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Variant epitope sequences between dengue virus serotypes induce an altered profile of cytokine production and target cell lysis the altered peptide ligand effect. During a second dengue virus infection, the presence of pre-existing memory B and T cells which were induced by the prior infection alters the kinetics and specificity of the immune response, and this is referred to as original antigenic sin. Clinical studies have shown associations between specific immune responses and disease severity.

However, no single measure has shown a high correlation with clinical outcome. Further studies are needed to establish reliable correlates of protective or pathological immune responses. Dengue virus vaccines currently in development contain different components of the dengue virus genome.

Immune responses to the different vaccines may not be equivalent; incorporation of immunological studies into clinical trials is desirable to establish the necessary knowledge base to guide vaccine development and introduction. Dengue is a mosquito-borne viral disease of expanding geographical range and incidence. The existence of four viral serotypes and the association of prior dengue virus infection with an increased risk for more severe disease have presented significant obstacles to vaccine development.

An increased understanding of the adaptive immune response to natural dengue virus infection and candidate dengue vaccines has helped to define the specific antibody and T cell responses that are associated with either protective or pathological immunity during dengue infection. Further characterization of immunological correlates of disease outcome and the validation of these findings in vaccine trials will be invaluable for developing effective dengue vaccines.

Dengue as a clinical entity is thought to date back at least several hundred years, and its aetiology was recognized as a mosquito-borne virus nearly years ago.

Military physicians in the United States and Japan began efforts to develop a vaccine against dengue during the Second World War, when the virus strains were isolated. Progress since that time has been disappointingly slow. The geographical range of dengue virus transmission has expanded considerably in tropical and subtropical regions of the globe, and the number of cases of dengue illness reported worldwide has increased more than fold since the s 1.

Only in the last few years did the first dengue vaccine enter a field efficacy trial. The slow pace of vaccine development reflects the unique set of challenges that dengue presents, which are of great relevance to basic and applied immunology Box 1. This Review briefly summarizes the key clinical, virological and epidemiological facts about dengue. The primary focus is to review recent studies of antibody and T cell responses to dengue virus and their association with favourable protection against infection or illness or unfavourable enhancement of disease clinical outcomes.

Dengue virus, the causative agent of dengue, is a small, enveloped virus that contains a single-stranded, positive-sense messenger RNA genome and is a member of the family Flaviviridae. All four dengue virus serotypes cause the same clinical manifestations and show similar patterns of systemic dissemination, with tropism principally for monocytes, macrophages and dendritic cells 2 , 3. Dengue viruses are transmitted to humans by mosquitoes of the genus Aedes. The distribution of Aedes spp.

These regions also include popular destinations for tourists from temperate developed countries, presenting a constant risk for the spread of dengue virus into non-endemic areas 4 , 5. Most dengue virus infections pass with minimal or no symptoms.

The classical clinical presentation of dengue virus infection, dengue fever, is an acute illness lasting approximately 4—7 days. Fever, chills and malaise are common but nonspecific. Severe retro-orbital headache and myalgias are more characteristic symptoms of dengue. Other common disease features include leukopenia, thrombocytopenia sometimes severe and elevated levels of hepatic transaminases. Symptoms and signs of infection resolve without complications in the vast majority of cases.

However, distinctive features of spontaneous bleeding, plasma leakage, or both may appear towards the end of the illness. The dengue plasma-leakage syndrome, named dengue haemorrhagic fever, occurs in only a small percentage of patients, but is the most important contributor to a severe clinical outcome.

Increased vascular permeability in dengue haemorrhagic fever results in decreased circulating plasma volume, haemoconcentration, and pleural and peritoneal effusions, and severe, life-threatening shock can ensue. The transient nature of plasma leakage, its association with the late febrile phase and the paucity of structural damage to the vasculature in autopsy studies initially suggested that circulating factors were primarily responsible for this phenomenon.

Studies have shown that plasma levels of pro-inflammatory and vasoactive cytokines are elevated in patients with dengue haemorrhagic fever before and at the time of plasma leakage, and the degree of elevation correlates with disease severity reviewed in Ref. As in the case of infection with several other viruses such as influenza viruses and hantaviruses , the scenario envisioned is that excessive immune activation creates a cascade of cytokine production resulting in increased vascular permeability: a 'cytokine storm'.

Experimental and observational studies indicate that the adaptive immune response to dengue virus has both protective and detrimental aspects. Individuals who have been infected with one dengue virus serotype primary dengue virus infection have long-term protective immunity against re-infection with the same serotype. There is also transient resistance to infection with other dengue virus serotypes, but this heterotypic protective immunity lasts only a few months, after which these individuals are once again susceptible to infection with other serotypes secondary dengue virus infection 7.

Subsequently, the remaining cross-reactive immune response to other serotypes has the potential to increase the risk for developing dengue haemorrhagic fever, at least in some individuals. Indeed, several prospective studies found that, in children above the age of 1 year, dengue haemorrhagic fever is fold to fold more frequent during secondary dengue virus infection than during primary infection.

However, even during primary infection, dengue haemorrhagic fever occurs in a small percentage of patients in this age group 8 , 9 , Infants born to mothers with established immunity to dengue virus are a special group at high risk for dengue haemorrhagic fever and hospitalization during primary infection in the first year of life 11 , 12 , as discussed below. Despite many studies using in vitro and animal models, our knowledge of protective and pathological immune responses to dengue virus relies primarily on clinical and epidemiological studies.

Primates are the only vertebrates known to be infected by dengue virus in nature. Both humans and non-human primates are susceptible to dengue virus infection, but the viral strains isolated from humans and non-human primates are genetically distinct, indicating that these transmission cycles diverged in the distant past Furthermore, dengue haemorrhagic fever is not known to occur in non-human primates in either natural or experimental settings. Laboratory animals, such as mice and other rodents, are susceptible to experimental dengue virus infection, and various disease models have been described in mice.

Although these models display some features of human dengue disease, they each have significant limitations reviewed in Ref. For example, these models have, for the most part, relied on mouse-adapted viruses that appear to be attenuated with respect to human infection.

New models such as 'humanized' mice are promising 15 , 16 , but have not yet yielded new insights into dengue virus-specific immune responses.

Targets of the antibody response to dengue virus. The precursor membrane pre-M and envelope E structural proteins and non-structural protein 1 NS1 are the principal targets of the antibody response to dengue virus infection in humans Fig.

Antibody responses have also been detected to other non-structural proteins, including NS3 and NS5. However, these responses are weak, especially in primary dengue virus infections 17 , NS3 and NS5 localize exclusively within virus-infected cells, but cell lysis owing to viral cytopathic effect or immune cell-mediated lysis may make these proteins accessible for binding to B cell receptors.

Dengue virions bind to cell surface receptors these have not been completely characterized , and the virions are internalized through endocytosis. Acidification of the endocytic vescicle leads to rearrangement of the surface envelope E glycoprotein, fusion of the viral and vesicle membranes and release of viral RNA into the cytoplasm.

Viral genomic RNA is then translated to produce viral proteins in endoplasmic reticulum ER -derived membrane structures, and the viral proteins and newly synthesized viral RNA assemble into immature virions within the ER lumen. Cleavage of the viral precursor membrane pre-M protein by the host cell enzyme furin leads to the formation of mature virions, which are secreted from the cell.

In addition, some of the synthesized non-structural protein 1 NS1 is expressed on the plasma membrane of the cell or secreted, and some virions are secreted in an immature form. Mature and immature virions induce antibody responses to the E protein, and these antibodies can function in neutralization or in antibody-dependent enhancement of infection. Immature virions also induce antibody responses to the pre-M protein.

Antibodies specific for NS1 can interact with membrane-bound NS1 and cause complement-dependent lysis of virus-infected cells. At high levels of epitope occupancy, antibodies can block the binding of virions to the cellular receptor or can block fusion at a post-binding stage. At lower epitope occupancy levels, antibodies can enhance the uptake of virions into cells by interacting with immunoglobulin Fc receptors. Dengue virus E protein. The most extensive characterization of B cell epitopes has been accomplished for the E glycoprotein, which is the principal surface component of the dengue virion.

The three main domains that are bound by antibodies correspond to the three domains in the crystal structure, with multiple epitopes residing within each domain 19 , 20 Fig. Antibodies to all of the epitopes display varying degrees of cross-reactivity across the four dengue virus serotypes and other flaviviruses. Importantly, owing to the dimeric conformation of the E protein on the virion surface and its tight packing in the mature form, not all of the antibody epitopes are equally accessible for antibody binding.

For example, under saturating conditions, only of the available E protein domain III epitopes recognized by one monoclonal antibody could be occupied, owing to steric interference at the remaining sites Another domain III epitope is accessible only during the dynamic rearrangement of the E protein that occurs at physiological temperatures The fusion loop in domain II of the E protein is almost completely inaccessible in the mature virion, and antibodies to this epitope apparently bind to either immature virions or a post-entry or pre-fusion transition state after low pH-induced rearrangement of the E protein into a trimeric conformation The serological response to the E protein after natural dengue virus infection in humans is highly serotype cross-reactive Corresponding to the findings using serum, most E protein-specific human monoclonal antibodies were found to bind to more than one dengue virus serotype 25 , Domain III of the E protein, which contains the putative receptor-binding region that allows the virus to target host cells, is the most variable in amino acid sequence between serotypes.

Antibodies specific for this domain show the greatest degree of serotype specificity, but make up a minor component of the overall antibody response during infection 24 , Dengue virus pre-M and NS1 proteins. The pre-M protein forms a heterodimer with the E protein during initial virion assembly and is subsequently cleaved by host cell-expressed furin during the final stage of virion maturation before egress Following cleavage, the remaining fragment — the M protein — is completely hidden by the E protein dimers in the mature virion and is inaccessible to antibody binding However, incomplete cleavage appears to be a common occurrence for dengue virus, at least in vitro , yielding immature and partially mature particles that can be bound by pre-M protein-specific antibodies Antibodies to the pre-M protein are highly serotype cross-reactive.

The NS1 protein is a glycoprotein that is produced in infected cells but is not incorporated into the virion. NS1 forms a multimeric structure and can be found on the surface of infected cells or can be released as a soluble molecule in cell culture and in vivo 31 , 32 , Antibodies specific for NS1 are also highly serotype cross-reactive Functions of dengue virus-specific antibodies.

Antibodies specific for dengue virus proteins mediate a wide range of functions in vitro. Neutralization of infection by dengue virus-specific antibodies can occur through several different mechanisms, including inhibition of binding to cell surface receptors or post-binding inhibition of viral fusion 34 , Neutralizing antibodies are directed against the E protein and include antibodies to nearly all of the epitopes.

However, measurement of the neutralizing activity of immune sera or monoclonal antibodies is affected by the assay method and by the cell substrate used The tropism of dengue virus for monocytes and macrophages, which both express receptors for immunoglobulins, also creates the opportunity for dengue virus-specific antibodies to enhance viral entry, a phenomenon termed 'antibody-dependent enhancement of infection'. Antibody-dependent enhancement of infection occurs because host cell uptake of virus—antibody complexes is more efficient than the entry of free virus through the host cell-expressed receptor s.

Antibody-dependent enhancement of infection can be mediated by E protein-specific antibodies under conditions of low antibody concentration or low antibody avidity, when the number of antibody molecules bound per virion is below the threshold necessary for neutralization of the virus Antibody-dependent enhancement can also be mediated by pre-M protein-specific antibodies In this case, uncleaved pre-M protein on immature or partially mature virions is targeted by the host antibody response, and pre-M protein cleavage and virion maturation may occur as the virus—antibody complexes are taken up by the host cell.

Infection of monocytes by virus—antibody complexes can also alter cellular responses to infection, including the upregulation of IL production in genetically predisposed individuals 38 , Dengue virus-specific antibodies of the appropriate subclasses can also bind to complement proteins and promote their activation.

Antibodies specific for NS1 on the host cell plasma membrane can also direct complement-mediated lysis of infected cells NS1-specific antibodies may also contribute to antibody-dependent cellular cytotoxicity 42 , Targets of the T cell response to dengue virus. Dengue virus proteins are translated from the viral genomic RNA as a single polyprotein, which is subsequently cleaved to yield the three structural proteins and seven non-structural proteins.

This coding strategy should generate equimolar amounts of all ten proteins. In keeping with this, T cell epitopes are found throughout the dengue virus polyprotein 44 Fig. These epitopes appear to follow the general principles of T cell epitope immunogenicity, and they show MHC molecule binding kinetics that are similar to those of other immunodominant viral epitopes. Limitations in the availability of reagents may explain the apparent immunodominance of NS3 for T cell recognition, at least in part.

However, a recent study using overlapping peptides covering the entire DENV-2 polyprotein also found that the highest ex vivo T cell responses were directed to the NS3 region Viral attachment, internalization, fusion and translation proceed as described in Fig.

Newly synthesized viral proteins enter the MHC class I and II presentation pathways and viral peptide epitopes are presented on the cell surface within the binding groove of MHC molecules. The predominant sequences for each of the four serotypes are shown.

Residues that are completely conserved are shown in black and residues that are not completely conserved are shown in red. A high percentage of the T cell clones studied have shown reactivity to more than one dengue virus serotype, although serotype-specific T cell clones have also been found and some exceptional T cell clones differentially recognize viral strains within the same serotype Functions of dengue virus-specific T cells. Dengue virus-specific T cells recognize virus-infected cells and respond with a diverse set of effector functions, including proliferation, target cell lysis and the production of a range of cytokines Fig.

However, the mechanism of viral peptide presentation by MHC class II molecules in this in vitro system has not been defined. Therefore, the relevance of this in vitro observation to the elimination of virus-infected cells, such as monocytes and macrophages, in vivo is uncertain.

A broad array of cytokines is produced by dengue virus-specific T cells in response to the recognition of peptide—MHC complexes on target cells. As is the case for dengue virus-specific antibodies, amino acid differences between serotypes can affect the avidity of the interaction between peptide—MHC complexes on dengue virus-infected cells and the T cell receptors of individual dengue virus-specific T cell clones, and this has functional consequences Fig.

The functional avidities of individual dengue virus-specific T cells have been assessed in vitro mainly by testing T cell functional responses to graded concentrations of synthetic peptides. T cells recognize and lyse target cells at peptide concentrations lower than those required to stimulate the same T cells to proliferate 53 , 54 , Furthermore, the peptide concentrations required to stimulate various cytokine responses differ.

Peptide variants found in different dengue virus serotypes act as altered peptide ligands , shifting the peptide dose—response curve towards either increased or decreased responsiveness of the T cell. The potential for an individual to be infected with dengue virus on several different occasions during a lifetime, as described above, is a distinctive clinical and immunological feature of dengue.

Importantly, the second and subsequent dengue virus infections always involve different viral serotypes than the previous infection s , owing to long-lasting homotypic protective immunity against the primary strain.

If exceptions to this rule exist in nature, they have yet to be firmly documented. Nevertheless, secondary dengue virus infections differ immunologically from primary infections as a consequence of the fact that the immune response to the secondary infection occurs in the context of pre-existing heterotypic immunity that is serotype cross-reactive.

Memory B and T cells induced by the prior exposure to a different dengue virus serotype are capable of responding more rapidly than naive cells during the acute secondary infection. However, because of sequence diversity between the dengue virus serotypes, the memory B and T cells that are re-activated during secondary infection may not have optimal avidity for the corresponding epitopes of the new infecting virus.

The alteration in immune response, skewed by the 'memory' of the previous infection, is referred to as 'original antigenic sin'. For antibody responses, affinity maturation occurs within the first few weeks after the onset of primary dengue virus infection With subsequent dengue virus infection, antibody responses are notably different and are characterized by much higher antibody titres and a broader pattern of neutralization of the four dengue virus serotypes.

Titres of antibodies specific for the virus serotype that caused the earlier infection increase substantially, and often remain higher than the titres of antibodies specific for the currently infecting serotype 57 , 59 , the phenomenon that led to the original coinage of the term original antigenic sin.

For T cell responses, there are fewer data available comparing primary and subsequent dengue virus infections. Overall, T cell responses after primary dengue virus infections are characterized by higher homotypic than heterotypic responses 46 , However, this pattern breaks down at the level of individual T cell epitopes, and the degree of serotype cross-reactivity is different for the various measurements of T cell function 47 , T cell responses after secondary infections are highly serotype cross-reactive Some studies have shown higher responses to the previously encountered dengue virus serotype, consistent with preferential expansion of memory T cell populations with higher avidity for that serotype than the new infecting serotype However, our recent studies have revealed a more complex pattern of serotype cross-reactivity, suggesting that other factors that are unique to the individual patient have a strong influence on the T cell response to secondary infection H.

Friberg, H. Bashyam, T. Toyosaki-Maeda, J. Potts, T. Greenough, S. Kalayanarooj, R. Gibbons, A. Nisalak, A. Srikiatkhachorn, S. Green, H. Stephens, A. Mathew, unpublished observations. Antibody responses associated with protection. Adoptive transfer of immune serum or monoclonal antibodies specific for pre-M, E or NS1 proteins can protect mice from lethal challenge with dengue virus 20 , 41 , 62 , Similarly, passive transfer of antibodies can protect against infection with dengue virus in non-human primate models NS1-specific antibodies mediate complement-dependent lysis of infected cells 41 ; however, this may not fully explain their protective effects in vivo Assessment of the protective effects of dengue virus-specific antibodies in humans relies on associations from prospective cohort studies, in which exposure to dengue virus is difficult to evaluate.

High titres of dengue virus-specific neutralizing antibodies have been associated with a lower likelihood of severe disease during secondary infection 66 , 67 , but conflicting results have also been reported Infection and viraemia can clearly occur, even in patients with pre-existing high titres of neutralizing antibodies that can bind to the infecting viral serotype In these cases, the antibodies detected are presumed to be cross-reactive antibodies from a prior heterotypic dengue virus infection; the available assays are not able to distinguish such heterotypic antibodies from homotypic antibodies, which are thought to provide sterile immunity.

Studies of primary dengue virus infection in infants born to mothers with established immunity to dengue virus provide a means to isolate the effects of passively acquired dengue virus-specific antibodies. The incidence of dengue virus infection, and in particular dengue haemorrhagic fever, is low during the first few months of life, and a minimum neutralizing antibody titre for protection against infection has been suggested However, the problems with current neutralizing antibody assays discussed above confound the interpretation of the results from these studies as well.

T cell responses associated with protection. T cell activity requires the presentation of viral peptides on the surface of infected cells in the context of MHC molecules and, unlike B cells, T cells do not recognize intact virions.

Therefore, it would not be possible for dengue virus-specific T cells to provide sterilizing immunity against viral infection.

However, there have been fewer studies of T cell-mediated protection than of antibody-mediated protection. An alternative approach, involving immunization with antigens that induce dengue virus-specific T cells but not neutralizing antibodies, has also shown that T cells are sufficient to protect mice from lethal infection 69 , 70 , It is more challenging to clearly define a protective role for dengue virus-specific T cells in humans. Other than congenital antibody deficiencies, there are no clinical scenarios in which memory T cells are present in the absence of dengue virus-specific antibodies.

Nevertheless, by collecting blood samples from prospectively enrolled individuals in dengue-endemic areas, it is possible to test for correlations between pre-infection dengue virus-specific T cell responses and the outcome of infection. So far, these studies have been done only in small study cohorts. One study compared patients who were hospitalized during their subsequent dengue virus infection with patients who were not hospitalized a decision made independently by the clinician that presumably reflected the severity of disease.

However, pre-challenge blood samples did not identify an immunological correlate of outcome in that study. A protective effect of dengue virus-specific T cells can also be inferred from studies of HLA associations with dengue disease.

Specific HLA alleles were found to be significantly more common among patients with dengue fever than among those with the more severe dengue haemorrhagic fever in one or more studies reviewed in Ref. T cell epitopes have been defined for some of these alleles, but no data are available to implicate specific epitopes in any protective effect. Antibody responses associated with disease. The well-established finding that patients with secondary dengue virus infections have an increased risk for developing dengue haemorrhagic fever provides strong evidence for a pathological side to the dengue virus-specific immune response.

This association, juxtaposed with the occurrence of dengue haemorrhagic fever during primary infection in infants under 1 year of age, has focused the attention of many groups on the possible detrimental effects of dengue virus-specific antibodies.

Antibody-dependent enhancement of infection provides a straightforward explanation for more severe disease in both settings, as increased infection of immunoglobulin receptor-expressing cells such as monocytes and macrophages could explain the greater level of cytokine production that occurs. Antibody-dependent enhancement of dengue virus infection has been demonstrated in vivo using adoptive transfer of dengue virus-specific immunoglobulins; in monkeys, increased virus titres were observed 76 and, in immunodeficient mice, increased virus titres and mortality were noted Moreover, infection-enhancing activity was displayed in vitro by sera obtained from subjects who had serological evidence of previous dengue virus infection prior to secondary dengue virus infection and by sera from the mothers of infants who later developed dengue haemorrhagic fever during primary dengue virus infection 12 , 66 , 78 , 79 , Several lines of evidence question whether antibody-dependent enhancement of infection alone is sufficient to explain dengue haemorrhagic fever.

First, dengue haemorrhagic fever can occur, albeit at a lower frequency, in primary dengue virus infection in older children and adults, and this indicates that antibody-dependent enhancement is not required for the development of plasma leakage Second, although average peak virus titres are higher in patients with dengue haemorrhagic fever than in patients with dengue fever, virus titres are several logs below peak levels by the time plasma leakage occurs, and there are many patients who have high virus titres but do not develop plasma leakage 81 , 82 , La Conquista del Derecho.

Juan Ibarrondo. ETA Juan Ibarrondo. Irati Goikoetxea Asurabarrena. Hilketez ari gara, zapalketaz, bazterketaz, mehatxuez, estortsioaz, doluaz, bakardadeaz, eta minaren kontzientzia hartzen ez duen jende-gizarte-herria nekez izango da askea.

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