(Journal of Leukocyte Biology. 2002;72:429-439.)
© 2002
by Society for Leukocyte Biology
The viral manipulation of the host cellular and immune environments to enhance propagation and survival: a focus on RNA viruses
Surendran Mahalingam*,
Jayesh Meanger
,
Paul S. Foster* and
Brett A. Lidbury
* Division of Molecular Biosciences, The John Curtin School of Medical Research, The Australian National University, Canberra;
Macfarlane Burnet Institute for Medical Research and Public Health, Fairfield, Victoria, Australia; and
Gadi Research Centre, Division of Science and Design, University of Canberra, Australia
Correspondence: Surendran Mahalingam, Ph.D., Division of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200 Australia. E-mail: Surendran.Mahalingam{at}anu.edu.au
 |
ABSTRACT
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Virus infection presents a significant challenge to host survival. The
capacity of the virus to replicate and persist in the host is dependent
on the status of the host antiviral defense mechanisms. The study of
antiviral immunity has revealed effective antiviral host immune
responses and enhanced our knowledge of the diversity of viral
immunomodulatory strategies that undermine these defences. This review
describes the diverse approaches that are used by RNA viruses to trick
or evade immune detection and response systems. Some of these
approaches include the specific targeting of the major
histocompatibility complex-restricted antigen presentation pathways,
apoptosis, disruption of cytokine function and signaling, exploitation
of the chemokine system, and interference with humoral immune
responses. A detailed insight into interactions of viruses with the
immune system may provide direction in the development of new vaccine
strategies and novel antiviral compounds.
Key Words: transcription factors • apoptosis • immune modulation • cytokines • chemokines • antibody • HIV • antigen processing • antigen presentation • immune evasion
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INTRODUCTION
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Viruses serve as parasites and genetic elements in their hosts and
drive the evolutionary process [1
]. Not only do they
have considerable plasticity, enabling them to evolve in new
directions, but their genetic and metabolic interactions with cells
uniquely position them to mediate subtle, cumulative evolutionary
changes in their hosts as well [1
]. The past decade has
seen an explosion of interest in mechanisms of immune evasion and host
manipulation by viruses. The intense focus stems from a desire to gain
a fundamental understanding of the complexities of virus-host
interactions, mechanisms of viral pathogenesis, as well as a reflection
through viral evasion mechanisms of key antiviral immune pathways and
cellular functions. Understanding how viruses manipulate cells may also
provide some important insights into new approaches to rational drug
design and vaccines. As a measure of the activity of this field, many
outstanding reviews have already been written on this subject
[2
3
4
]. These past reviews summarize a vast array of
strategies that viruses use in their quest to avoid immune detection
and effect. The number of strategies uncovered has allowed for a
classification of viral immune avoidance mechanisms into groupings,
such as "viral inhibitors of antigen presentation," "viral
inhibitors of humoral immunity," "viral interference of
interferon," "modulators of cytokine and chemokine activity," and
"inhibitors of apoptosis" [3
4
5
] (see below). It is
clear from such classifications that viruses have "learned" to
target all arms of the immune response as well as normal cellular
processes, such as apoptosis, during their long co-evolutionary host
relationships. As such strategies are used by viruses, we also accept
that the immune response has evolved more effective tools with which to
repel invading pathogens; hence, we often use an "arms race"
metaphor to describe virus-host interactions.
Much of the focus has been on large DNA viruses, which are thought to
have "stolen genes from the host that were subsequently modified for
the benefit of the virus" [4
, 6
] in
addition to possibly developing some nonhost homologous genes, which,
through the co-evolutionary relationship, have also been beneficial to
the virus, subsequently selected for and exploited. The case for the
smaller genome RNA viruses is emerging, but provides fewer examples of
immune evasion techniques. The fundamental molecular biology of RNA
viruses restricts their capacity to build large genomes with low
fidelity RNA polymerases [4
], so therefore leaves
little if any genomic capacity to develop individual evasion genes.
This molecular scenario implies that small genome RNA viruses have
needed to be in some ways more ingenious in surviving the rigors of the
mammalian immune response. A theme of this review will be to look more
closely at "tricky" RNA virus evasion strategies and explore how it
has been possible for them to survive long term. In this context, we
will particularly consider the impact of host immune proteins
manipulation by viruses and how this allows a virus to transform a host
cellular environment to meet its needs, often at the expense of the
host’s requirements.
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VIRAL GENETIC "BUDGETS" AND THE "COST TO THE INFECTED HOST"
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We have recently proposed a theory on the "genetic budget of
viruses and the cost to the infected host" [7
]. This
theory proposes that large genome DNA viruses, as alluded to in the
introduction, have developed an "acquisition" strategy for survival
in the hostile host environment, while small genome RNA viruses have
survived via "erroneous replication" strategies. The central thrust
of the theory posits that the acquisition strategy is less likely to be
detrimental to the infected host, as the close genetic relationship has
allowed the virus to very precisely target host pathways and functions.
This has resulted in a much-reduced impact on the infected host, on
whom the virus ultimately depends for survival. Conversely, erroneous
replication strategies used by RNA viruses are not specifically
tailored to host responses, leading to many random virus mutations that
are more likely to result in inappropriate or overzealous host
responses and have a detrimental effect on the host while a
relationship equilibrium is negotiated.
In the context of this review, we will consider the following human
disease-causing RNA viruses: measles virus (MV;
paramyxoviridae), influenza (orthomyxoviridae),
respiratory syncytial virus (RSV; paramyxoviridae), ebola
virus (EV; filoviridae), Ross River virus (RRV;
alphaviridae), hepatitis C virus (HCV;
flaviviridae), and HIV (lentiviridae). These
examples comprise four negative-strand RNA viruses (virus with a
single-stranded RNA genome of the opposite polarity as mRNA), two
positive-strand viruses (virus with a single-stranded RNA genome of the
same polarity as mRNA), and one retrovirus (virus with two copies of
single-stranded RNA genome of the same polarity as mRNA), respectively.
With the possible exception of MV, the RNA virus examples mentioned
above represent significant challenges to the formulation of long-term
and effective vaccines. What special characteristics of RNA virus
immune evasion need to be better understood before effective vaccines
can be developed?
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STRATEGIES OF RNA VIRUS IMMUNE EVASION
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Antiviral defense mechanisms are numerous and range from
relatively primitive, constitutively expressed, nonspecific defenses to
sophisticated mechanisms that are specifically induced in response to
viral antigens [8
]. Described below are several
strategies that RNA viruses have evolved to counteract the
various compartments of these defense mechanisms (Table 1
).
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Table 1. Summary of Strategies Employed by RNA Viruses to Avoid Immune Detection
and/or Clearance by the Infected Host
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Interference with antigen presentation
T cells recognize antigens in association with host major
histocompatibility complex (MHC) molecules on antigen-presenting cells.
The MHC class I-restricted CD8+ cytotoxic T lymphocytes
(CTLs) recognize antigenic peptides synthesized within target cells.
The role of CD8+, MHC class I-restricted CTLs is critical
in the recovery from primary virus infection [9
]. On the
other hand, class II MHC-restricted CD4+ T helper (Th)
cells recognize peptides derived exogenously. CD4+ T cells
are activated during virus infections and can therefore influence
antibody production, CTL, and macrophage activity as well as production
of antiviral cytokines [10
]. Expression of these cell
surface molecules is important to initiate and sustain an effective
immune response. It is not surprising that the HIV has evolved
strategies to down-regulate the surface expression of class I, class
II, and CD4 molecules [11
]. Down-regulation of CD4
expression prevents activation of infected Th cells via the MHC class
II pathway and thus helps virus evade immune detection.
Inhibition of cytokine action
Cytokines are the messenger molecules that play an
important role in inflammation, cellular activation, proliferation, and
differentiation [12
]. Their effects involve a wide range
of mechanisms including alteration of the expression of MHC molecules,
adhesion molecules, and costimulatory molecules and direct activation
or deactivation of immune cells [8
]. Cytokines such as
interferons (IFNs), tumor necrosis factor (TNF), and interleukin-12
(IL-12) are frequently targeted by viruses to divert their potent
antiviral effects. In this context, we will briefly describe the IFN
system. The IFN response represents an early host defense mechanism
against viral infections (inhibitory against a number of DNA and RNA
viruses) and is known to be an important component of innate immunity
[13
]. The antiviral activity of IFNs, the property that
led to their discovery almost 40 years ago, is mediated by a number of
intracellular, antiviral pathways that are activated by IFNs
(Fig. 1
) [14
]. The binding of IFN to its receptor results
in the phosphorylation of transcription factor complexes [signal
transducer and activator of transcription (STAT) complexes], which
translocate to the nucleus and bind to the transcription coactivator
elements on order to stimulate the downstream, antiviral genes.
Examples of these antiviral genes are IFN-ß, RNA-dependent protein
kinase (PKR), 2' 5' A synthetase, nitric oxide (NO), and secondary
transcription factors [e.g., IFN-regulatory factor 1 (IRF-1), IRF-3,
and IRF-7]. The latter factors are also important for the
transcription of many antiviral genes. These IFN-inducible proteins
mediate antiviral effects by interfering with the regulation of viral
and cellular macromolecular synthesis and degradation. Given the
efficiency by which the IFN system can inhibit replication of a
multitude of viruses, it is perhaps not surprising that some viruses
have evolved mechanisms to evade this host defense. Several RNA viruses
are known to inhibit the IFN system by different mechanisms including
targeting the IFN-inducible protein PKR and 2' 5' A synthetase as well
as suppression of primary (STAT complexes) and secondary (IRFs)
transcription factor activation.
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Figure 1. The IFN- and IFN- JAK-STAT signaling cascades. IFN- stimulates
the induction of immediate early genes (IEGs) through a signaling
pathway that employs Jak-1, Jak-2, Stat-1 and Stat binding elements.
Activated Stat1 homodimer translocates to the nucleus where it binds
the gamma-activation site (GAS) and activates transcription of a subset
of genes that includes the PKR, 2' 5 A synthetase, IRF-1, and Stat1.
Newly generated IRF-1 bind to an IFN-response stimulation (IRS) site
and activate (in concert with other factors) transcription of genes as
inducible nitric oxide synthase (NOS2) and IFN-ß. In contrast,
IFN- stimulates the induction of immediate early genes through a
pathway that employs Jak-1, Tyk-2, Stat-2, IRF-9/p48, and the
interferon-stimulated response element (ISRE). Phosphorylated
Stat1/Stat2-heterodimer in concert with IRF-9 (p48) forms the
interferon-stimulated gene factor 3 (ISGF3) complex that binds to the
element ISRE and increases transcription of a subset of genes that
includes the PKR, IRF-1, IRF-7, 2' 5' A synthetase and Stat1.
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Modulation of chemokine activity
Leukocyte trafficking to sites of viral infection is an important
component of the early host inflammatory response, and chemokines are
key effector molecules that orchestrate this process [15
,
16
]. They are produced in response to exogenous stimuli
such as viruses and bacterial lipopolysaccharide (LPS) and endogenous
stimuli such as IL-1, TNF, and IFNs [17
]. The chemokine
superfamily mediates development and recruitment of immune cells to
sites of insult by signaling through a family of G protein-coupled
receptors. Given that the virus relies on a cell to replicate,
reproduce, and survive, it makes sense that RNA viruses, like many DNA
viruses, would need to modulate chemokine action to encourage migration
of suitable cells to the site of infection. There is no doubt
that chemokine and chemokine receptors are critical for defense against
viruses; however, it is also clear that viruses such as HIV and
RSV have evolved to accommodate the workings of the host chemokine
system.
Modulation of apoptosis
Programmed cell death, or apoptosis, is a natural cellular
response to injury or virus infection. Following viral infections, T
cells and natural killer (NK) cells are triggered to secrete cytotoxic
cytokines such as TNF and lymphotoxin [18
]. In addition,
contact between these immune cells and virally infected cells results
in the release of perforin and granzyme proteins or delivery of FasL to
Fas on the target cell [18
]. Apoptosis before virus
replication has been completed would be a disastrous outcome for the
virus; consequently, viruses such as HIV have evolved means to defuse
this pathway to create a suitable environment for their replication.
Manipulation of humoral immunity
Antibodies are important in preventing reinfection with many
viruses. Antibody-mediated mechanisms that are thought to control virus
infections include the neutralization of virus particles and the
cytolysis of antibody-coated, infected cells [19
]. The
killing of virus-infected cells can also be mediated by the binding of
complement to antibody on virus-infected cells. The importance of
complement in virus infection is also reflected by the ability of some
viruses to block the complement pathway. The humoral immune response
relies on the ability to effectively process and eliminate immune
complexes, a process in which complement and Fc receptors play key
roles. We discuss some examples of viruses that manipulate this
response.
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NEGATIVE-STRAND RNA VIRUSES
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Measles virus (MV)
MV is a highly contagious agent that is responsible for many
childhood deaths, particularly in the developing world (>1 million
deaths per annum in children in the Third World) and is transmitted via
respiratory/oral secretions. After initial infection, virus can
disseminate to other areas of the body. Of particular concern are
neurological infections that may lead to subacute sclerosing
panencephalitis some years after the primary infection. Despite the
generation of a vigorous immune response against MV, immunity to other
pathogens is depressed. This generalized immunosuppression allows the
establishment of opportunistic infections and results in many
complications associated with measles [20
].
Recent findings have revealed several mechanisms on MV-mediated
immunosuppression. For instance, it has been demonstrated in neuronal
tissue that MV-RNA fails to activate double-stranded, RNA-activated
PKR. PKR is believed to be a key component in the control of protein
synthesis in virus-infected cells. Induction of PKR by IFNs leads to
phosphorylation of eukaryotic initiation factor 2 (eIF2), which
inhibits protein synthesis and protects cells from virus infection
[14
]. The inability to activate this antiviral protein
leads to virus-mediated disruption to transcription factor nuclear
factor (NF)-
B binding, subsequent blockage to the IFN-ß response,
and ultimately a lack of MHC class I expression [21
].
The authors suggested that this mechanism allowed the virus to hide and
persist in neuronal tissue by escaping the attention of CTLs. As
neuronal cells apparently lack alternative activation pathways for
IFN-ß, this could explain why long-term disease might manifest in the
brain. Furthermore, the MV-mediated disruption to type I IFN induction
has been found not only to be restricted to neuronal cells, but also in
phytohemagglutin-stimulated peripheral blood lymphocytes
[22
]. At the time of writing this review, the viral
product responsible for type I IFN interference was not known, although
it has been speculated based on evidence from studies on the close MV
relative Sendai virus that the nonstructural C protein is a likely
candidate [22
].
The MV repertoire also includes the blockage of IL-12 induction in
macrophages via MV hemagglutinin (HA) binding to the cellular
complement receptor CD46 [3
, 4
,
23
, 24
]. This may result in the suppression
of several facets of the immune component such as IFN- secretion by
immune cells, development of Th1 responses, enhancement of lytic
activity in NK cells, and CTL [23
24
25
].
Furthermore, work by Ravanel and colleagues [26
] have
shown that MV nucleoprotein (NP) can bind to the surface of B cells. It
was demonstrated that the murine and human Fc- receptor II
(FcRII) are receptors for MV-NP and that the binding of NP inhibits
immunoglobulin synthesis by activated B cells.
Influenza virus
Influenza virus remains a significant cause of morbidity and
mortality worldwide, particularly in the elderly and immunosuppressed
individuals. Up to 20% of the population can become ill during a
single epidemic, with 50,000 deaths per year occurring in the United
States alone [27
].
The fragmented influenza genome allows genetic recombination within and
between species (humans, pigs, poultry), leading to the problems of
"antigenic drift" and "antigenic shift." The difference between
antigenic drift and antigenic shift is as follows: antigenic drift
refers to point mutation in major epitopes of HA that are recognized by
immune cells and prevents highly efficient immune clearance of virus;
antigenic shift is the reassortment of genes between influenza viruses
that infect different species of host that result in major changes in
the viral HA, which prevents existing antibodies from clearing the
virus rapidly. Problems of antigenic drift manifest, for at-risk
groups, as a yearly requirement to be vaccinated. Long-term immunity
does not significantly develop against influenza via wild-infection or
vaccination. The problems associated with antigenic shift can be
catastrophic as changes to viral antigenic properties are so pronounced
that large proportions of the population may have no immunity at all to
the new strain, which could lead to serious pandemics.
As a leading infectious disease concern, influenza has traditionally
been at the forefront of virus pathogenesis research. Beyond the
already appreciated problems of antigenic shift and drift, recent
studies have shown that the sole nonstructural protein of influenza A
virus, NS1, is a key virulence factor for its ability to inhibit type I
IFN (IFN-/ß) responses in the infected host (Fig. 2
) [28
, 29
]. This ability of NS1 to
block IFN-/ß activation has been found to be associated with the
perturbation of PKR activation [30
]. It is known that
transactivation of the IFN-ß promoter depends on NF-B and several
other transcription factors. Further investigation subsequently found
that the activation of IRF-3 and NF-B was also inhibited by NS1
[31
, 32
]. This evidence points to viral
proteins performing dual or multiple functions; in addition to its
polymerase activity, NS1 has been shown to be capable of perturbing
type I IFN expression via compromising transcriptional activation
pathways in infected cells. Consistent with these observations, it was
also demonstrated that infection of tissue culture cells with deleted
NS1 virus (delNS1), but not with wild-type influenza A virus, induced
high levels of mRNA synthesis from IFN-/ß genes, including IFN-ß
[30
]. Interestingly, cells infected with delNS1 virus
showed high levels of NF-B activation compared with those infected
with wild-type virus [32
].
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Figure 2. RNA viruses subversion of the IFN system. The figure shows various
strategies that RNA viruses use to antagonize the IFN system. Dotted
arrow represents suppression or inhibition [29
].
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Another approach used by influenza virus to inhibit PKR-mediated
phosphorylation of eIF2 is through the activation of a host PKR
inhibitory protein, P58IPK [33
,
34
]. In normal conditions, P58IPK is bound to
I-P58IPK in an inactive complex. However, this complex is
disrupted in cells infected with influenza virus resulting in the
release of P58IPK, which then interacts with PKR and
inhibits its kinase activity.
Respiratory syncytial virus (RSV)
RSV is the principal etiological agent of bronchiolitis and
pneumonia in infants and young children worldwide, causing an estimated
4500 deaths and 91,000 hospitalizations annually in the United States.
RSV is also responsible for an estimated 3.3 million cases of
respiratory tract diseases in the elderly annually in the United
States. Thus, there is an urgent need for a safe and effective RSV
vaccine. Protective immunity against RSV is provided by
virus-neutralizing antibodies against the surface fusion and attachment
(G) proteins.
More recently, Tripp and colleagues [35
] have made an
exciting discovery on chemokine mimicry by RSV. They reported that the
G glycoprotein (GP) of RSV has structural similarities to a
CX3C chemokine Fractalkine and binds to cells in a manner
similar to Fractalkine through the chemokine receptor
CX3CR1. Interestingly, this interaction appears to have two
important functions in RSV infection [35
]. First, the
interaction of the CX3C motif on the G GP with
CX3CR1 on cells is capable of inducing migration of
leukocytes and thus modulating the immune response (Fig. 3 a
). Second, G GP binding via CX3CR1 appears to
facilitate infection. In this regard, it is likely that G GP of RSV
competes with Fractalkine for binding to CX3CR1 on cells
and evades Fractalkine-mediated immune responses, which result in
delayed virus clearance.
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Figure 3. Strategies used by viruses to subvert the host chemokine system. (a)
RSV: Virus-encoded, chemokine-like protein that can compete with host
chemokines for binding to host chemokine receptor. This process can
result in the delay in viral clearance as well as enhancement of viral
infectivity. (b) HIV: Virus-encoded, chemokine-like protein (Tat) by
HIV that can promote chemotaxis of monocytes/macrophages to enhance
infection.
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In the context of IFN antagonistic effects, like influenza, bovine RSV
NS1 and NS2 proteins have been shown to cooperatively antagonize an
/ß IFN-induced antiviral response [36
]. Although
not known, it is possible that the NS1 and NS2 proteins of human RSV
may be mediating similar processes (Klaus Conzelmann, personal
communication).
Ebola virus (EV)
EV, a member of the Filoviridae, burst from obscurity with
spectacular outbreaks of severe, haemorrhagic fever. It was first
associated with an outbreak of 318 cases and a case-fatality rate of
90% in Zaire; it caused 150 deaths among 250 cases in Sudan.
Explanations for its immense virulence and detrimental impact on the
host are slowly emerging, with viral genes and proteins observed to
alter host responses. The property of type 1 IFN antagonism described
above for influenza has also been identified for EV and has been
attributed to the viral VP35 protein [37
], suggesting
again the roles for proteins encoded by small, genome-size RNA viruses
in cell interactions and immune evasion. In addition to VP35, the EV GP
has been recognized as a key determinant of immune evasion capacity.
Immune evasion, cell-altering activities recognized thus far are
down-regulation of ß1 integrin [38
], significant
reductions in complement receptor type 3/FcRIIIB linkage in
neutrophils [39
], and suppression of mitogen-stimulated
lymphocyte proliferation [40
]. Furthermore, the mucin
domain of EV GP has been proposed as the mediator of viral
pathogenicity, with studies showing enhanced cytotoxicity and vascular
permeability in endothelial cell cultures and blood vessel explants
[41
]. Recently, it was determined that this virus
envelope GP binds to the human folate receptor as a mediator of entry
[42
]. With such an array of activities attributable to
individual viral proteins such as GP, vaccination strategies focused on
viral determinants will be very challenging for EV, particularly with
an inactivated virus capable of eliciting reactions that are
potentially damaging to the host [40
].
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POSITIVE-STRAND RNA VIRUSES
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Ross River virus (RRV)
RRV is an indigenous Australian alphavirus and the agent
responsible for the greatest incidence of arboviral disease in
Australia. Disease resulting from infection is not fatal but involves a
syndrome of symptoms, which include arthritis/arthralgia, myalgia,
lethargy, and/or rash. These symptoms are often episodic but can be
responsible for persistent debilitation for over 12 months after
primary infection [43
].
Macrophage and monocyte infiltrates have been associated with human
disease [43
, 44
], and F4/80+
cells have been recently identified as the cellular agent of severe
muscle damage in RRV-infected mice [45
]. Furthermore,
RRV grows in human and murine macrophages after infection via a
"natural" cellular receptor or through FcRs involving
"antibody-dependent enhancement" (ADE) mechanisms of infection
[45
, 46
]. In studies using LPS-stimulated
murine macrophage cultures (RAW 264.7), RRV was found to specifically
ablate at the RNA and protein level the expression of the antivirals
TNF and inducible NO synthase (NOS2) post-ADE infection
[47
]. Similar to IFN evasion mechanisms described
earlier for measles and influenza infections, the ablation of TNF and
NOS2 production by RRV was found to be associated with the perturbation
of NF-B (Fig. 4
) and STAT 1 complexes. These observations explained why RRV could
grow to high titers in macrophages despite LPS stimulation and may
provide insights into ADE associated with other human, disease-causing
viruses. In this regard, ADE of dengue virus infections has long been
implicated in the pathogenesis of dengue hemorrhagic fever
[48
]. Interestingly, a recent study by Yang and
colleagues [49
] showed suppression of IFN- production
in the ADE of heterotypic dengue infections. However, others have
reported an increase in IFN- production in dengue infections
[50
]. The reasons for these differences are not clear
but may be related to experimental conditions and cells used in these
studies.
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Figure 4. ADE of RRV infection in vitro. Suppression of NF-B complex in
LPS-stimulated macrophages infected with RRV in the presence of
anti-RRV antibody. NMS, normal mouse serum.
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The RRV gene/protein responsible for the ablation of antiviral factors
post-ADE infection is still unknown. There has been traditional
interest in the structural protein E2 as important to RRV virulence and
antibody evasion [51
, 52
], but based on the
observations of NF-B and IRF disruption for influenza, the role of
nonstructural viral genes/proteins will also need to be closely
considered in future studies on antiviral evasion by RRV.
Hepatitis C virus (HCV)
HCV is an emerging virus of great medical importance and almost
always causes chronic infections. The high incidence of HCV persistence
after infection suggests that this virus has evolved mechanisms in
order to evade the host response. Little is known about the mechanisms
that allow HCV to achieve lifelong persistence in infected individuals
because the lack of an effective in vitro culture system has impaired
virologic studies. However, recent discoveries may explain the
long-term persistence of HCV in the host. One hypothesis to explain
this phenomenon is that HCV escapes immune recognition through its
intrinsic hypermutability. Here, altered peptide ligands with
antagonistic activity can be an effective mechanism to shut off
antiviral CTL responses to HCV [53
]. Furthermore, as
observed in HIV infection (see below), evasion from CD4+ T
cell responses may be particularly effective during HCV infection, as
strong CD4+ T cell responses have been associated with an
improved disease outcome [54
55
56
]. It has also been
shown that HCV core protein can interact with cellular RNA helicases
and potentiate TNF-mediated triggering of NF-B activity, and may
block proapoptotic signals in HCV-infected cells [57
,
58
]. It is believed that signaling through the TNF
receptor may be partly responsible for the chronic state of HCV
infection, as the core protein alone when administered to mice results
in general immunosuppression [59
]. HCV may also suppress
immune response(s), leading to dampening of cellular immunity. This
observation is supported by recent studies demonstrating that vaccinia
virus (VV) expressing HCV structural protein can suppress host immune
responses to VV by down-regulating viral-specific CTL responses and
cytokine production. Using a series of VV recombinants expressing
various C-terminally truncated polyproteins, this immunosuppressive
effect was mapped to the core protein [59
].
One of the nonstructural proteins of HCV, NS5A, has been shown to bind
and inhibit PKR [60
], while another study showed that
the HCV envelope protein E2 contains a sequence identical with
phosphorylation sites of PKR and eIF2 [61
]. E2
inhibited the kinase activity of PKR and blocked its inhibitory effect
on protein synthesis and cell growth. Furthermore, the expression of
NS5A in human cells can induce IL-8 expression, and this effect
correlated with the inhibition of antiviral effects of IFN- via
reduced 2' 5' A synthetase activity [62
,
63
]. Optimal activity of 2' 5' A synthetase is important
for the activation of latent RNase (RNase L), which induces the
degradation of RNAs followed by inhibition of protein synthesis.
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RETROVIRUS
|
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Human immunodeficiency virus (HIV)
HIV is the viral agent spread by contact with infected blood or
semen that causes AIDS. Although rates of infection have stabilized in
many western countries, this virus is poised to inflict an enormous
disease impact on many African and some Asian communities. Therefore,
HIV/AIDS remains a primary worldwide health concern.
HIV induces a strong antiviral response, while simultaneously and
progressively disrupting the immune system. The question remains as to
how HIV manages to persist in the face of such a strong antiviral
response. One of the answers lies in the ability of HIV to mutate key
epitopes, which are recognized by the immune response ("antigenic
variation"). The range of immune evasion and host-altering mechanisms
used by HIV have been the subject of immense scientific interest, as
clues are sought into basic questions of pathogenesis and the virus’s
resistance to the formulation of effective vaccine and therapeutic
approaches. As summarized in Table 1
, HIV has the most extensive
repertoire of immune-evasion tactics thus far identified, covering all
aspects of the host response to infection, from early type I IFN
activity to the disruption of MHC function. Corresponding knowledge of
the viral gene products responsible for the impact on host responses is
also quite extensive, and the HIV genes Tat, Nef, Env, and Vpu feature
prominently, thus further enhancing the earlier comments on the
amazing, multifunctional capacities of viral RNA genomes. As a
retrovirus, there is no guarantee that HIV will be a reliable guide to
immune evasion potentials across the broad range of RNA virus families,
but what HIV does emphasize is the enormous extent to which apparently
simple viruses have been able to combat the sophisticated mammalian
immune system.
There are several mechanisms that HIV uses to modulate immune
responses. For instance, the HIV-1 Nef, Env, and Vpu proteins are
engaged in down-regulating the expression of the surface CD4 molecule
[64
, 65
]. Because Nef is an early gene
product, it acts more rapidly. By contrast, Env and Vpu are late viral
proteins that modulate CD4 expression along its biosynthetic pathway.
Thus, the combined actions of Nef, Env, and Vpu almost completely
eliminate CD4 from the surface of HIV-1-infected cells
[11
, 66
]. Down-regulation of CD4 may also
prevent activation of infected Th cells via the MHC class II
antigen-presentation pathway and thus help the virus evade immune
detection. In addition, Nef protein is also capable of down-regulating
human leukocyte antigen (HLA) class I molecules, which can result in
impaired CTL recognition in vitro (Fig. 5
) [67
]. Such events expose an infected cell to lysis
by NK cells. However, this does not appear to be the case, as HIV-1 Nef
leads to the down-regulation of HLA-A and HLA-B, but not HLA-C and
HLA-E [68
]; therefore, infected cells are protected from
NK-mediated destruction via HLA-C and HLA-E expression. The elements on
HIV Nef that are involved in the selective down-regulation of HLA
molecules are different from the ones that are involved in the
Nef-dependent CD4 down-regulation, suggesting a dichotomous effect of
Nef on these two cell molecules [69
, 70
].
View larger version (24K):
[in this window]
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|
Figure 5. Nef-mediated MHC-I down-regulation. (a) In the absence of Nef,
prominent expression of MHC class I-presenting viral peptides results
in an efficient lysis of infected cells by CTLs. (b) In the presence of
Nef, lack of MHC-I expression results in CTLs unable to recognize
infected cells and therefore is protected from lysis.
|
|
The Tat protein of HIV, which is expressed early in the viral life
cycle, also influences a variety of immune regulatory processes through
diverse mechanisms. The HIV-1 Tat protein is a potent chemoattractant
for monocytes [71
]. It was shown that Tat displays
conserved amino acids corresponding to critical sequences of the
chemokines. This viral protein serves to recruit monocytes/macrophages
toward HIV-producing cells and facilitates activation and infection
(Fig. 3b) . The reported down-regulation of HLA class I and class II
molecules by Tat remains controversial, with some investigators
reporting no effect and others observing an effect
[72
73
74
]. Tat may also have direct effects on the
development of B cell lymphomas and display a profound impact on the
replication of viruses such as Kaposi’s sarcoma herpesvirus, human
papillomavirus, and human papovavirus [70
]. These
viruses themselves have immune-modulating mechanisms and thereby
contribute to HIV-associated diseases.
HIV-infected cells contain a number of molecules capable of modulating
the activity of PKR and 2' 5' A synthetase. The HIV-1 transactivation
response (Tar) RNA binding protein was shown to be a potent inhibitor
of double stranded RNA-mediated activation of PKR [75
].
On the other hand, Tar RNA has been reported to bind and activate 2' 5'
A synthetase in vitro [76
]. However, this activation by
Tar was inhibited by Tat protein [77
].
In the mid 1990s, virus interaction with the chemokine system took
center stage after the discovery that HIV exploits chemokine receptors
as coreceptors for entry into CD4+ cells
[78
]. Structural proteins of HIV (gp120), by virtue of
its interaction with the cellular receptors for viral entry, may
influence the activity of cells expressing CD4, CCR5, and CXCR4. Beside
induction of apoptosis in human endothelial cells and CD4+
T cells, the binding of gp120 to chemokine receptors CCR5 and CXCR4 may
have functional consequences such as dysregulated lymphocyte homing or
neurodegenerative effects [79
]. Another study found that
recombinant gp120/gp41 complex (gp160) from macrophage-tropic HIV-1
induces a signal through CCR5 on CD4+ T cells and that this
envelope-mediated signal transduction induces chemotaxis of T cells
[80
]. This chemotactic response may contribute to the
pathogenesis of HIV in vivo by chemoattracting activated
CD4+ cells to sites of viral replication. HIV-mediated
signaling through CCR5 may also enhance viral replication in vivo by
increasing the activation state of target cells. Alternatively,
envelope-mediated CCR5 signal transduction may influence
viral-associated cytopathicity or apoptosis. It is clear that these
strategies point out the potential for viral gene products to alter
multiple steps in the host response(s) to infection with HIV.
|
THE PROSPECT OF EFFECTIVE VACCINES AGAINST DECEPTIVE RNA VIRUSES
|
|---|
It is clear that traditional vaccine strategies that rely on
generating antibody and/or CTL responses will not be sufficient to
combat elusive RNA viruses (examples of which have been highlighted by
this review) as a result of the evolved capacity of these viruses to
counter sophisticated immune responses [81
]. In fact, it
could be hypothesized that the application of ineffective
vaccine-mediated immune responses may hasten the evolution of
additional immune-evasion activities. The fundamental study of RNA
virus immune-evasion tactics may eventually expose viral weaknesses
that can be exploited by vaccines, but beyond such obvious conclusions,
innovative and lateral strategies must be identified. Such innovative
solutions will not eventuate without fuller appreciation of the nuances
of virus-host interaction. Future vaccines may not be only designed to
stimulate T-B lymphocytes, but may be targeted at the actual infected
cell or tissue to activate a natural, innate antiviral response before
infection is established. Also, stimulating or suppressing particular
receptors could aid the host response or diminish the ability of
viruses to penetrate cells.
What special characteristics of RNA virus immune evasion have we
learned that can be applied in the design of effective new generation
vaccines? As mentioned earlier in this review, the influenza A virus
NS1 protein exhibits IFN antagonist activity, allowing influenza virus
to replicate in IFN-competent systems. Talon and colleagues
[82
] have recently proposed an alternative, rational
approach to the design of live virus vaccines by alteration of viral
IFN antagonists. They reported that deletion of virally encoded IFN
antagonists or mutagenesis of these proteins to reduce activity can be
used as a general strategy to construct live viral vaccines that are
optimally attenuated and immunogenic. Indeed, these viruses show
significant growth attenuation in immunologically mature, embryonated
chicken eggs and in mice. Furthermore, they demonstrated that
immunization of mice with NS1-altered flu viruses provides protective
immunity in mice against the replication and/or pathogenicity of
wild-type influenza virus.
|
CONCLUDING REMARKS
|
|---|
Research studies conducted in the past several years have clearly
demonstrated how RNA viruses have evolved diverse mechanisms to evade
the host immune response. In summary, HIV has the broadest array of
immune evasion techniques so far identified, targeting humoral and
cell-mediated (via MHC perturbation) immunity, type I IFN activity and
cytokine/chemokine responses to infection. In the context of the
earlier discussed theory on the viral "genetic budget," it must be
considered that a virus-like HIV, which uses the faulty enzyme reverse
transcriptase in routine replication, has additional molecular
opportunities to develop via "erroneous replication" strategies an
expanded immune-evasion arsenal. It is likely that other RNA viruses
will have additional immune-evasion strategies identified in due
course, but whether nonretroviruses ultimately have the same range of
mechanisms to repel the host’s immune response will be decided only by
continuing investigations. Considering that the error rate introduced
by RNA polymerases is sufficiently high, however, it is highly possible
that other RNA viruses have the ability to develop multiple
immune-evasion strategies. Such a question will be ultimately answered
only once the full multifunctionality of viral RNA genomes is
completely realized. With such additional insight, traditional vaccine
strategies will be abandoned for many RNA viruses, challenging
scientists to devise new approaches that circumvent or in some way
neutralize the impact of viral evasion factors.
|
ACKNOWLEDGEMENTS
|
|---|
S. M. is a recipient of the Australian National Health and
Medical Research Council Peter Doherty Fellowship. We thank Mr. Geoff
Sjollema for excellent technical assistance.
Received January 31, 2002;
revised April 24, 2002;
accepted April 25, 2002.
|
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ABSTRACT
INTRODUCTION
