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(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{dagger}, Paul S. Foster* and Brett A. Lidbury{ddagger}

* Division of Molecular Biosciences, The John Curtin School of Medical Research, The Australian National University, Canberra;
{dagger} Macfarlane Burnet Institute for Medical Research and Public Health, Fairfield, Victoria, Australia; and
{ddagger} 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


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ABSTRACT
 
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
 
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"
 
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
 
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

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-{gamma} and IFN-{alpha} JAK-STAT signaling cascades. IFN-{gamma} 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-{alpha} 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.

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
 
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{alpha} (eIF2{alpha}), 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)-{kappa}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-{gamma} 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-{gamma} receptor II (Fc{gamma}RII) 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-{alpha}/ß) responses in the infected host (Fig. 2 ) [28 , 29 ]. This ability of NS1 to block IFN-{alpha}/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-{kappa}B and several other transcription factors. Further investigation subsequently found that the activation of IRF-3 and NF-{kappa}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-{alpha}/ß genes, including IFN-ß [30 ]. Interestingly, cells infected with delNS1 virus showed high levels of NF-{kappa}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 ].

Another approach used by influenza virus to inhibit PKR-mediated phosphorylation of eIF2{alpha} 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.

In the context of IFN antagonistic effects, like influenza, bovine RSV NS1 and NS2 proteins have been shown to cooperatively antagonize an {alpha}/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/Fc{gamma}RIIIB 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
 
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-{kappa}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-{gamma} production in the ADE of heterotypic dengue infections. However, others have reported an increase in IFN-{gamma} 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-{kappa}B complex in LPS-stimulated macrophages infected with RRV in the presence of anti-RRV antibody. NMS, normal mouse serum.

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-{kappa}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-{kappa}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{alpha} [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-{alpha} 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
 
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 ].



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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.


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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.


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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.


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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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REFERENCES
 
    1
  1. Lederburg, J. (1994) Emerging infections: private concerns and public responses ASM News 60,233
    2. 2
  2. Hayder, H., Mullbacher, A. (1996) Molecular basis of immune evasion strategies by adenoviruses Immunol. Cell Biol. 74,504-512[Medline]
    3. 3
  3. Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J., Ploegh, H. L. (2000) Viral subversion of the immune system Annu. Rev. Immunol. 18,861-926[Medline]
    4. 4
  4. Alcami, A., Koszinowski, U. H. (2000) Viral mechanisms of immune evasion Immunol. Today 21,447-455[Medline]
    5. 5
  5. Mahalingam, S., Karupiah, G. (1999) Chemokines and chemokine receptors in infectious diseases Immunol. Cell Biol. 77,469-475[Medline]
    6. 6
  6. Mahalingam, S., Karupiah, G. (2000) Modulation of chemokines by poxvirus infections Curr. Opin. Immunol. 12,409-412[Medline]
    7. 7
  7. Chaston, T. B., Lidbury, B. A. (2001) Genetic ‘budget’ of viruses and the cost to the infected host: a theory on the relationship between the genetic capacity of viruses, immune evasion, persistence and disease Immunol. Cell Biol. 79,62-66[Medline]
    8. 8
  8. Ramshaw, I. A., Ramsay, A. J., Karupiah, G., Rolph, M. S., Mahalingam, S., Ruby, J. C. (1997) Cytokines and immunity to viral infections Immunol. Rev. 159,119-135[Medline]
    9. 9
  9. Zinkernagel, R. M., Althage, A. (1977) Antiviral protection by virus-immune cytotoxic T cells: infected target cells are lysed before infectious virus progeny is assembled J. Exp. Med. 145,644-651[Abstract/Free Full Text]
    10. 10
  10. Doherty, P. C., Allan, W., Eichelberger, M., Carding, S. R. (1992) Roles of alpha beta and gamma delta T cell subsets in viral immunity Annu. Rev. Immunol. 10,123-151[Medline]
    11. 11
  11. Piguet, V., Schwartz, O., Le Gall, S., Trono, D. (1999) The downregulation of CD4 and MHC-I by primate lentiviruses: a paradigm for the modulation of cell surface receptors Immunol. Rev. 168,51-63[Medline]
    12. 12
  12. Pau, W. E. (1999) Fundamental Immunology 3rd ed. Lippincott-Raven New York.
    13. 13
  13. Vilce, J., Sen, I. C. (1996) Fields, B. N. Knipe, D. N. Howley, P. M. Chanock, R. M. Melnick, J. L. Monath, T. P. Roizman, B. Straus, S. E. eds. Interferons and Other Cytokines ,375-399 Lippincott-Raven Philadelphia.
    14. 14
  14. Samuel, C. E., Ozato, K. (1996) Induction of interferons-induced genes Biotherapy 8,183-187[Medline]
    15. 15
  15. Baggiolini, M. (1998) Chemokines and leukocyte traffic Nature 392,565-568[Medline]
    16. 16
  16. Mahalingam, S., Clark, K., Matthaei, K. I., Foster, P. S. (2001) Antiviral potential of chemokines Bioessays 23,428-435[Medline]
    17. 17
  17. Baggiolini, M., Dewald, B., Moser, B. (1997) Human chemokines: an update Annu. Rev. Immunol. 15,675-705[Medline]
    18. 18
  18. Shresta, S., Pham, C. T., Thomas, D. A., Graubert, T. A., Ley, T. J. (1998) How do cytotoxic lymphocytes kill their targets? Curr. Opin. Immunol. 10,581-587[Medline]
    19. 19
  19. Lanzavecchia, A. (1990) Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes Annu. Rev. Immunol. 8,773-793[Medline]
    20. 20
  20. Griffin, D. E., Bellini, W. J. (1996) Fields, B. N. Knipe, D. N. Howley, P. M. Chanock, R. M. Melnick, J. L. Monath, T. P. Roizman, B. Straus, S. E. eds. Measles Virus ,1267-1312 Lippincott-Raven Philadelphia.
    21. 21
  21. Dhib-Jalbut, S., Xia, J., Rangaviggula, H., Fang, Y. Y., Lee, T. (1999) Failure of measles virus to activate nuclear factor-kappa B in neuronal cells: implications on the immune response to viral infections in the central nervous system J. Immunol. 162,4024-4029[Abstract/Free Full Text]
    22. 22
  22. Naniche, D., Yeh, A., Eto, D., Manchester, M., Friedman, R. M., Oldstone, M. B. (2000) Evasion of host defenses by measles virus: wild-type measles virus infection interferes with induction of alpha/beta interferon production J. Virol. 74,7478-7484[Abstract/Free Full Text]
    23. 23
  23. Kurita-Taniguchi, M., Fukui, A., Hazeki, K., Hirano, A., Tsuji, S., Matsumoto, M., Watanabe, M., Ueda, S., Seya, T. (2000) Functional modulation of human macrophages through CD46 (measles virus receptor): production of IL-12 p40 and nitric oxide in association with recruitment of protein-tyrosine phosphatase SHP-1 to CD46 J. Immunol. 165,5143-5152[Abstract/Free Full Text]
    24. 24
  24. Marie, J. C., Kehren, J., Trescol-Biemont, M. C., Evlashev, A., Valentin, H., Walzer, T., Tedone, R., Loveland, B., Nicolas, J. F., Rabourdin-Combe, C., Horvat, B. (2001) Mechanism of measles virus-induced suppression of inflammatory immune responses Immunity 14,69-79[Medline]
    25. 25
  25. Trinchieri, G. (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity Annu. Rev. Immunol. 13,251-276[Medline]
    26. 26
  26. Ravanel, K., Castelle, C., Defrance, T., Wild, T. F., Charron, D., Lotteau, V., Rabourdin-Combe, C. (1997) Measles virus nucleocapsid protein binds to FcgammaRII and inhibits human B cell antibody production J. Exp. Med. 186,269-278[Abstract/Free Full Text]
    27. 27
  27. Murphy, F. A. (1994) New, emerging, and reemerging infectious diseases Adv.Virus Res. 43,1-52[Medline]
    28. 28
  28. Garcia-Sastre, A., Egorov, A., Matassov, D., Brandt, S., Levy, D. E., Durbin, J. E., Palese, P., Muster, T. (1998) Influenza A virus lacking the NS1 gene replicates in interferon- deficient systems Virology 252,324-330[Medline]
    29. 29
  29. Garcia-Sastre, A. (2001) Inhibition of interferon-mediated antiviral responses by influenza A viruses and other negative-strand RNA viruses Virology 279,375-384[Medline]
    30. 30
  30. Bergmann, M., Garcia-Sastre, A., Carnero, E., Pehamberger, H., Wolff, K., Palese, P., Muster, T. (2000) Influenza virus NS1 protein counteracts PKR-mediated inhibition of replication J. Virol . 74,6203-6206[Abstract/Free Full Text]
    31. 31
  31. Talon, J., Horvath, C. M., Polley, R., Basler, C. F., Muster, T., Palese, P., Garcia-Sastre, A. (2000) Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein J. Virol . 74,7989-7996[Abstract/Free Full Text]
    32. 32
  32. Wang, X., Li, M., Zheng, H., Muster, T., Palese, P., Beg, A. A., Garcia-Sastre, A. (2000) Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon J. Virol. 74,11566-11573[Abstract/Free Full Text]
    33. 33
  33. Gale, M., Tan, S. L., Katze, M. G. (2000) Translational control of viral gene expression in eukaryotes Microbiol. Mol. Biol. Rev. 64,239-280[Abstract/Free Full Text]
    34. 34
  34. Lee, T. G., Tomita, J., Hovanessian, A. G., Katze, M. G. (1990) Purification and partial characterization of a cellular inhibitor of the interferon-induced protein kinase of Mr 68,000 from influenza virus-infected cells Proc. Natl. Acad. Sci. USA 87,6208-6212[Abstract/Free Full Text]
    35. 35
  35. Tripp, R. A., Jones, L. P., Haynes, L. M., Zheng, H., Murphy, P. M., Anderson, L. J. (2001) CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein Nat. Immunol. 2,732-738[Medline]
    36. 36
  36. Schlender, J., Bossert, B., Buchholz, U., Conzelmann, K. K. (2000) Bovine respiratory syncytial virus nonstructural proteins NS1 and NS2 cooperatively antagonize alpha/beta interferon-induced antiviral response J. Virol. 74,8234-8242[Abstract/Free Full Text]
    37. 37
  37. Basler, C. F., Wang, X., Muhlberger, E., Volchkov, V., Paragas, J., Klenk, H. D., Garcia-Sastre, A., Palese, P. (2000) The Ebola virus VP35 protein functions as a type I IFN antagonist Proc. Natl. Acad. Sci. USA 97,12289-12294[Abstract/Free Full Text]
    38. 38
  38. Takada, A., Watanabe, S., Ito, H., Okazaki, K., Kida, H., Kawaoka, Y. (2000) Downregulation of beta1 integrins by Ebola virus glycoprotein: implication for virus entry Virology 278,20-26[Medline]
    39. 39
  39. Kindzelskii, A. L., Yang, Z., Nabel, G. J., Todd, R. F., Petty, H. R. (2000) Ebola virus secretory glycoprotein (sGP) diminishes Fc gamma RIIIB-to-CR3 proximity on neutrophils J. Immunol. 164,953-958[Abstract/Free Full Text]
    40. 40
  40. Chepurnov, A. A., Tuzova, M. N., Ternovoy, V. A., Chernukhin, I. V. (1999) Suppressive effect of Ebola virus on T cell proliferation in vitro is provided by a 125-kDa GP viral protein Immunol. Lett. 68,257-261[Medline]
    41. 41
  41. Yang, Z. Y., Duckers, H. J., Sullivan, N. J., Sanchez, A., Nabel, E. G., Nabel, G. J. (2000) Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury Nat. Med. 6,886-889[Medline]
    42. 42
  42. Chan, S. Y., Empig, C. J., Welte, F. J., Speck, R. F., Schmaljohn, A., Kreisberg, J. F., Goldsmith, M. A. (2001) Folate receptor-alpha is a cofactor for cellular entry by Marburg and Ebola viruses Cell 106,117-126[Medline]
    43. 43
  43. Fraser, J. R. (1986) Epidemic polyarthritis and Ross River virus disease Clin. Rheum. Dis. 12,369-388[Medline]
    44. 44
  44. Soden, M., Vasudevan, H., Roberts, B., Coelen, R., Hamlin, G., Vasudevan, S., La Brooy, J. (2000) Detection of viral ribonucleic acid and histologic analysis of inflamed synovium in Ross River virus infection Arthritis Rheum 43,365-369[Medline]
    45. 45
  45. Lidbury, B. A., Simeonovic, C., Maxwell, G. E., Marshall, I. D., Hapel, A. J. (2000) Macrophage-induced muscle pathology results in morbidity and mortality for Ross River virus-infected mice J. Infect. Dis. 181,27-34[Medline]
    46. 46
  46. Linn, M. L., Aaskov, J. G., Suhrbier, A. (1996) Antibody-dependent enhancement and persistence in macrophages of an arbovirus associated with arthritis J. Gen. Virol. 77,407-411[Abstract/Free Full Text]
    47. 47
  47. Lidbury, B. A., Mahalingam, S. (2000) Specific ablation of antiviral gene expression in macrophages by antibody-dependent enhancement of Ross River virus infection J. Virol. 74,8376-8381[Abstract/Free Full Text]
    48. 48
  48. Kliks, S. C., Nisalak, A., Brandt, W. E., Wahl, L., Burke, D. S. (1989) Antibody-dependent enhancement of dengue virus growth in human monocytes as a risk factor for dengue hemorrhagic fever Am. J. Trop. Med. Hyg. 40,444-451
    49. 49
  49. Yang, K. D., Yeh, W. T., Yang, M. Y., Chen, R. F., Shaio, M. F. (2001) Antibody-dependent enhancement of heterotypic dengue infections involved in suppression of IFN gamma production J. Med. Virol. 63,150-157[Medline]
    50. 50
  50. Chaturvedi, U. C., Elbishbishi, E. A., Agarwal, R., Raghupathy, R., Nagar, R., Tandon, R., Pacsa, A. S., Younis, O. I., Azizieh, F. (1999) Sequential production of cytokines by dengue virus-infected human peripheral blood leukocyte cultures J. Med. Virol. 59,335-340[Medline]
    51. 51
  51. Vrati, S., Faragher, S. G., Weir, R. C., Dalgarno, L. (1986) Ross River virus mutant with a deletion in the E2 gene: properties of the virion, virus-specific macromolecule synthesis, and attenuation of virulence for mice Virology 151,222-232[Medline]
    52. 52
  52. Vrati, S., Kerr, P., Weir, R. C., Dalgarno, L. (1996) Entry kinetics and mouse virulence of Ross River virus mutants altered in neutralization epitopes J. Virol. 70,1745-1750[Abstract/Free Full Text]
    53. 53
  53. Wang, H., Eckels, D. D. (1999) Mutations in immunodominant T cell epitopes derived from the nonstructural 3 protein of hepatitis C virus have the potential for generating escape variants that may have important consequences for T cell recognition J. Immunol. 162,4177-4183[Abstract/Free Full Text]
    54. 54
  54. Rosenberg, E. S., Billingsley, J. M., Caliendo, A. M., Boswell, S. L., Sax, P. E., Kalams, S. A., Walker, B. D. (1997) Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia Science 278,1447-1450[Abstract/Free Full Text]
    55. 55
  55. Cerny, A., Chisari, F. V. (1999) Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence Hepatology 30,595-601[Medline]
    56. 56
  56. Frasca, L., Del Porto, P., Tuosto, L., Marinari, B., Scotta, C., Carbonari, M., Nicosia, A., Piccolella, E. (1999) Hypervariable region 1 variants act as TCR antagonists for hepatitis C virus-specific CD4+ T cells J. Immunol 163,650-658[Abstract/Free Full Text]
    57. 57
  57. You, L. R., Chen, C. M., Yeh, T. S., Tsai, T. Y., Mai, R. T., Lin, C. H., Lee, Y. H. (1999) Hepatitis C virus core protein interacts with cellular putative RNA helicase J. Virol. 73,2841-2853[Abstract/Free Full Text]
    58. 58
  58. You, L. R., Chen, C. M., Lee, Y. H. (1999) Hepatitis C virus core protein enhances NF-kappaB signal pathway triggering by lymphotoxin-beta receptor ligand and tumor necrosis factor alpha J. Virol. 73,1672-1681[Abstract/Free Full Text]
    59. 59
  59. Large, M. K., Kittlesen, D. J., Hahn, Y. S. (1999) Suppression of host immune response by the core protein of hepatitis C virus: possible implications for hepatitis C virus persistence J. Immunol. 162,931-938[Abstract/Free Full Text]
    60. 60
  60. Gale, M. J., Korth, M. J., Tang, N. M., Tan, S. L., Hopkins, D. A., Dever, T. E., Polyak, S. J., Gretch, D. R., Katze, M. G. (1997) Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein Virology 230,217-227[Medline]
    61. 61
  61. Taylor, D. R., Shi, S. T., Romano, P. R., Barber, G. N., Lai, M. M. (1999) Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein Science 285,107-110[Abstract/Free Full Text]
    62. 62
  62. Polyak, S. J., Khabar, K. S., Paschal, D. M., Ezelle, H. J., Duverlie, G., Barber, G. N., Levy, D. E., Mukaida, N., Gretch, D. R. (2001) Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response J. Virol. 75,6095-6106[Abstract/Free Full Text]
    63. 63
  63. Khabar, K. S., Al-Zoghaibi, F., Al-Ahdal, M. N., Murayama, T., Dhalla, M., Mukaida, N., Taha, M., Al-Sedairy, S. T., Siddiqui, Y., Kessie, G., Matsushima, K. (1997) The alpha chemokine, interleukin 8, inhibits the antiviral action of interferon alpha J. Exp. Med. 186,1077-1085[Abstract/Free Full Text]
    64. 64
  64. Aiken, C., Konner, J., Landau, N. R., Lenburg, M. E., Trono, D. (1994) Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain Cell 76,853-864[Medline]
    65. 65
  65. Chen, B. K., Gandhi, R. T., Baltimore, D. (1996) CD4 down-modulation during infection of human T cells with human immunodeficiency virus type I involves independent activities of vpu, env, and nef J. Virol. 70,6044-6053[Abstract/Free Full Text]
    66. 66
  66. Dalgleish, A. G., Beverley, P. C., Clapham, P. R., Crawford, D. H., Greaves, M. F., Weiss, R. A. (1984) The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus Nature 312,763-767[Medline]
    67. 67
  67. Collins, K. L., Chen, B. K., Kalams, S. A., Walker, B. D., Baltimore, D. (1998) HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes Nature 391,397-401[Medline]
    68. 68
  68. Cohen, G. B., Gandhi, R. T., Davis, D. M., Mandelboim, O., Chen, B. K., Strominger, J. L., Baltimore, D. (1999) The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells Immunity 10,661-671[Medline]
    69. 69
  69. Mangasarian, A., Piguet, V., Wang, J. K., Chen, Y. L., Trono, D. (1999) Nef-induced CD4 and major histocompatibility complex class I (MHC-I) down-regulation are governed by distinct determinants: N-terminal alpha helix and proline repeat of Nef selectively regulate MHC-I trafficking J. Virol. 73,1964-1973[Abstract/Free Full Text]
    70. 70
  70. Brander, C., Walker, B. D. (2000) Modulation of host immune responses by clinically relevant human DNA and RNA viruses Curr. Opin. Microbiol. 3,379-386[Medline]
    71. 71
  71. Albini, A., Ferrini, S., Benelli, R., Sforzini, S., Giunciuglio, D., Aluigi, M. G., Proudfoot, A. E., Alouani, S., Wells, T. N., Mariani, G., Rabin, R. L., Farber, J. M., Noonan, D. M. (1998) HIV-1 Tat protein mimicry of chemokines Proc. Natl. Acad. Sci. USA 95,13153-13158[Abstract/Free Full Text]
    72. 72
  72. Howcroft, T. K., Strebel, K., Martin, M. A., Singer, D. S. (1993) Repression of MHC class I gene promoter activity by two-exon Tat of HIV Science 260,1320-1322[Abstract/Free Full Text]
    73. 73
  73. Tosi, G., De Lerma Barbaro, A., D’Agostino, A., Valle, M. T., Megiovanni, A. M., Manca, F., Caputo, A., Barbanti-Brodano, G., Accolla, R. S. (2000) HIV-1 Tat mutants in the cysteine-rich region downregulate HLA class II expression in T lymphocytic and macrophage cell lines Eur. J. Immunol. 30,19-28[Medline]
    74. 74
  74. Matsui, M., Warburton, R. J., Cogswell, P. C., Baldwin, A. S., Jr, Frelinger, J. A. (1996) Effects of HIV-1 Tat on expression of HLA class I molecules J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 11,233-240[Medline]
    75. 75
  75. Park, H., Davies, M. V., Langland, J. O., Chang, H. W., Nam, Y. S., Tartaglia, J., Paoletti, E., Jacobs, B. L., Kaufman, R. J., Venkatesan, S. (1994) TAR RNA-binding protein is an inhibitor of the interferon-induced protein kinase PKR Proc. Natl. Acad. Sci. USA 91,4713-4717[Abstract/Free Full Text]
    76. 76
  76. Maitra, R. K., McMillan, N. A., Desai, S., McSwiggen, J., Hovanessian, A. G., Sen, G., Williams, B. R., Silverman, R. H. (1994) HIV-1 TAR RNA has an intrinsic ability to activate interferon-inducible enzymes Virology 204,823-827[Medline]
    77. 77
  77. Schroder, H. C., Ugarkovic, D., Wenger, R., Reuter, P., Okamoto, T., Muller, W. E. (1990) Binding of Tat protein to TAR region of human immunodeficiency virus type 1 blocks TAR-mediated activation of (2'-5') oligoadenylate synthetase AIDS Res. Hum. Retroviruses 6,659-672[Medline]
    78. 78
  78. Berger, E. A., Murphy, P. M., Farber, J. M. (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease Annu. Rev. Immunol. 17,657-700[Medline]
    79. 79
  79. Huang, M. B., Hunter, M., Bond, V. C. (1999) Effect of extracellular human immunodeficiency virus type 1 glycoprotein 120 on primary human vascular endothelial cell cultures AIDS Res. Hum. Retroviruses 15,1265-1277[Medline]
    80. 80
  80. Weissman, D., Rabin, R. L., Arthos, J., Rubbert, A., Dybul, M., Swofford, R., Venkatesan, S., Farber, J. M., Fauci, A. S. (1997) Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor Nature 389,981-985[Medline]
    81. 81
  81. Ada, G. (2001) Vaccines and vaccination N. Engl. J. Med. 345,1042-1053[Free Full Text]
    82. 82
  82. Talon, J., Salvatore, M., O’Neill, R. E., Nakaya, Y., Zheng, H., Muster, T., Garcia-Sastre, A., Palese, P. (2000) Influenza A and B viruses expressing altered NS1 proteins: a vaccine approach Proc. Natl. Acad. Sci. USA 97,4309-4314[Abstract/Free Full Text]



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