Discuss the strategies for virus survival in host populations.

 Must consider that the host can be divided into the host cell and the multicellular
host. Interactions at either scale will affect the survival of the virus in the host
population.
 The virus can induce various modifications to the host cell that favour viral
replication and survival
o Subversion of cellular metabolism by host protein synthesis shut off
 Poliovirus
 Within 1 hour of infection the infected cell ceases to
synthesise host proteins and only poliovirus proteins are
made.
 Ribosomes recognise mRNAs by binding to the ‘5’-cap’ (7-
methyl G). Poliovirus protease destroys a component of
the cap-binding complex so that host mRNA is no longer
recognised. An RNA secondary structure close to the 5’
end of poliovirus RNA, called an internal ribosome entry
site (IRES) is recognised by ribosomes in the absence of
the ca-binding complex. Thus poliovirus RNA is
translated by a cap-independent mechanism and only
poliovirus RNA is translated
 Poxvirus
 Destruction of host DNA and increased rates of mRNA
turnover
 Encode enzymes that cleave off mRNA caps, from virus
and cellular mRNAs, and since the virus mRNAs are much
more abundant, virus mRNAs predominate and the
translated proteins are viral.
 This strategy also helps the virus switch from early to late
virus gene expression more rapidly because the early
mRNAs are destroyed once their synthesis stops
o Cell Stimulation
 DNA viruses require high levels of deoxyribonucleotides (dNTPs)
and in resting cells dNTP pools are low
 Non-replicating cells (i.e., the majority of cells in the multicellular
host) are therefore poor hosts for DNA viruses
 Papovaviruses, Adenoviruses, Herpesviruses
 All DNA viruses
 Synthesise factors that stimulate the cell into cycle
o Eg. Simian virus 40 T antigen
o These factors are made early in infection
o After stimulation viral DNA synthesis and capsid
protein synthesis can proceed much more
efficiently
 Poxviruses
 Vaccinia Virus
o Expresses its own epidermal growth factor that is
secreted from the infected cell and stimulates
neighbring cells to divide, making them ideal
infection targets
 o Also induces hypoxic response that results in
altered cellular biochemistry to the advantage of
the virus
o Changes in Nucleotide Metabolism
 Alternative method of increasing dNTP pools
 Virus expresses its own enzymes which produce dNTPs
 Poxviruses, Herpesviruses
 Larger DNA viruses
 Encode enzymes that produce dNTPs:
o Thymidine kinase
o Thymidylate kinase
o Ribonucleotide reductase
 However, viruses that lack genes for these enzymes cab grow
perfectly well in actively growing cells in culture, but fail to grow
in resting cells
 Viral genes of this type are therefore said to be “non-
essential”
o Membrane Modification
 Viruses may insert some of their proteins into the plasma
membrane (PM) of the host cell. Particularly true of enveloped
virus released by budding
 New cell-surface proteins may change the behavior of a
cell with respect to its neighbors
 Measles Virus
 Infected cell may fuse with surrounding uninfected cells
o The virus infection has now passed from infected
to uninfected cell without becoming extracellular
(and a target for antibody) in the process
o Said to be cell-associated viruses
o Cytopathic Effect (cpe)
 Morphological changes of host cell caused by virus infection
 Eg. Plaque formation with vaccinia cirus
 Different viruses can produce distinct types of cpe in
specific cell types that can be helpful in diagnosis
 Often include alterations to the cytoskeleton (actin and tubulin
containing filaments), which are exploited by the virus to faciliate
intracellular movement of virus particles
o Suppresion of Host Signalling Pathways Leading to Innate Immunity
 When cell is infected by a virus, the cells senses the infection by
detecting the presence of PAMPs such as viral nucleic acid by
PRRs
 PRRs activate pathways leading to an innate immune
response
o Induces release of IFNs or apoptosis which is
detrimental to replication and spread of virus
 Herpesviruses and Poxviruses
 Large DNA viruses
  Encode many proteins that block the innate immune
response (this will be discussed later when we consider
virus survival in the multicellular host)
o Lytic or non-lytic infection
 Most common outcome of infection is death of host cell (lytic
infection)
 Some infections are non-lytic, in which case the host cell may
survive and divide indefinitely while continuing to produce virus
particles
 The productive cycel of DNA viruses is lytic
 Non-enveloped RNA viruses are lytic
 Viruses which cause host shut-off are lytic
o Cell Transformation
 Means that the cell now exhibits uncontrollable growth, fails to
respond to the presence of neighboring cells (contact inhibition),
and has many of the properties associated with malignant cells in
vivo
 Transformation by certain DNA viruses
 Some DNA ciruses stimulate their host cell into cell cycle
soon after infection in order to create a suitable
environement for virus replication. This is normally
followed by virus DNA synthesis, virus capsid protein
synthesis, the appearance of new virus particles and cell
death
 Eg. Papilloma viruses
o Induce proliferation (resulting in a wart) before
synthesis of new virus takes place
o Occasionally virus replication fails but
‘stimulation’ continues and the cell continues
dividing
 HPV strains 16 & 18 which may result in
cervical carcinoma
 Transformation by retroviruses
 Can recombine genetically with high frequency and
occasionally acquire a hostcell gene in the process
 If the cellular gene that is acquired plays an important
role in the control of cell growth then the outcome may
be that the recombinant virus will ‘transform’ cells
becausee the gene will be epressed at abnormally high
levels
 Eg. Rous Sarcoma virus
o Transforms cells in culture and forms rapidly
developing sarcomas in chickens
o Acquisition of gene called src (that encodes a
tyrosine kinase)
o Causes abnormal growth of infected cell
 Survival of virus in a multicellular host
o When in the body the virus must be able to evade the innate and
adaptive immune system in order to survive
 Innate immunity
 IFNs
o Are species specific, soluble glycoproteins that
are released from cells and bind to specific
receptors on cells to induce activation of an anti-
viral state
o Viruses have evolved ways of interfering with
IFNs
o Poxviruses
 Stopping activation of the PRR-induced
signalling cascades so IFNβ is not
produced
 Releasing soluble IFN-binding proteins
that capture IFN in solution and so stop
IFN binding to the IFN-receptors on cells
 Inhibiting the JAK-STAT signalling cascade
to block induction of ISGs
 Targeting the ISG proteins directly to
block their action
 Apoptosis
o Programmed cell death
o Can be avoided by blocking the action of caspases
or by targeting the Bcl-2 family of pro-apoptotic
proteins, which function at the mitochondrion to
induce apoptosis
 Cytokines and Chemokines
o Chemokines are small chemo-attractant cytokines
that recruit leukocytes to the site of infection
o Cytokines promote the inflammatory response
(IL-1, IL-2, IL-18) and TNF and IFNγ drive the
development of cellular immunity such as
cytotoxic T lymphocytes
o Strategies that avoid Cytokine and Chemokines
 Herpesviruses and Poxviruses
 Secrete proteins from the cell that
bind these molecules outside the
cell and stop them from reaching
their natural receptors
 Epstein-Barr Virus
 Express a viral cytokine (vIL-10)
that drives the immune system
towards a Th2, rather than a Th1
response
o Avoiding the CTL response
which is most effective at
detecting and removing
infected cells
 Adaptive Immunity
  Antibodies are not very effectve at removing infected
cells
 CTL are unable to combat free virus particles, but are
efficient at recognising and destroying virus-infected cells
o Particularly important for viruses that largely
remain cell-associate (eg. HCMV and Measles
Virus)
 Herpesviruses have developed many ways of blocking the
presentation of peptides on class I MHC molecules
o Blocking transport peptides into the ER (HSV and
Adenovirus)
o Causing the degradation of class I MHC molecules
by inducing their transport back into the cytosol
for proteolytic degradation (HCMV)
o Retaining class I MHC molecules intracellulary
and so preventing their transport to the cell
surface (adenovirus and HCMV)
 In order to survive in a host population the virus must also have the ability to
spread from one host to another which is influenced by various factors
o Virion Stability
 Enveloped viruses are less stable than non-enveloped ones
 Enveloped viruses (eg. Measles virus, Influenza virus, and HSV)
are usually spread by close contact
 Small non-envelopd viruses are very stable outside the host and
can be transmitted over long distances (eg. 1981 FMDV epidemic
in southern England)
 Picornaviruses that area spread via the oro-faecal route
(poliovirus, hepatitis A virus) are stable in water
o Duration of shedding
 Acute infection
 Shed for a short time but high levels of virus are shed
 Eg Influenza virus
 Persistent Infections
 Shed repeatedly over longer time periods and small doses
of virus are shed
 Eg HSV
o Virus Concentration
 Acute viruses shed virions in high concentrations
 Eg. Rotavirus shed in watery diarrhoea
o Availability of susceptible hosts
 Population size
 Eg. Measles virus
o Physically unstable and survives for only a short
time outside host
 Number of susceptible hosts
 Bet ween epidemics the virus is maintained by small
numbers of susceptible hosts
 Intermittent infections in Faroe Islands
 o New epidemics only occurred when there was a
sufficient number of susceptible hosts and when
the virus was introduced from an external source
 Only hwen populations reached sufficiently high density could
diseases such as measles and smallpox endure in man