Transcript Scientific Writing

MICR 306 Advanced
Applications of Viruses (3)
Prof. J. Lin
University of KwaZulu-Natal
Westville campus
Microbiology Discipline
2014
School of Life Sciences
Consequences of Viral Infection
Consequences
(Animals and Plants)
• Lytic infection results in the destruction of the
host cell.
• In the case of enveloped viruses, release of
virions (budding process) may be slow, and the
host cell may not be lysed and can continue to
produce virus referred to as persistent
infections.
• Virus might also cause latent infection. A small
group of viruses causes extremely slowly
developing infections (e.g. Measles;
papilomavirus).
Cancer (Transformation)
• Cellular phenomenon of uncontrolled
growth due to discrete changes in the
cellular genome which in some cases are
inheritable.
Viruses
are
probably
responsible for about 15% of human
cancers and as a risk factor are second
only to tobacco.
• Transformation: the introduction of
inheritable changes in a cell causing
changes in the growth phenotype and
immortalisation.
Cell Cycle
1) Hyperactive
CAUSES OF CANCERS
Cancers are the result of a disruption of the normal
restraints on cellular proliferation leading to
unrestrained cell growth. There are two basic
classes of these genes in which mutation can
lead to loss of growth control:
• Those genes that are stimulatory for growth
and which cause cancer when hyperactive.
Mutations in these genes will be dominant.
• Those tumor repressor (suppressor) genes
that inhibit cell growth and which cause
cancer when they are turned off. Mutations in
these genes will be recessive.
Cancers caused by Viruses
DNA tumor viruses and the RNA tumor viruses
• The region of the viral genome (DNA in
DNA tumor-viruses or RNA in RNA-tumor
viruses) that can cause a tumor is called
an ONCOGENE. This foreign gene can be
carried into a cell and cause it to take on
new properties such as immortalization
and anchorage-independent growth
TRANSFORMATION.
• The ability to integrate their own genome
into that of the host cell is not, however, a
pre-requisite for tumor formation.
ONCOGENES IN RETROVIRUSES
• Rous sarcoma virus (RSV): src (for sarcoma) is not needed for
viral replication. It is an extra gene to those (gag/pol/env) necessary
for the continued reproduction of the virus. Deletions/mutations in src
abolish transformation and tumor promotion but the virus is still
capable of other functions.
Many retroviruses have lost part of their genome to
accommodate an oncogene.
This has two consequences:
1)
The protein encoded by the oncogene is often part of
a fusion protein with other virally-encoded amino acids
attached
2)
Virus is in trouble as cannot make all of itself. To
replicate and bud from the host cell needs products of
another virus, that is a helper virus
ONCOGENES
Many
oncogenes have
been identified.
Some viruses
can have more
than one
oncogene (e.g.
erbA, erbB).
DNA TUMOR VIRUSES
DNA tumor viruses have two life-styles:
• In permissive cells, all parts of the viral genome are
expressed. This leads to viral replication, cell lysis and cell
death.
• In cells non-permissive for replication, viral DNA is
integrated into the cell chromosomes (usually but not
always) at random sites. Only part of the viral genome is
expressed. The early, control functions (e.g. Polyoma
virus T antigens) of the virus, are expressed. Viral
structural proteins are not expressed and no progeny virus
is released.
DNA TUMOR VIRUSES INVOLVED IN
HUMAN CANCERS
• Papilloma viruses are wart-causing viruses that
also certainly cause human neoplasms and cause
natural cancers in animals.
Warts are usually benign but can convert to
malignant carcinomas. Papillomas may cause 16%
of female cancers worldwide and 10% of all
cancers. There are 51 types of papilloma viruses
but, clearly, not all are associated with cancers.
NORMAL FUNCTION OF ONCOGENES
c-oncs are normal cellular genes that are expressed and
function at some stage of the life of the cell.
sub-divide the cellular oncogenes into
Products of oncogenes that are nuclear proteins: e.g. myc,
myb. These are involved in control of gene expression (that is the
regulation of transcription-they are transcription factors) or the control
of DNA replication  constitutively active rather than under control
of normal regulatory processes.
Products of oncogenes that are cytoplasmic or
membrane-associated proteins: e.g. abl, src, ras. This type
does not exhibit altered expression but seems to convert from protooncogene to oncogene by mutation. Thus, in src-induced tumors,
strong over expression of the oncogene has no effect.
The signal transduction pathway
Components of the pathway can be divided into 4 broad
groups:
a)Cell surface where receptors interact with growth factors and
components of the extracellular matrix.
b)Transmembrane signaling apparatus including the cytoplasmic
domain of receptors and submembranous components that are
functionally linked to surface receptors, conveying signals from the
outside of the cell to the interior.
c)Cytosolic elements i.e. soluble proteins and second messengers.
d)Nuclear proteins including DNA binding proteins and tumor
suppressors, factors which control directly and indirectly gene
regulation and replication.
FUNCTION OF PROTO-ONCOGENEEXAMPLE
ENCODED PROTEINS
Control of DNA transcription (found in nucleus)
myc
Signaling of hormone/growth factor binding
such as a tyrosine kinase
src is a membrane-bound tyr
kinase.
GTP-binding proteins involved in signal
transduction from a surface receptor to the
nucleus
ras
Growth factors
sis is an altered form of
platelet-derived growth factor B
chain
Growth factor receptors
erb-B is a homolog of the epidermal
growth factor receptor (it is also a
tyrosine kinase). fms is a homolog of
the macrophage colony-stimulating
factor (M-CSF) receptor
How do viruses transform cells?
• By subverting the normal cell control mechanisms:
There is a class of cell genes which generally speaking
promote cell replication. These are sometimes called
oncogenes or proto-oncogenes or c-oncogenes. Viruses,
especially retroviruses can affect the activity of these
genes. Indeed retroviruses sometimes carry their own
versions of these genes, called v-oncogenes.
• Another class of genes suppresses cell replication, these
are called tumour suppressors. Many viruses especially
DNA viruses prevent their proper functioning. Cell
transformation by viruses is accompanied by the
persistence of all or a part of the viral genome. It is also
accompanied by the continual expression of a limited
number of viral genes.
POLYOMA VIRUSES
Simian virus 40 is a monkey polyoma virus that causes
sarcomas in juvenile hamsters. SV 40 Tumor antigens are
oncogenes
Polyoma virus was so named because it causes a wide
range of tumors in a number of animal species
Human polyoma viruses
• they will cause tumors when injected into animals. This
virus causes progressive multifocal leukoencephalopathy, a
disease associated with immunosuppression. In 1979,
the rate of occurrence of this disease was 1.5 per 10 million
population. It has become much more common because of
AIDS and is seen in 5% of AIDS patients.
ADENOVIRUSES
• Polyoma and adenoviruses seem to cause cell transformation in a
similar manner: the integration of early function genes into the
chromosome and the expression of these DNA synthesis-controlling
genes without the production of viral structural proteins. Early protein
E1A  oncogene, binding to Rb protein (suppressor gene).
HERPESVIRUSES
Epstein-Barr virus
• There is considerable circumstantial evidence that implicates these
enveloped DNA viruses in human neoplasms. They are highly
tumorigenic in animals. It is notable that herpes viruses exist
primarily as episomes in the cell and do not integrate into the host
cell genome. By the time that tumors arise, no trace of the virus can
usually be found. Herpes virus DNA is found in only a small number
of herpes-transformed cells. They may have a hit and run
mechanism of oncogenesis, perhaps by causing chromosomal
breakage or other damage.
HEPATITIS B VIRUS
• Hepatitis B virus (Class VII) is very different from the other
DNA tumor viruses. Indeed, even though it is a DNA virus,
it is much more similar to the oncornaviruses (RNA tumor
viruses) in its mode of replication. Hepatitis B is a vast
public health problem and hepatocellular carcinoma
(HCC), which is one of world's most common cancers.
There is a very strong correlation between HBsAg (hepatitis
B virus surface antigen) chronic carriers and the incidence
of HCC. 51% of deaths of HBsAg carriers are caused by
liver cirrhosis or HCC compared to 2% of the general
population. (average life expectancy after diagnosis of liver
cancer is 6 months)
CELLS HAVE PROTO-ONCOGENES
There are homologs of all retrovirus oncogenes in cells that are
not infected by a retrovirus. These cellular homologs are
often genes involved in growth control and
development/differentiation (as might be expected) and
have important non-transforming functions in the cell. Some
can cause cancer under certain circumstances and,
presumably, those not shown to cause cancer have the
ability to do so under the correct conditions. The cellular
homologs of viral oncogenes are called proto-oncogenes
Definition of a proto-oncogene: A host gene that is homologous to an
oncogene that is found in a virus but which can induce
transformation only after being altered (such as mutation or a
change of context such as coming under the control of a highly active
promotor).
CHRONICALLY TRANSFORMING
RETROVIRUSES
The observation that an acutely transforming virus such as
RSV contains an extra gene, the oncogene, explains their
high neoplastic potential but, in contrast, chronically
transforming retroviruses only produce tumors slowly and
they carry no gene equivalent to a v-onc. An example is
avian leukosis virus (ALV).How
ALV can integrate into the cell genome at many different sites
but, in ALV-induced tumors, the virus is ALWAYS found
in a similar position near a cellular gene called c-myc.
This is the cellular proto-oncogene. Thus, inserting the
genome of ALV and other chronically transforming
retroviruses next to a c-onc has the same effect as
carrying in a v-onc.
The protein coded for by this
gene is found in the nucleus of
normal cells and is involved
in control of DNA
synthesis. It can be shown
that over-expression of cmyc leads to rapid DNA
replication.
most tumors dominant mutations
dominant. i.e. a function is gained that makes the cell
grow when it should not . If we have a receptor that
sends a signal when it binds a growth factor by
switching on its tyrosine kinase activity and that
receptor becomes mutated so that its tyrosine
kinase activity is permanently activated, the cell will
get the aberrant growth signal even in the
heterozygote. Thus the mutant allele is dominant
over the normal allele.
CELLULAR ONCOGENES INDUCED
CANCER
1) viruses can either bring an oncogene into the cell or
2) can take control of a cellular proto-oncogene to give
rise to a tumor.
Cellular proto-oncogenes could give rise to tumors in the
absence of retroviral infection by chromosomal
rearrangements that can bring a c-onc under the control
of the wrong promotor/enhancer. Alternatively, the c-onc
might be mutated in a particular way so that it was
over-expressed or it might code for a mutant protein
with an altered function.
p53 and human cancer
80% of colon cancers involve the p53 gene
ANTI-ONCOGENES (Tumor
suppressor genes)
Retinoblastoma: A recessive tumor
recessive : the cancer causing mutation  causes a loss of function
• Although we have learned a lot from families that inherit
p53 mutations, it is clear that most p53 mutations come
from non-inherited environmental factors: carcinogens
(benzopyrene in smoke, aflatoxin in molds on peanuts
and corn, UV light) that result in point mutations.
• What has this got to do with DNA tumor viruses? The
presence of a virus can mimic mutation and take the tumor
suppressor out of action by complexing it in an inactive
form that cannot bind to the specific site on DNA. 
hepatitis C which causes hepatocellular carcinoma. In
the case of a human papilloma virus-infected cell, p53 is
bound by the E6 protein and directed to a protease that
recognizes a cleavage site in p53, thereby destroying it.
In addition, E7 protein binds and inactivates Rb protein.