img
RNA is not affected since it utilizes a cap-independent initia-
VIRAL COUNTERDEFENSES
tion process. This elegant mechanism for specifically inter-
fering with host protein synthesis does not appear to be the
Mammals have evolved elaborate defenses to ward off infec-
sole pathway used by the virus. Additional mechanisms also
tion by viruses. Viruses, in turn, have evolved counterdefenses
contribute to shutdown of host protein synthesis. Shutoff of
that allow them to persist and continue to infect mammals.
host protein synthesis not only prevents the synthesis of IFN,
These counterdefenses vary from the simple to the elaborate.
for example, but it also frees up the translation machinery of
An overview of these mechanisms is given in Table 10.9.
the cell for the virus.
The simplest counterdefense is to shut down the host cell
As a second example, the alphaviruses also rapidly shut
rapidly after infection and to produce progeny virus very
off host protein synthesis. As for poliovirus, more than
rapidly. Rapid shutoff of the host cell may prevent it from
one mechanism appears to be used. One mechanism is an
synthesizing IFN or other cytokines required for function of
interference with the cell Na­K pump, which results in an
both the innate and adaptive immune systems. It will also
increase in the Na+ concentration and a decrease in the K+
shut off production of MHC class I molecules required for
concentration in the cell. This inhibits translation of cellular
recognition of an infected cell by CTLs. Rapid growth allows
mRNAs, but has no effect on translation of viral mRNAs.
the virus to go through several rounds of virus production
These first two examples refer to plus-strand RNA
before sufficient cytokine production has occurred and cells
viruses. As a third example, the minus-strand RNA virus
have responded to establish the antiviral state, and before the
vesicular stomatitis virus also grows rapidly and profoundly
adaptive immune system can gear up. Many viruses take this
inhibits cellular protein synthesis. This shutoff is effected by
approach, in particular RNA viruses, which have a limited
the M protein, which has been shown to be a potent inhibitor
coding capacity. As one example, soon after infection with
of the transcription and transport of cellular mRNA.
poliovirus, the cap-binding protein required for cap-depen-
Some DNA viruses also inhibit host protein synthesis
dent initiation of protein synthesis is cleaved and host cap-
shortly after infection. A component of the herpes simplex
dependent protein synthesis ceases. Translation of poliovirus
virion that enters the cell during infection inhibits host-cell
protein synthesis, beginning very soon after infection. As
TABLE 10.9 Major Strategies Used by Viruses
infection progresses, additional proteins contribute to a more
to Evade Host Defenses
profound inhibition of host-cell macromolecular synthesis.
Although shutoff of host protein synthesis impairs the
Rapid shutdown of host macromolecular synthesis
host defense systems, most viruses, even viruses with limited
Evasive strategies of viral antigen production
coding capacity, also use additional mechanisms to impede
Restricted gene expression; virus remains latent with minimal or no
the host immune system. Viruses with smaller genomes
expression of viral proteins
may encode only one or two proteins that interfere with
Infection of sites not readily accessible to the immune system
host immunity, whereas viruses with large genomes, such
Antigenic variation; antigenic epitopes mutate rapidly
as herpes simplex virus, have the luxury of encoding a large
Interference with MHC class I antigen presentation (see Table 10.10)
number of proteins that interfere with host defenses.
Downregulation of transcription of MHC class I molecules
Downregulation of transcription of TAP
Virus Evasion of the Adaptive
Interference with proteolysis to produce peptide epitopes
Immune System
Binding to TAP to inhibit its function
More than 50 viral proteins have been identified that mod-
Retention of MHC class I molecules within the cell
ulate the defense mechanisms used by mammals to control
Destabilization and degradation of MHC class I molecules
viral infection and to eliminate the viruses once infection
Interference with natural killer cell function
is initiated. Most have been described only within the last
Interference with MHC class II antigen presentation
decade or so, and more viral mechanisms to interfere with
Interference with antiviral cytokine function (see also Table 10.13)
host defenses will surely be discovered in the future. The
Encoding of viral homologues of cellular regulators of cytokines
most elaborate evasion mechanisms are utilized by viruses
Neutralization of cytokine activities
that contain larger genomes, and thus can afford to encode
Production of soluble cytokine receptors
many proteins for this purpose.
Interference with interferons (see also Tables 10.12 and 10.15)
Interference with IFN induction
Interference with the Expression of Peptides by
Interference with IFN signaling (effects on PKR, STAT1 and
Class I MHC Molecules
STAT2, etc.)
Many viruses downregulate the expression of class I
Inhibition of apoptosis (see also Table 10.11)
MHC molecules on the surface of infected cells, thereby
img
rendering the cells invisible to CTLs. A partial summary of
Adenoviruses prevent the presentation of peptides by class
the proteins used and the mechanisms involved is given in
I MHC molecules by one of two different methods. These
Table 10.10. Rapid shutdown of the cell can accomplish this,
are illustrated schematically in Fig. 10.21. Some adenovi-
and this appears to occur following infection by picornavi-
ruses, such as Ad2, produce an integral membrane protein of
ruses, for example. However, the picornaviruses also utilize
19 kDa, a product of the E3 gene, which binds tightly to class
additional mechanisms to interfere with antigen presentation.
I MHC molecules in the lumen of the ER. This prevents their
Poliovirus protein 3A interacts with the membranes of the
export to the cell surface. Ad12, in contrast, produces a prod-
endoplasmic reticulum to prevent transport of proteins from
uct from the E1 gene that interferes with the transcription
the ER to the Golgi apparatus. This prevents the transport
of genes in the MHC locus. Transcription of the genes for
of MHC bearing polio-specific peptides to the cell surface.
class I molecules, the genes for TAP, and the genes for the
This mechanism, which can only be used by viruses that are
MHC-encoded components of the proteasome is inhibited.
not enveloped and that do not secrete proteins during the
Thus, synthesis of new class I molecules is inhibited, and
replication cycle, has the added advantage that previously
the production and transport of peptides required for MHC
transported MHC remains at the cell surface to ward off NK
presentation cannot be upregulated.
cells. Interestingly, foot-and-mouth disease virus also pre-
Several poxviruses are known to downregulate the expres-
vents transport of proteins to the cell surface but it is viral
sion of class I MHC at the surface of the infected cell. One
protein 2BC that is responsible.
mechanism used appears to be the production of proteins
More elaborate mechanisms that interrupt presentation
that bind MHC and target it for degradation.
of antigens by MHC are used by many viruses, includ-
The herpesviruses have learned to coexist with the
ing the lentiviruses, the adenoviruses, the herpesviruses,
immune system, enabling them to establish lifelong infec-
and the poxviruses. The lentivirus HIV-1 uses two differ-
tions. They encode a wide variety of gene products that
ent mechanisms to downregulate class I MHC expression.
interfere with the presentation of peptides by class I MHC
The Tat protein interferes with the transcription of mRNA
molecules. Several of these are illustrated schematically
for class I MHC molecules, thereby leading to reduced
in Fig. 10.22. Human cytomegalovirus (HHV-5) encodes
synthesis of class I molecules. The Nef protein downregu-
four different proteins that interfere with class I presenta-
lates the surface expression of class I MHC molecules by
tion by interacting with cellular proteins that form compo-
relocalizing them to the trans-Golgi network. It does this
nents of the presentation pathway. One protein, called US3,
through interactions with another cellular protein called
binds to class I MHC molecules and retains them in the ER.
PACS-1, which is involved in sorting proteins to the trans-
Two other proteins, US2 and US11, independently cause
Golgi network.
class I MHC molecules to be immediately recycled to the
TABLE 10.10
Some Viruses That Alter Antigen Presentation by Class I MHC Molecules
Interference level
Virus family
Virus
Virus protein
Mechanism
Downregulation of MHC class I
Adenoviridae
Ad 2
E3-19K
Viral protein binds to class I molecules and keeps
expression at cell surface
them in the ER
Ad12
E1A
Inhibits transcription of class I mRNA
Herpesviridae
HHV-5
US2, US11
Gene products lead to degradation of class I molecules
Binds to β2 microglobulin
HHV-5
UL18
Picornaviridae
PV
3A
Inhibits secretory pathway
Retroviridae
HIV
Tat
Inhibits transcription of MHC class I mRNA
Nef
Downregulates surface expression of class I proteins
Alteration of antigen processing
Adenoviridae
Ad12
E1A
Inhibits transcription of TAP1 and TAP2
Herpesviridae
HHV-1
ICP47
Binds to TAP and prevents transport of antigenic
peptide to MHC class I
HHV-5
US6
Blocks transport by TAP
HHV-4
EBNA-1
EBNA-1 protein with Gly-Ala repeat is not processed
by proteasome
Alteration of spectrum of antigens
Hepadnaviridae
HepB
Ag epitopes
Epitopes mutate so that they are no longer
presented
recognized by CTLs
Virus abbreviations: Ad 2, adenovirus 2; Ad12, adenovirus 12; HHV-5, human cytomegalovirus; PV, poliovirus; HIV, human immunodeficiency virus;
HHV-1, herpes simplex virus; HHV-4, Epstein-Barr virus; HepB, hepatitis B virus.
img
Proteosome
Nucleus
(Inhibits transcription
E1A
TAP
of TAP mRNA)
E1A
(Inhibits transcription
of class I molecules)
TAP
ER
E3-19K
(Keeps class I
molecules in the ER)
Transport vesicle
Inhibition by Ad2
Inhibition by Ad12
MHC class I molecules
FIGURE 10.21  Mechanisms by which adenoviruses inhibit peptide presentation by class I MHC molecules on
infected cells.
cytoplasm following synthesis, where they are degraded by
obviously swiped the gene from its host at some time in the
the proteasome. The recycling of class I molecules to the
past) and binds peptide. Its function is not well understood.
cytoplasm is thought to occur by speeding up the kinetics of
It interacts with monocytes and presumably interferes with
the normal cellular turnover pathway that recycles products
their function. It may have other functions as well. In any
event, binding of β2 microglobulin reduces the pool avail-
in the ER back to the cytoplasm. A fourth HCMV protein,
US6, binds to TAP and prevents transport of peptides into
able for formation of class I MHC molecules.
the lumen of the ER. Herpes simplex viruses (HSV) also
Mouse CMV also downregulates expression of class I
encodes a protein (ICP47) that blocks transport of peptides
molecules but uses different mechanisms to do so. An early
by TAP. Interestingly, the HSV ICP47 binds to TAP from the
gene, m06, encodes a protein that binds to MHC class I mol-
cytoplasmic side of this protein, which spans the ER mem-
ecules in the ER. The bound MHC class I molecules exit the
brane, whereas HCMV US6 binds from the lumenal side.
ER and pass through the Golgi apparatus. Rather than con-
Thus, these proteins represent independent solutions to the
tinuing on to the cell surface, however, they are redirected to
problem of preventing transport of peptides across the ER
lysosomes where they are degraded.
membrane by TAP. Loss of TAP transport prevents the pres-
entation of herpes peptides at the cell surface.
Interference with the Activity of Complement
A fifth HCMV protein, UL83, is also involved in prevent-
ing the presentation of peptides by class I MHC molecules.
Infected cells can be killed by a complement-mediated
This protein phosphorylates an early HCMV protein within
pathway in which antibodies first bind to viral antigens
an important T-cell epitope. Phosphorylation prevents the
present on the surface. Virus neutralization by antibodies is
processing and presentation of this epitope.
also enhanced by complement. Herpesviruses express proteins
Finally, a HCMV protein, UL18, binds β2 microglobulin.
that interfere with complement activation. HSV expresses a
UL18 is homologous to MHC class I molecules (the virus
protein on the cell surface, called gC, that binds complement
img
EBNA-1 (Protein not processed)
Nucleus
Proteosome
TAP
US2, US11 (Causes MHC molecules
to be degraded)
ICP47
(Blocks transport
by TAP )
US6
(Blocks transport
ER
by TAP )
UL18 (Binds to β2
microglobulin)
US3
(Keeps class I molecules
in the ER)
Transport vesicle
Interference by HHV-1
Interference by HHV-5
MHC class I molecules
Interference by HHV-4
FIGURE 10.22
Mechanisms by which herpesviruses interfere with the immune defenses of the host cell, by altering
peptide presentation by class I MHC molecules. Mechanisms used by human cytomegalovirus (HHV-5) are shown in red,
by herpes simplex virus (HHV-1) in orange, and by Epstein­Barr virus (HHV-4) in ochre.
component C3b, thereby preventing initiation of the comple-
a latent infection in neurons, which are immunologically
ment cascade. HSV also expresses a molecule, consisting of a
privileged and express only low levels of class I MHC mol-
complex of viral proteins gE and gI, that has an Fc receptor. It
ecules. Epstein­Barr virus does express a protein in latently
binds IgG through the Fc domain, which serves to block com-
infected cells but this protein contains a glycine­alanine tract
plement activation. HCMV also expresses an Fc receptor.
that interferes with processing by the proteasome, rendering
Poxviruses also interfere with the complement system
this protein invisible to the class I pathway.
in a variety of ways. The best understood mechanism is the
secretion of a protein by vaccinia-infected cells called VCP
Infection of Cells of the Immune System to Thwart
(vaccinia complement control protein). This protein binds
Immune Response
both C3b and C4b, preventing the activation of the comple-
ment cascade by either the alternative or classical pathway.
Another mechanism for evasion of the immune system
VCP appears to have other functions as well, and other pox-
is to infect immune effector cells. HIV lytically infects
CD4+ TH cells, which leads to a profound immunosuppres-
virus proteins appear to interfere with complement by less
well understood mechanisms.
sion because these cells are required to mount an immune
response. Similarly, measles virus infects many cells of the
immune system, including T and B lymphocytes and mono-
Latent Infections That Avoid CTL Surveillance
cytes. Infection by measles virus results in immunosuppres-
The herpesviruses establish latent infections that persist
sion that lasts for some weeks after infection. As another
for the life of the host. The alphaherpesviruses express no
example, the herpesvirus Epstein­Barr virus infects B cells.
protein in the latently infected cell and, furthermore, establish
Other viruses are also known that infect T cells, B cells, mac-
rophages, or other cells that are important for the immune
the viral DNAs. This activity would normally induce apop-
response. In addition, if a virus infects the thymus early
tosis mediated by p53. Other aspects of viral replication also
in the life of the animal, while the immune system is still
have the potential to induce apoptosis.
developing, immune tolerance may result such that the virus
For viruses that replicate rapidly, such as many RNA viruses,
will not be recognized as foreign. This enables the virus to
apoptosis does not seem to inhibit the production of virus. It may
establish an infection that lasts for the life of the animal.
actually lead to increased virus production, perhaps because of
less competition for the resources of the infected cell. Apoptosis
may even result in more rapid spread of viruses to neighboring
Rapid Drift
cells because of cell fragmentation and uptake of the fragments
Some viruses evade the adaptive immune system by rapid
by neighboring cells with less inflammation than would occur
drift in the antigens that are recognized by it. Most viruses,
otherwise, since apoptosis itself does not induce inflamma-
but especially RNA viruses, undergo rapid evolution, and
tion. For viruses that replicate more slowly, however, such as
immune pressure can cause their sequence to drift. Viruses
most DNA viruses, premature apoptosis results in significant
that are able to undergo reassortment, of which influenza
declines in virus yield. Thus, many viruses have evolved ways
virus is the classic example, are able to produce new forms
to inhibit or delay apoptosis in infected cells. An overview of
very rapidly that have altered antigenic epitopes. Viruses such
mechanisms used by viruses in different families to interfere
as the lentiviruses, of which HIV is the best known, establish
with apoptosis is given in Table 10.11. Viruses may interfere
a chronic infection in their host, and during this infection
with the caspase activation pathway or with intracellular sig-
these viruses undergo continuing genetic drift, which may be
naling that leads to apoptosis, produce anti-apoptotic proteins
responsible, at least in part, for their persistence.
or proteins that regulate the activities of p53, or interfere with
apoptosis in still other ways.
Prevention of Killing by Natural Killer Cells
Production of Serpins
Downregulation of class I MHC expression renders a cell
more sensitive to lysis by NK cells, the backup mechanism that
Many of the poxviruses produce proteins that inhibit the
eliminates cells that do not express class I molecules on their
activity of caspases. These proteins are related to serpins
surface. The cytomegaloviruses (CMVs) resist NK cell activity,
(serine protease inhibitors), which are small proteins that
however, even though they severely downregulate the expres-
serve as substrates for serine proteases, but which remain
sion of MHC. In cells infected by CMVs, the molecules that are
bound to the protease after cleavage and block their activ-
required for the stimulation of the killing activity of NK cells
ity. Serpins are important in the regulation of inflammatory
are downregulated by mechanisms that are poorly understood.
responses. The poxvirus serpins inhibit caspases, which are
The CMV protein UL18 is also important in some way. Mouse
cysteine proteases. They appear to act similarly to host ser-
CMV deleted for this gene replicates poorly in mice, and NK
pins in that they are cleaved by the caspase but remain bound
cells appear to be responsible for the poor replication.
to it and render it inactive. These viral products, of which
HIV also resists NK activity. Here the mechanism seems
crmA of cowpox virus is an example, appear to block apop-
to be a selective interference with the expression of class I
tosis induced by any pathway requiring activation of cas-
MHC molecules. Human cells are protected from NK killing
pases. An overview of poxvirus interference with apoptotic
primarily by HLA-C and HLA-E molecules. HIV-1 selectively
pathways is shown in Fig. 10.23.
downregulates expression of HLA-A and HLA-B molecules,
which are the human class I molecules recognized by the
Interference with Fas or TNF Signaling
majority of CTLs. It does not affect expression of HLA-C
or HLA-E molecules. Thus, the infected cells are resistant
The poxvirus rabbit myxoma virus encodes a homologue of
to killing by NK cells. They remain sensitive to killing by
the TNF receptor (TNFR), called T2. This protein inhibits the
interaction of TNF-α with TNFR and thus prevents activation
CTLs, but their sensitivity to CTLs is greatly reduced.
of the apoptotic pathway by TNF-α (Fig. 10.23). Some other
poxviruses also produce TNFRs to neutralize TNF-α activity.
Virus Counterdefenses against Apoptosis
Another approach is taken by the poxvirus molluscum con-
Infection of an animal cell by a virus often results in apop-
tagiosum virus, which encodes proteins named MC159/160
tosis of the cell, or would result in apoptosis if the virus did
that have death effector domains similar to those present in
not block its induction. NK cells or CTLs induce apoptosis
a cellular protein called FADD. FADD associates with cas-
as a way of killing infected cells. However, the replication
pase-8 and recruits it to activated Fas or TNF receptors in the
activities of the virus itself are often apoptosis inducing. For
cell surface, resulting in the activation of caspase-8. The viral
example, DNA viruses deregulate the cell and cause it to
proteins disrupt this interaction and prevent the activation of
enter S phase, which is required for optimal replication of
caspase-8 signaled by Fas ligand or TNF (Fig. 10.23).
img
TABLE 10.11
Viruses That Interfere with Apoptosis
Virus family
Virus
Viral protein
Mode of interference
Poxviridae
Cowpox
crmA
Serpin homologue, inhibits proteolytic activation of caspases
Vaccinia
SPI-2
crmA homologue, inhibits activation of caspases
T2 is a homologue of TNFR, and inhibits interaction of TNA-α with
Myxoma
M11L, T2
TNFR; M11L has a novel function
Molluscum contagiosum
M159, 160
Has death domains like FADD, inhibits FADD activation of caspase-8
Asfarviridae
African swine fever
LMW5-HL
Homologue of Bcl-2
γ34.5 gene
Herpesviridae
HHV-1
Prevents shutoff of protein synthesis in neuroblastoma cells
SaHV-1
ORF 16 product
Homologue of Bcl-2
HHV 8
KS bcl-2
Homologue of Bcl-2
K13
vFLIPS, prevents activation of caspases by death receptors
HHV-4 (latent)
LMP1
Upregulates transcription of Bcl-2 and A20 mRNAs; inhibits
p53-mediated apoptosis
HHV-4 (lytic)
BHFR1
Inhibits p53 activity; has some sequence similarity to Bcl-2
HHV-5
IE-1, IE-2
Downregulates transcription of p53 mRNA
Gammaherpesvirinae
Viral FLIPs
Inhibits signaling from death domains to caspases
Polymaviridae
SV40
Large T antigen
Binds to and inactivates p53
Papillomaviridae
HPVs
E6
Binds to p53 and targets it for ubiquitin-mediated proteolysis
Adenoviridae
Adenovirus
E1B-55K
Binds to and inactivates p53
E3-14.7K
Interacts with caspase-8
E3 10.4K/14.5K
Blocks caspase-8 activation by destruction of Fas
E4 orf 6
Binds to and inactivates p53
E1B 19K
Functional homologue of Bcl-2; interacts with Bax, Bi, and Bak
Baculoviridae
AcMNPV
p35
Forms a complex with caspases; inhibits caspase-mediated cell death
IAP
Like FLIPs, inhibits activation of caspases
Hepadnaviridae
HepB
pX
Binds to p53
Flaviviridae
HepC
Core protein
Represses transcription of p53 mRNA
Virus name abbreviations: HHV-8, Kaposi's sarcoma herpesvirus; HHV-5, human cytomegalovirus; HHV-1, herpes simplex virus; HHV-4, Epstein­Barr
virus; SaHV-1, Saimiriine herpesvirus 1; HPV, human papillomaviruses; AcMNPV, Autographa californica nucleopolyhedrovirus; HepB, hepatitis B virus;
HepC, hepatitis C virus.
Source:Adapted from reviews by O'Brien (1998) and Tortorella et al. (2000).
Several herpesviruses also produce proteins that inter-
Production of Homologues of Bcl-2
fere with the activation of caspase-8 through its interac-
Bcl-2 is a cellular protein that inhibits apoptosis. Several
tions with FADD. These viral FLIPs thus inhibit apoptosis
herpesviruses and adenoviruses, as well as at least one poxvi-
in a manner similar to the molluscum contagiosum virus
rus (fowlpox virus) and one asfarivirus (African swine fever
MC159/160.
virus), produce homologues of Bcl-2, probably obtained
Another mechanism to interfere with Fas-induced acti-
originally from the host, that act as anti-apoptotic agents. The
vation of the apoptotic pathway is simply to reduce the
adenovirus homologue, called E1B-19K, is multifunctional.
number of Fas molecules at the cell surface. The adeno-
It appears to inhibit apoptosis not only as a Bcl-2 homologue
viruses produce two proteins, known as RIDα and RIDβ,
but also by interfering with FADD-mediated activation of
that cause Fas at the cell surface to be internalized and
the caspase pathway. An overview of herpesvirus interfer-
degraded. The RID proteins also inhibit apoptosis induced
ence with the induction of apoptosis is shown in Fig. 10.24
by TNF, but the mechanism is not known. The importance
and of adenovirus interference in Fig. 10.25.
of the TNF-α pathway is shown by the fact that the adeno-
The herpesvirus EBV has evolved another solution to the pro-
viruses produce four different proteins, found in different
duction of Bcl-2. It does not encode a Bcl-2 homologue, but pro-
parts of the infected cell, that antagonize the effects of
duces a protein that upregulates the production of cellular Bcl-2.
TNF-α.
img
Killing via Receptor
Killing by CTL via
the Granzyme B Pathway
FasL or TNF-a
Ligand
T2
Receptor
Fas or TNFR
Cytotoxic T-cell
Perforin Channel
crmA
Granzyme B
Cytoplasmic
SPI-1
FADD
death domains
Death effector
MC159
domains
Procaspase
Activation
Procaspase
cleavages
Caspase Cascade
Virus
Inhibiting
factor
cowpox
crmA
myxoma
T2
vaccinia, variola
SPI-1
molluscum contagiosum
MC 159
Apoptosis
FIGURE 10.23
Poxviruses inhibit apoptosis by interfering with the ligand­receptor pathway and by interfering
directly with the caspase cleavage pathway. The latter mechanisms blocks induction of apoptosis by the granzyme B
pathway (right) as well as by receptor signaling (left). Points of interference by products of cowpox, myxoma, vaccinia,
and molluscum contagiosum viruses are shown in red. Drawn from data in Turner and Moyer (1998).
Control of p53 Concentrations
lomavirus product E6, which binds p53 and causes it to be
rapidly degraded. Many of these products were described in
Many of the DNA viruses induce cellular DNA synthesis,
Chapter 7.
which leads to an increase in p53 concentration. This anti-
tumor protein plays a central role in the control of the cell
cycle, and one of its functions is as a transcriptional activa-
Other Viral Proteins That Oppose Apoptosis
tor. Its concentration in normal cells is controlled by rapid
turnover and by its activation of the transcription of a gene
There are yet other viral proteins that cause the infected
called mdm-2, which also requires interaction with p300. The
cell to resist apoptosis by mechanisms that are not well
mdm-2 protein binds p53 and inhibits its ability to act as a
understood. In the poxviruses these include proteins that
transcription factor, thus regulating its own synthesis. This
contain ankyrin repeats, a protein encoded by molluscum
feedback loop is inactivated by DNA viruses in the process
contagiosum virus that is 75% identical to human gluta-
of stimulating the cell to enter S phase and p53 accumulates.
thione peroxidase (and may therefore prevent accumulation
High concentrations of p53 induce apoptosis, probably as
of oxidizing agents that can provoke apoptosis), a protein
a result of its transcriptional activities. Many DNA viruses
that acts at the mitochondrial checkpoint, as well as still
resist p53-induced apoptosis by sequestering p53 or other-
other proteins. The multiple mechanisms used by poxviruses
wise interfering with its function as a transcriptional activator,
to inhibit apoptosis illustrate the importance of preventing
or by causing it to be rapidly degraded. These include at least
apoptosis by the infected cell. Herpesviruses and adenovi-
some herpesviruses, adenoviruses, papillomaviruses, and
ruses also produce proteins in addition to those described
hepatitis B virus. Examples include the SV40 T antigen, the
before that inhibit apoptosis, again showing the importance
adenovirus E1B-55K protein (see Fig. 10.25), the hepatitis B
of controlling the apoptotic pathway after infection by these
virus pX, two proteins encoded by Epstein­Barr virus (called
viruses. It is interesting that the adenoviruses are so efficient
EBNA-5 and BZLF1) which bind p53, two proteins (called
at suppressing apoptosis that they encode another protein,
IE1 and IE2) encoded by cytomegalovirus that interfere with
the adenovirus death protein, which leads to cell death and
p53-directed transcription (see also Fig. 10.24), and the papil-
release of virus. This protein, which is produced only late
img
the following paragraphs. The fact that such a large number
Killing due to External Stimuli
of viruses belonging to many different families have evolved
UV irradiation
Hypoxia
such a diverse set of mechanisms to counter this pathway
E2F
Viral infection
g 34.5 Unscheduled
illustrates the importance of this pathway in controlling viral
DNA synthesis
infections in vertebrates.
p53
Several viruses, including adenoviruses, Epstein­Barr
Mdm2
IE1, IE2
virus, and hepatitis C virus, encode small RNA products that
bind to PKR in lieu of dsRNA, but which do not activate
BZLF1
p53
PKR. The adenoviral RNA is called VAI RNA and was the
Bax
first of these products to be described. PKR has two dsRNA
binding domains. The current model for the activation of PKR
??
BHRF1
posits that dsRNA must be bound by both domains for acti-
vating autophosphorylation to occur, and VAI RNA seems
KS bcl-2
to be incapable of binding to both sites simultaneously. After
Orf 16
activation, dimerization of the enzyme is required for further
Procaspase
phosphorylation in trans to occur, and whether RNA bind-
ing is required for this is not known. Regardless of mecha-
nism, the net result is that the viral RNAs act as inhibitors of
Inhibit Apoptosis
the cofactor dsRNA and prevent activation of PKR.
Many viruses, including vaccinia virus, reoviruses, influ-
Factor
Virus
Caspase cascade
enza viruses, rotaviruses, and at least two herpesviruses,
g 34.5
HHV-1
encode protein products that bind dsRNA, thus making it
BHRF1, BZLF1
HHV-4
unavailable as a cofactor for activation of PKR. Furthermore,
KS bcl-2
HHV-8
vaccinia virus appears to limit the production of dsRNA by
Apoptosis
IE1, IE2
HHV-5
using an arrangement of genes and stop transcription sig-
nals that reduces transcription from both strands, at least
Orf 16
SaHV-1
early after infection. Sequestering of dsRNA also inhibits
FIGURE 10.24  Various members of the herpesvirus family inhibit
the induction of IFN, since dsRNA is a primary inducer of
different steps in p53-mediated apoptosis. They interfere with Bax (an
interferon, as well as the activation of RNase L.
inducer of apoptosis), encode Bcl-2 homologues, and interact with p53
itself. The gammaherpesviruses also interfere with Fas-mediated signaling
Many viruses interfere with the activity of PKR directly
(not shown) by encoding products called viral FLIPs that interact with
(Table 10.12). They encode products that bind PKR and
death domains and prevent signaling (similar to the action of poxvirus
prevent it from phosphorylating eIF2α. These products may
MC159 illustrated in Fig. 10.23). HHV-1, herpes simplex virus; HHV-4,
inhibit the dimerization of PKR required for its activity, or
Epstein­Barr virus; HHV-5, human cytomegalovirus; HHV-8, Kaposi's
may sequester the protein, or may bind to inactive or acti-
sarcoma herpesvirus; SaHV-1, Saimirine herpesvirus 1. Adapted from Hill
and Masucci (1998).
vated protein and prevent it from functioning, or may recruit
cellular proteins that inhibit PKR function. Of interest is the
fact that such proteins are not confined to viruses of verte-
brates but one is also found in some insect baculoviruses.
after infection, may simply allow apoptosis to proceed, or
Competitive inhibitors that are homologues of eIF2α are
the protein may initiate some other pathway that results in
produced by some viruses, including vaccinia, HIV, and
the death of the cell.
ranaviruses of frogs. These pseudosubstrates inhibit the
phorphorylation of authentic eIF2α.
Evasion of the Antiviral State
Poliovirus induces the degradation of PKR. Although the
virus encodes more than one protease, it is thought that the
Many viruses encode products that specifically interfere
virus induces a cellular protease to degrade PKR.
with the activation of the PKR pathway that leads to shut-
Finally, herpesvirus, papillomavirus, and SV40 viruses
down of protein synthesis. Several different mechanisms
promote the dephosphorylation of eIF2α. They encode prod-
are used: synthesis of competitive RNA that binds PKR
ucts that interact with cellular phosphatases to induce them
but does not activate it; synthesis of products that seques-
to dephosphorylate eIF2α, thus maintaining it in an active
ter dsRNA; production of proteins that bind PKR and pre-
vent it from phosphorylating eIF2α; competitive inhibitors
state.
of the eIF2α substrate; activation of cellular proteins that
The RNase L pathway is also inhibited by viral prod-
ucts that bind dsRNA or by decoy RNAs. However, herpes
inhibit or degrade PKR; production of products that result in
dephosphorylation of eIF2α (Table 10.12). An overview of
simplex virus targets RNase L activity directly. It makes an
analogue of 2-5oligo(A) that binds to RNase L but which
the viruses that use these various mechanisms is presented in
img
Killing due to External Stimuli
Killing via Receptor
E1A
UV irradiation
Hypoxia
Unscheduled
E1A
E1A/E4
Ligand
E2F
FasL
DNA synthesis
Viral infection
p53
Mdm2
Receptor
Fa
E1B-55K
E3-10.4/14.5K
p53
E4B-36K
E1B-19K
Bax
E3-14.7K
Cytoplasmic
E1A/E4
??
death domains
FADD
E3-11.6K
Bcl-2
Death effector
domains
Activation
Procaspase
Procaspase
cleavages
E1B-19K
Caspase cascade
Induce Apoptosis
Inhibit
Apoptosis
Apoptosis
FIGURE 10.25  Adenoviruses have been shown to both induce apoptosis (blue arrows and text) and to encode factors
which inhibit apoptosis (red symbols and text). These moieties interfere with "killing via receptor" and with the p53-
mediated pathway of apoptosis. Drawn from data in Chinnadurai (1998).
does not activate the enzyme. By preventing the binding of
virus growth in the present host but also the persistence of
authentic 2-5oligo(A), the analogue prevents the activation
the virus in nature. These two are often antagonistic, and
of RNase L.
compromises are required. Viruses also produce products
that defeat specific aspects of the innate response induced
by cytokines. Of these, products that evade the antiviral
Viral Counterdefenses against Cytokines
state induced by IFN were described earlier. A partial list-
and Chemokines
ing of strategies used by some viruses to modulate cytokine
activities is given in Table 10.13, and a listing of defense
The cytokines and chemokines are powerful regulators of
molecules encoded by poxviruses is given in Table 10.14.
both innate and adaptive immune defenses. Because of the
importance of these agents in the regulation of the immune
response, and because of their potential effectiveness against
Interference with Signal Transduction Pathways
viral infection, many viruses have devised methods to dis-
rupt their activities. These include the encoding of homo-
Adenoviruses, herpesviruses, poxviruses, hepatitis C virus,
logues or analogues of cytokines and chemokines or of their
hepatitis B virus, and most or all minus-strand RNA viruses
receptors. Some of these were acquired from the host at some
make products that interfere with signal transduction by the
time in the past and modified to meet the purposes of the
dsRNA sensors that lead to the production of IFN or with
virus, whereas others are viral products that have evolved
signal transduction by the IFN receptor on binding of its
to interact with the cytokine system. Because the networks
ligand. The mechanisms used by the minus-strand viruses
of cytokine and chemokine interactions are complex, the
are summarized in Table 10.15.
pathways by which the viral products exert their effects are
Hepatitis C virus establishes a chronic infection in the
often poorly understood. It is in the interest of the virus to
majority of infected individuals. One reason that the virus
divert the immune responses in directions that not only favor
is so successful in establishing chronic infections is that it
img
TABLE 10.12
Viral Regulation of PKR
can occur via such other TLR receptors, but the fact that
HCV specifically targets the dsRNA signaling pathways
Mechanism
Viral gene
illustrates the importance of this mechanism for induction of
of action
Virus family
Virus
product
IFN following viral infection.
A number of paramyxoviruses are also known to inter-
dsRNA binding
Poxviridae
Vaccinia
E3L
proteins
fere with this signaling pathway. The V proteins of several
σ3
Reoviridae
Reovirus
paramyxoviruses interfere at some undefined stage, and the
Group A rotavirus
NSP5?
W protein of Nipah virus blocks the activity of IRF-3 in the
Group C rotavirus
NSP3
nucleus.
Orthomyxoviridae Influenza
NS1
Many viruses interfere with the signal transduction path-
Herpesviridae
Herpes simplex
Us11
ways activated upon binding of IFN to its receptor on the cell
(HHV-1)
surface, thereby preventing the induction of gene expression
Epstein­Barr
SM
normally caused by IFN. As described before, activation of
(HHV-4)
the transcription factor STAT1 by IFN-γ and its subsequent
RNA
Herpesviridae
Epstein­Barr
EBER
dimerization, and the activation of the transcription factors
inhibitors
(HHV-4)
RNA
STAT1 and STAT2 by IFN-α/β and their subsequent het-
Adenoviridae
Adenovirus
VAI RNA,
erodimerization, are critical for the transcription of genes
VAII
activated by the activities of the IFNs (Fig. 10.18). Human
RNA?
cytomegalovirus produces a protein called IE1-72kDa that
Flaviviridae
Hepatitis C
IRES
forms a complex with STAT1 and STAT2 in the nucleus of
PKR
Flaviviridae
Hepatitis C
NS5A, E2
the cell and prevents their association with IRF-9, thereby
interaction
Orthomyxoviridae Influenza
p58
preventing these transcription factors from functioning. Most
Poxviridae
Vaccinia
E3L
of the minus-strand RNA viruses are also known to inhibit
Herpesviridae
Herpes simplex
Us11
the STAT1­STAT2 pathways. The V proteins of several para-
(HHV-1)
myxoviruses cause either STAT1 or STAT2 to be degraded
Human
vIRF-2
by the host proteasome. SV5 and mumps viruses cause the
herpesvirus-8
degradation of STAT1, which inactivates both the type I and
Competitive
Poxviridae
Vaccinia
K3L
type II IFN responses. Human PIV2 V protein targets STAT2,
inhibitor
Retroviridae
HIV
Tat
and thus only the type I IFN response is ablated.
PKR
Picornaviridae
Poliovirus
Cellular
Other paramyxoviruses inhibit IFN action by binding to
degradation
protease
STAT1 or STAT2 to block their activity. Nipah virus V pro-
(activated
by ??)
tein causes STAT1 and STAT2 to aggregate in the nucleus.
eIF2α
γ34.5
The C proteins of Sendai virus, of which there are four, pro-
Herpesviridae
Herpes simplex
phosphatase
(HHV-1)
duced by in-frame translation starting from four different
Papillomaviridae
HPV type 18
E6
start codons, all bind to STAT1 to block its activity. In some
cell lines, binding of the two larger C proteins leads to deg-
Polyomaviridae
SV-40
Large-T
antigen
radation of STAT1, but in all cells the binding of C proteins
is sufficient to inhibit its activity.
Abbreviations: HIV, human immunodeficiency virus; HPV, human
Other minus-strand RNA viruses inhibit the activity of
papillomavirus; SV-40, simian virus 40.
IFN by mechanisms that are not as yet established. A summary
Source: Adapted from Table 1 in Langland et al. (2006).
of the proteins involved is shown in Table 10.15.
Production of Cytokine-Binding Proteins
A number of viruses make proteins that bind to
prevents TLR3 or RIG-1 from signaling the presence of
cytokines. Many of these cytokine-binding proteins are
dsRNA. The viral NS3/4A protease cleaves both TRIF, an
homologues of cellular cytokine receptors and have cer-
intermediate in the TLR3 signaling pathway, and MAVS, an
tainly been acquired from the host. Most of these viral
intermediate in the RIG-1 signaling pathway (see Fig. 10.17).
proteins are secreted from the cell as soluble proteins that
Each of these proteins is cleaved once at a specific site,
neutralize the activity of cytokines by binding to them in
and once cleaved they are no longer active in the signaling
a nonproductive fashion. Others function at the surface of
pathway. The result is that dsRNA cannot induce produc-
the infected cells.
Various poxviruses encode receptors for IFN-γ, IFN-α/β,
tion of IFN following infection by the virus. Other TLR
pathways are not known to be affected, and IFN induction
IL-1, IL-6, IL-8, and TNF (Table 10.14). Most poxviruses
img
TABLE 10.13
Virus Manipulation of Cytokine Signaling
Virus family
Virus
Cellular target or homologue
Viral factor
Mode of action
Herpesviridae
HHV-5
TNF receptor
UL144
Unknown function, retained intracellularly
Chemokine receptors
US28
Competitive CC-chemokine receptor, sequesters
CC-chemokines
HHV-8
Type 1 IFNs
vIRF K9
Blocks transcription activation in response to IFN
vIRF-2
May modulate expression of early inflammatory genes
Virus-encoded chemokines
vMIP-I, vMIP-II
TH-2 chemoattractant, chemokine receptor antagonist
γ134.5
HHV-1
Type 1 IFNs
Reverses IFN-induced translation block
2-5(A)
RNase L
RNA analogue, inhibits RNase L
HHV-4
Type 1 IFNs
EBNA-2
Downregulates IFN-stimulated transcription
PKR
EBER-1
Blocks PKR activity
Chemokine receptors
BARF-1
Secreted, sequesters CSF-1
IL-10
BCRF-1
IL-10 homologue, antagonizes TH-1 responses
Adenoviridae
Adenovirus
Type 1 IFNs
E1A
Blocks IFN-induced JAK­STAT pathway
PKR
VA 1 RNA
Blocks PKR activity
TNF-α
E3 proteins
Various mechanisms
Hepadnaviridae
HepB
Type 1 IFNs
Terminal protein
Blocks IFN signalling
Flaviviridae
HepC
PKR
E2
Inhibits PKR activation in response to type 1 IFN
Retroviridae
HIV
PKR
TAR RNA
Recruits cellular PKR inhibitor TRBP
Poxviridae
See Table 10.14
Abbreviations: HHV-5, human cytomegalovirus; TNF, tumor necrosis factor; HHV-8, Kaposi's sarcoma herpesvirus; HHV-1, herpes simplex virus; HHV-4,
Epstein­Barr virus; IFN, interferon; PKR, dsRNA-dependent protein kinase; CSF-1, colony stimulating factor; HIV, human immunodeficiency virus.
Source: Adapted from Table 3 of Tortorella et al. (2000).
secrete a receptor for IFN-γ that is distantly related to the
virus genes usually results in an attenuation of virus growth
human receptor. This receptor neutralizes the activity of
in experimental animals.
IFN-γ and presumably functions to prevent IFN-γ-induced
Poxviruses make a number of proteins that bind various
events. The potential efficacy of interference with IFN-γ
chemokines. Neutralization of the activity of chemokines
is shown by the receptor secreted by rabbit myxoma virus.
results in damping the inflammatory response to viral infec-
This virus causes an infection of European rabbits that has
tion. Some of these chemokine-binding proteins are soluble
a 99% fatality rate (Chapter 7). Mutants that lack the IFN-γ
proteins and some are expressed on the surface of the infected
receptor cause nonfatal illness in these rabbits.
cell. Rabbit myxoma virus, for example, produces two pro-
Many poxviruses also produce a receptor for IFN-α/β
teins that bind chemokines. One protein binds with high affin-
and for TNF-α. TNF-α is a cytokine that has multiple roles
ity to a subset of chemokines called CC-chemokines. The
second protein is the IFN-γ receptor described before.
in the control of virus-infected cells. It plays a role in apop-
The rabbit myxoma virus IFN-γ receptor, but not that of
tosis, but is also important in noncytolytic clearing of virus
infection. The TNF-α receptor encoded by rabbit myxoma
other poxviruses, binds a number of chemokines through
virus is multifunctional. It is secreted in part and binds TNF-
their heparin-binding domains. This binding is of low affin-
α to neutralize it. However, it is partially retained within the
ity. Thus, this protein is multifunctional, and binding of IFN-γ
cell where it interferes with signal transduction that induces
and chemokines are independent of one another.
apoptosis. The importance of TNF-α in control of viral
Many beta- and gammaherpesviruses also produce
infections is shown by the fact that some poxviruses produce
cytokine or chemokine receptors. Human CMV, for exam-
two different TNF receptors to neutralize its activity, and by
ple, produces four chemokine receptors, whereas HHV-8
the fact that adenoviruses produce four different proteins,
produces one. Epstein­Barr virus encodes a receptor for the
found in different parts of the infected cell, that antagonize
cytokine macrophage colony-stimulating factor (CSF-1).
the effects of TNF.
In most cases, deletion of viral genes that interfere with
IL-1, IL-6, and IL-8 are also neutralized by gene products
cytokine or chemokine activity attenuates the virus in experi-
encoded by various poxviruses. Deletion of any of these pox-
mental animals. However, in some cases deletion of such
img
TABLE 10.14 Pox Defense Molecules
System
Target
Virus
Gene
Viral protein
Properties
Cellular homologue
Complement
C4B and C3B
Vaccinia
C3L
VCP
4 SCRs, secreted, binds, and
C48-binding protein
Variola
D15L
SPICE
inhibits C4B and C3B,
binds heparan sulfate
?
Vaccinia
B5R
4 SCRs, EEV class I membrane
Complement control
42-kD protein
?
Variola
B6R
glycoprotein, for virus egress
proteins
IFNα/β BP
Binds to and inhibits IFN-α
Interferon
Type 1 IFN
Vaccinia
B18R
IFN receptor
PKR
Vaccinia
K3L
Binds PKR, inhibits
phosphorylation of eIF-2α,
Variola
C3L
K3L protein
Swinepox
K3L
leads to IFN resistance
dsRNA
Vaccinia
E3L
Binds dsRNA, nuclear
E3L protein
Variola
E3L
localization, inhibits activation
of PKR, leads to IFN resistance
IFN-γ
Myxoma
T7
Vaccinia
B8R
vIFN-γR
IFN-γ receptor
Secreted, binds and inhibits
Variola
B8R
IFN-γ
Swinepox
C61
vIL-1β
IL-1β receptor
Cytokine receptor homologues
Vaccinia
B15R
Secreted glycoprotein, binds, and
inhibits IL-1β
Cowpox
B14R
receptor
Myxoma
T2
Vaccinia
G2R
vTNF R
Secreted, binds and inhibits
TNF receptor
TNF-α, TNF-β
Variola
C22L
(CrmB)
Cowpox
crm B
Variola
B6L
Secreted, binds soluble IL-18,
hIL-18 BP
Cowpox
C8L
vIL-18BP
inhibits induction of IFNγ
MCV
MC054
Cytokine homologues
Orf
???
vIL-10
Secreted, binds to IL-10 receptors
IL-10
on inflammatory cells, blocks
activation
CC-chemokine inhibitors
Myxoma
p35
T1 and T7
Secreted, bind to CC-chemokines,
None
Vaccinia
inhibit binding of chemokines
Variola
to heparan sulfate
Cowpox
Serine protease inhibitors
Myxoma
M152R
Serp-2
Block serine proteases
SERPIN
Cowpox
crmA
Crm A
intracellularly, reduce
Vaccinia
B14R
SPI-1
inflammation, inhibit ICE,
prevent apoptosis
Myxoma
Serp-1
Secreted, binds to proteases like
SERPIN
plasmin, thrombin
Abbreviations: MCV, molluscum contagiosum; SCR, 60 amino acid sequence called: "Short consensus repeat"; EEV, extracellular enveloped virions;
PKR, dsRNA-dependent protein kinase; IFN, interferon; SERPIN, serine protease inhibitor superfamily; VCP, vaccinia complement control protein;
BP, binding protein.
Source: Adapted from reviews by Tortorella et al. (2000), by Smith and Kotwal (2002), and by Seet et al. (2003).
genes leads to an increase in the virulence of the virus. The
for many, perhaps all, virus replication is enhanced by the
increased virulence appears to result from a more severe
expression of increased amounts of the cytokine or chemo-
inflammatory response to virus infection.
kine, in contrast to the ablation of the activity of other cytokines
or chemokines by virus-encoded receptors described in
the previous section. As examples, HHV-8 produces three
Secretion of Virokines
chemokines and one cytokine (IL-6), and Epstein­Barr
Many beta- and gammaherpesviruses secrete cytokine
virus encodes a homologue of IL-10. The chemokines may
or chemokine analogues, called virokines. The full range of
serve to attract target cells, since these viruses infect B
activities of these products is unknown, but it appears that
cells. IL-6 and IL-10 are necessary for the growth of B cells
img
TABLE 10.15 Viral Interferon Antagonists of Negative-Strand RNA Viruses
Virus
Viral protein
Family
Genus
Species
involved
Effect of antagonist
Inhibit IFN induction; downregulate IRF-3, IRF-7, NF-κB;
Orthomyxoviridae
Influenzavirus A
FLUAV
NS1
inhibit activation of PKR
ML*
Thogotovirus
THOV
Blocks transcriptional activation of IFN
Paramyxoviridae
Rubulavirus
Mumps, SV5
V
Targets STAT1 for proteasome degradation
Henipavirus
Nipah
V
Inhibits IFN signaling
Respirovirus
Sendai
C proteins
Inhibit IFN signaling
Pneumovirus
HRSV
NS1 and NS2
Mechanism unknown; both proteins needed
Rhabdoviridae
Vesiculovirus
VSV
M
Inhibits cellular mRNA synthesis and translation, hence
inhibits IFN synthesis
Filoviridae
Ebolavirus
ZEBOV
VP35
Inhibits IFN induction
Bunyaviridae
Bunyavirus
BUNV
NSs
Inhibits IFN induction
Tospovirus
TSWV
NSs
Inhibits RNA silencing in plants
Abbreviations: FLUAV, influenzavirus A; THOV, Thogotovirus; ML* is a 38 amino acid carboxyl terminus extended form of M from alternative splicing;
HRSV, human respiratory syncytial virus; VSV, vesicular stomatitis virus; ZEBOV, Zaire ebolavirus; BUNV, buyamwera virus; TSWV, tomato spotted
wilt virus.
Source: Data from Garcia-Sastre (2004).
and presumably serve to expand the target cell population.
Using improved algorithms for predicting miRNA genes
Furthermore, as described earlier, these cytokines skew the
in nucleotide sequences, viral genomes have been searched
immune response toward a B-cell response, helped by TH-2
for likely miRNA sequences. It seems probable that viruses
cells, and away from a CTL response, helped by TH-1 cells.
might use RNAi strategies to downregulate cellular genes,
Thus, while expanding the number of host cells available
especially cellular genes involved in defending the host from
for infection by the virus, these cytokines also depress the
viral invasion. miRNA sequences have been found in sev-
number of CTLs that control the infected cell population.
eral different families of viruses and many of these predicted
pre-miRNA sequences have been shown to be expressed in
virus-infected cells and, at least in some cases, to be effi-
Viral Use and Misuse of Gene-Silencing
cient substrates for processing by DICER. A sampling of
Pathways
such miRNAs is shown in Table 10.16. Although the cellular
As has been noted earlier, for almost all defense mecha-
targets for most miRNAs that have been identified are not
nisms of a host cell or organism against assault by viruses,
known, in three cases: the herpes simplex virus latency tran-
the viruses have evolved counterdefenses, and the RNA
script, the adenovirus VAI and VAII RNAs, and miRNAs
interference pathway is no exception. Some viruses encode
encoded by SV40, the function of the miRNAs has been
suppressors of RNA silencing or SRS proteins. Others
established, as described next.
encode miRNAs that appear to jam the pathway and prevent
For herpes simplex virus, it has long been known that
it from interfering with virus replication. Still other viruses
only a single viral transcript, from the LAT gene, was essen-
go a step further and encode miRNAs that use the gene-
tial for maintenance of latent infection of neurons. The gene
silencing pathway to regulate their lifecycle or to silence
appeared to be transcribed into a 2-kb long-lived RNA that
cellular defense mechanisms. An overview of the little that
was retained in the nucleus, but no protein product was ever
is currently known in a rapidly developing field is given in
identified. It was shown that LAT promoted neuronal sur-
Table 10.16.
vival and inhibited apoptosis of infected neurons. Recent
Viruses in four different families have been shown to
studies have shown that LAT mRNA contains a dsRNA
encode SRS proteins. Studies have been done in plants,
stem-loop structure that the host cell recognizes as a pre-
insect cells, and mammalian cells, and it appears that SRS
miRNA and processes to miR-LAT. miR-LAT functions as
proteins are widely used in the virus world. These SRS pro-
a gene silencer and promotes degradation of two cellular
mRNAs, those for TGF-β and SMAD3, both of which are
teins have been shown to inhibit degradation of viral RNA
during virus infection.
involved in induction of apoptosis. Thus, miR-LAT keeps
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