rous (1911)
showed that a solid malignant tumour, fowl sarcoma, was caused by a virus, a discovery for which he was
awarded the Nobel prize belatedly in 1966. Viruses causing tumours in animals were first demonstrated
by Shope, who isolated the rabbit fibroma virus in 1932 and the papilloma virus in 1933. Though these
are benign tumours, papillomas may turn malignant. Bittner (1936) proposed that breast cancer in mice
could be caused by a virus transmitted from mother to offspring through breast milk. During the 19505
many viruses were identified which induced leukemia in rodents. Considerable interest was aroused by
the discovery by Stewart and Eddy (1957) of the polyoma virus which could produce a wide variety of
neoplasms when injected into newborn rodents. Injection of certain types of human adenovirus into
newborn hamsters was shown by Trentin (1962) to cause sarcomas.

Burkitt (1963) identified a peculiar geographical distribution of lymphoma in African children and
suspected that it may be caused by a virus transmitted by an insect. The Epstein-Barr virus isolated from
Burkitt’s lymphoma has been identified as the causative agent. Many viruses have been isolated from
human cancer or demonstrated electronmicroscopically in affected cells and tissues but most of them
were merely ‘passenger’ viruses present in the lesions and not the causative agents. However, it is now
acknowledged that virus infections account for 10 to 20 per cent of human malignancies. These include
hepatocellular carcinoma caused by Hepatitis B or C viruses, uterine cervical cancer by certain types of
papilloma viruses, anaplastic nasopharyngeal carcinomas by the EB virus and adult cutaneous T cell
lymphoma/leukemia by HTLV1.

Viruses that produce tumours in their natural hosts or in experimental animals, or induce malignant
transformation of cells on culture, are known as oncogenic viruses. Transformation represents the
various changes that accompany the conversion of a normal cell into the malignant cell (Table 61.1).
Transformation from normal to malignant cell is a multistep process and may be partial or complete. For
example, some viral agents can ‘immortalise’ infected cells, so that they become capable of continuous
multiplication in culture, without possessing other features of malignancy. Transformation is recognised
primarily by a change in morphology of cultured cells. Transformed cells are altered in shape and lose
the property of ‘contact inhibition’ so that, instead of growing as monolayer, they grow piled up, one
over another, forming ‘microtumours'. Foci of transformation can easily be made out and are used in the
assay of oncogcnic viruses, such as the Rous sarcoma virus.

About a quarter of the 600 or so animal viruses possess oncogenic potential (Table 61.2). The viruses
associated with cancers in human beings are shown in Table 61.3. Both RNA and DNA viruses are
oncogenic. While all oncogenic RNA viruses (formerly called oncornaviruses) belong to a single family
(retrovirus), oncogenic viruses occur among all major groups of DNA viruses, except parvovirus.
Retroviruses are responsible for naturally occurring leukemia and sarcoma in several species of animals.
Among DNA viruses, some herpesviruses and hepadnaviruses cause malignant tumours in their natural
hosts.
Table 61.1 Properties of cells transformed by viruses

I. Altered cell morphology: Fibroblasts become shorter, parallel orientation is lost, chromosomal
aberrations appear

II. Altered cell metabolism: Increased growth rate, increased production of organic acids and acid
mucopolysaccharides

III. Altered growth characteristics: Loss of contact inhibition, formation of heaped-up growth
(microtumours), capacity to divide indefinitely in serial culture, capacity to grow in suspension or in
semisolid agar

IV. Antigenic alterations: Appearance of new virus specified antigens (T antigen-TSTA), loss of surface
antigens, cells become agglutinable by lectins

V. Capacity to induce tumours in susceptible animals

Table 61.2 List of oncogenic viruses

RNA truses

l. Retroviruses R

1. Avian leukosis viruses

2. Murine leukosis viruses

3. Murine mammary tumour virus

4. Leukosis-sarcoma virus of various animals

5. Human T cell leukemia viruses

DNA Viruses

I. Papovavirus

1. Papillomaviruses of human beings, rabbits and other animals

2. Polyomavirus

3. Simian virus 40

4. BK and IV viruses
II. Poxvirus .

1. Molluscum contagiosum

2. Yaba virus

3 . Shope fibroma

III. Adenovirus

Many human and nonhuman types

IV. Herpesvirus

1. Marek’s disease virus

2. Lucke’s frog tumourvims

3. Herpes virus pan, papiO. ateles and saimiri

4. Epsteianarr virus

5. Herpes simplex virus types 1 and 2

6 Cytomegalovirus

V. Hepatitis B and C viruses

ONCOGENIC DNA VIRUSES

Papovaviruses

Papilloma viruses cause benign tumours in their natural hosts but some of them (for example,
condyloma acuminatum in humans, rabbit papilloma) may turn malignant. The association between
human papilloma virus (HPV) infection and cancer of cervix uteri, particularly HPV types 16 and 18, has
been established. The continuous cell line HeLa, derived many decades ago from a cervical carcinoma
and used widely in various laboratories, has been found to contain HPV-l8 DNA. In general, infectious
virus particles cannot be demonstrated in tumours induced by DNA viruses but papilloma in the wild
cottontail rabbit is an exception. Rabbit papilloma virus, or DNA extracted from it, can produce papilloma
in rabbits following subcutaneous injection.

The polyoma virus causes natural latent infection in laboratory and domestic mice. However, when
injected into infant mice or other rodents, it induces a wide variety of histologically diverse tumours. The
virus can be cultivated in mouse embryo fibroblasts or baby hamster kidney cells in which it induces
transformation. The polyoma virus produces a hemagglutinin.

The papovaviruses BK and IC, which cause widespread asymptomatic human infection, can induce
tumours in immunodeficient subjects.
Simian virus 40 (SV 40) was discovered in apparently normal monkey kidney cultures used for the
production of the polio vaccine. It causes an inapparent infection in rhesus and cynomolgus monkeys
and does not cause cytopathic effects in cell cultures from such monkeys. However, when fluid from such
cultures is inoculated into renal cell cultures derived from African green monkeys, cytopathic change
with prominent cytoplasmic vacuolation results. Injection into newborn hamsters produces tumours.
Transformation is induced in cultured cells from several species, including human cells. Millions of doses
of the polio vaccine prepared in monkey kidney cultures that may have harboured the SV 40 virus had
been used before the virus was discovered. These individuals have been followed up for over 25 years
and no SV 40-related tumours have been reported. T here was considerable apprehension when the
oncogenic effect of SV 40 was discovered. However, there is no evidence that the injection of the vaccine
containing SV 40 has induced cancer in humans.

Poxvirus

Three members of the poxvirus group induce benign tumours, rabbit flbroma, molluscum contagiosum
and Yaba virus. The last causes naturally occurring benign histiocytomas in monkeys. It is apparently
transmitted by insects. Similar tumours can be induced experimentally in many species of primates,
including human beings. The tumours regress spontaneously in a few weeks. Nonprimates are
unsusceptible.

Adenovirus

Though some types (12, 19, 21) of human adenovirus may produce sarcomas in newborn rodents after
experimental inoculation, they do not appear to have any association with human cancer.

Herpesvirus

Many herpesviruses have been associated with natural cancers in animals and humans.

Marek’s disease: This is a fatal contagious neurolymphomatosis of chickens. No infectious virus particle
can be isolated from the lesions or seen under the electron microscope. However, sick birds shed large
quantities of virus from their feather follicles. The virus is a typical herpesvirus. Marek’s disease can be
induced in young chicken by the injection of the virus. The virus grows well in chick embryo fibroblasts
producing cytopathic changes but no evidence of transformation. Marek’s disease can be prevented by a
live avirulent vaccine. This is the first instance of a malignant disease being controlled by a viral vaccine.

Lucke’s tumour of frogs: A herpesvirus is considered to be the causative agent of a renal adenocarcinoma
in frogs.

Herpesvirus saimiri: This virus was isolated from a culture of Squirrel monkey kidney cells. It causes fatal
lymphoma or reticulum cell sarcoma when injected into owls, monkeys or rabbits. Herpesvirus saimiri
infection has been suggested as a primate model for the study of interactions between the EB virus and
human beings.
Epstein-Barr virus: A herpesvirus, called the EpsteinBarr virus, is found regularly in cultured lymphocytes
from Burkitt’s lymphoma patients. In the body, the tumour cells contain no virus but cell lines
established from them contain 5-20 per cent of cells that produce the virus. The virus multiplies only in
human lymphoid cell lines. Serological surveys show that infection with the virus is worldwide. Infection
is usually asymptomatic. In young adults without pre-existing antibodies, EB virus infection induces
infectious mononucleosis. Lymphoma is believed to occur when the infection takes place in children
whose immune systems are compromised, as for instance, by chronic malaria. EB virus associated
lymphomas have been reported in transplant recipients. EBV has also been linked to nasopharyngeal
carcinoma in the Chinese male population in southeast Asia and East Africa.

Herpes simplex and cancer cervix: An association has been proposed between herpes simplex type 2
infection and cancer of the uterine cervix, though not proved. It has also been suggested that herpes
simplex type 1 infection may be associated with cancer of the lip. Herpesvirus type 8 has been linked to
Kaposi’s sarcoma.

Cytomegalovirus infection has been associated with carcinoma of the prostate and Kaposi sarcoma.

Hepatitis B Virus

HBV has been claimed to be directly or indirectly involved in the causation of hepatocellular carcinoma.
Studies in many countries have demonstrated an excess prevalence of markers of HBV infection in
patients with primary hepatocellular carcinoma as compared with matched controls or with the general
population. Hepatitis C virus infection has also been reported to lead to hepatocellular carcinoma.