Download Oncogenic viruses (Human cancer viruses)

Oncogenic viruses (Human cancer viruses)
Viruses are considered to be factors in the development of several
types of human tumors. The viruses that have been strongly associated
with human cancers are listed in Table 4. They include human
papillomaviruses, Epstein-Barr virus, human herpesvirus 8, hepatitis B
virus, hepatitis C virus, and two human retroviruses plus several
candidate human cancer viruses. Many viruses can cause tumors in
animals, either as a consequence of natural infection or after experimental
inoculation.
Table 4. Association of Viruses with Human Cancers.1
Virus Family
Virus
Human Cancer
Papillomaviridae Human papillomaviruses
Genital tumors
Squamous cell
carcinoma
Oropharyngeal
carcinoma
Herpesviridae
EB virus
Human herpesvirus 8
Nasopharyngeal
carcinoma
Burkitt's lymphoma
Hodgkin's disease
B cell lymphoma
Kaposi's sarcoma
Hepadnaviridae Hepatitis B virus
Hepatocellular carcinoma
Retroviridae
Adult T cell leukemia
HTL virus
Human
AIDS-related malignancies
immunodeficiency virus
Flaviviridae
Hepatitis C virus
Hepatocellular carcinoma
1
Candidate human tumor viruses include additional types of
papillomaviruses and polyomaviruses SV40, JC, and BK.
EB, Epstein-Barr; HTL, human T-cell lymphoma.
General Features of Viral Carcinogenesis
These features are summarized in Table 5
Table 5 Features 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
tumorigenesis.
are
important
determinants
of
virus-induced
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.
7. Viral strains may differ in oncogenic potential.
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.
Tumor Viruses Are of Different Types
Like other viruses, tumor viruses are classified among different virus
families according to the nucleic acid of their genome and the biophysical
characteristics of their virions. Most recognized tumor viruses either have
a DNA genome . DNA tumor viruses are classified among the papilloma, polyoma-, adeno-, herpes-, hepadna-, and poxvirus groups. DNA tumor
viruses encode viral oncoproteins that are important for viral replication
but also affect cellular growth control pathways.
Most RNA tumor viruses belong to the retrovirus family. Retroviruses
carry an RNA-directed polymerase (reverse transcriptase) that constructs
a DNA copy of the RNA genome of the virus. The DNA copy (provirus)
becomes integrated into the DNA of the infected host cell, and it is from
this integrated DNA copy that all proteins of the virus are translated.
Multistep Carcinogenesis
Carcinogenesis is a multistep process, ie, multiple genetic changes
must occur to convert a normal cell into a malignant one. Intermediate
stages have been identified and designated by terms such as
"immortalization," "hyperplasia," and "preneoplastic." Tumors usually
develop slowly over a long period of time. It appears that a tumor virus
usually acts as a cofactor, providing only some of the steps required to
generate malignant cells.
Interactions of Tumor Viruses with Their Hosts
Persistent Infections
The known tumor viruses establish long-term persistent infections in
humans. Because of differences in individual genetic susceptibilities and
host immune responses, levels of virus replication and tissue tropisms
may vary among persons.
Host Immune Responses
Viruses that establish persistent infections must avoid detection and
recognition by the immune system that would eliminate the infection.
Different viral evasion strategies have been identified, including
:infection of sites relatively inaccessible to immune responses (human
papillomavirus in the epidermis); mutation of viral antigens that allows
escape from antibody and T cell recognition (human immunodeficiency
virus); modulation of host major histocompatibility complex class I
molecules in infected cells (adenovirus, cytomegalovirus); inhibition of
antigen processing (Epstein-Barr virus); and infection and suppression of
essential immune cells (human immunodeficiency virus).
Mechanisms of Action by Human Cancer Viruses
Tumor viruses mediate changes in cell behavior by means of a limited
amount of genetic information. There are two general patterns by which
this is accomplished: The tumor virus introduces a new "transforming
gene" into the cell (direct-acting), or the virus alters the expression of a
preexisting cellular gene or genes (indirect-acting). In either case, the cell
loses control of normal regulation of growth processes. DNA repair
pathways are frequently affected, leading to genetic instability and a
mutagenic phenotype.
Cellular transformation may be defined as a stable, heritable change in
the growth control of cells in culture. No set of characteristics invariably
distinguishes transformed cells from their normal. Transformation to a
malignant phenotype is recognized by tumor formation when transformed
cells are injected into appropriate test animals.
Indirect-acting tumor viruses are not able to transform cells in culture.
Cell Susceptibility to Viral Infections
At the cellular level, host cells are either permissive or nonpermissive
for replication of a given virus. Permissive cells support viral growth and
production of progeny virus; nonpermissive cells do not. Especially with
the DNA viruses, permissive cells are not transformed unless the viral
replicative cycle that normally results in death of the host cell is blocked
in some way; nonpermissive cells may be transformed. In contrast, a
characteristic property of RNA tumor viruses is that they are not lethal for
the cells in which they replicate. Cells that are permissive for one virus
may be nonpermissive for another.
Some viruses are associated with a single tumor type, whereas others are
linked to multiple tumor types. These differences reflect the tissue
tropisms of the viruses.
In some viral systems, virus-transformed cells may release growth
factors that affect the phenotype of neighboring uninfected cells, thereby
contributing to tumor formation. It is also possible that as tumor cells
collect genetic mutations during tumor growth, the need for the viral
genes that drove tumor initiation may become unnecessary and will be
lost from some cells.
Retroviruses
Retroviruses contain an RNA genome and an RNA-directed DNA
polymerase (reverse transcriptase). RNA tumor viruses in this family
mainly cause tumors of the reticuloendothelial and hematopoietic systems
(leukemias, lymphomas) or of connective tissue (sarcomas).
Important properties of the retroviruses are listed in Table 6
Table 6. Important Properties of Retroviruses.
Virion: Spherical, 80–110 nm in diameter, helical nucleoprotein within
icosahedral capsid
Composition: RNA (2%), protein (about 60%), lipid (about 35%),
carbohydrate (about 3%)
Genome: Single-stranded RNA, linear, positive-sense, 7–11 kb, diploid;
may be defective; may carry oncogene
Proteins: Reverse transcriptase enzyme contained inside virions
Envelope: Present
Replication: Reverse transcriptase makes DNA copy from genomic RNA;
DNA (provirus) integrates into cellular chromosome; provirus is template
for viral RNA
Maturation: Virions bud from plasma membrane
Outstanding characteristics:
Infections do not kill cells
May transduce cellular oncogenes, may activate expression of cell genes
Proviruses remain permanently associated with cells and are frequently
not expressed
Many members are tumor viruses
Tumor Suppressor Genes
Polyomaviruses
Important properties of polyomaviruses are listed in Table 7.
Table 7. Important Properties of Polyomaviruses.
Virion: Icosahedral, 45 nm in diameter
Composition: DNA (10%), protein (90%)
Genome: Double-stranded DNA, circular, 5 kbp, MW 3 million
Proteins: Three structural proteins; cellular histones condense DNA in
virion
Envelope: None
Replication: Nucleus
Outstanding characteristics:
Stimulate cell DNA synthesis
Viral oncoproteins interact with cellular tumor suppressor proteins
Important model tumor viruses
Human viruses can cause human neurologic and renal disease
May cause human cancer
Papillomaviruses
Important properties of papillomaviruses are listed in Table 8
Table 8. Important Properties of Papillomaviruses.1
Virion: Icosahedral, 55 nm in diameter
Composition: DNA (10%), protein (90%)
Genome: Double-stranded DNA, circular, 8 kbp, MW 5 million
Proteins: Two structural proteins; cellular histones condense DNA in
virion
Envelope: None
Replication: Nucleus
Outstanding characteristics:
Stimulate cell DNA synthesis
Restricted host range and tissue tropism
Significant cause of human cancer, especially cervical cancer
Viral oncoproteins interact with cellular tumor suppressor proteins
Adenoviruses
The adenoviruses comprise a large group of agents widely distributed in
nature. They are medium-sized, nonenveloped viruses containing a linear
genome of double-stranded DNA (26–45 kbp). Replication is speciesspecific, occurring in cells of the natural hosts. Adenoviruses commonly
infect humans, causing mild acute illnesses, mainly of the respiratory and
intestinal tracts.
Herpesviruses
These large viruses (diameter 125–200 nm) contain a linear genome of
double-stranded DNA (125–240 kbp) and have a capsid with icosahedral
symmetry surrounded by an outer lipid-containing envelope.
Herpesviruses typically cause acute infections followed by latency and
eventual recurrence in each host, including humans.
In humans, herpesviruses have been linked to several specific types of
tumors. Epstein-Barr (EB) herpesvirus causes acute infectious
mononucleosis when it infects B lymphocytes of susceptible humans. EB
virus is etiologically linked to Burkitt's lymphoma, a tumor most
commonly found in children; to nasopharyngeal carcinoma (NPC), more
common to posttransplant lymphomas; and to Hodgkin's disease. These
tumors usually contain EB viral DNA .
Kaposi's sarcoma-associated herpesvirus, also known as human
herpesvirus 8 (KSHV/HHV8). It is suspected of being the cause of
Kaposi's sarcoma, primary effusion lymphoma, and a particular
lymphoproliferative disorder. KSHV has a number of genes that may
stimulate cellular proliferation and modify host defense mechanisms.
Poxviruses
Poxviruses are large, brick-shaped viruses with a linear genome of
double-stranded DNA (130–375 kbp). Very little is known about the
nature of these proliferative diseases, but the poxvirus-encoded growth
factor that is related to epidermal growth factors and to transforming
growth factor may be involved.
Hepatitis B Virus & Hepatitis C Virus
Hepatitis B virus a member of the Hepadnaviridae family, is
characterized by 42-nm spherical virions with a circular genome of
double-stranded DNA (3.2 kbp). One strand of the DNA is incomplete
and variable in length.
In addition to causing hepatitis, hepatitis B virus is a risk factor in the
development of liver cancer in humans and the development of
hepatocellular carcinoma.
Hepatitis C virus a member of the Flaviviridae family, contains a genome
of single-stranded RNA 9.4 kb in size. It appears that the majority of
infections become persistent, even in adults. Chronic infection with
hepatitis C virus is also considered to be a causative factor in
hepatocellular carcinoma. Most probably, hepatitis C virus acts indirectly
in the development of hepatocellular carcinoma.