Neutralization and antibody dependent enhancement of dengue viruses pdf

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neutralization and antibody dependent enhancement of dengue viruses pdf

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If the address matches an existing account you will receive an email with instructions to reset your password. If the address matches an existing account you will receive an email with instructions to retrieve your username. In general, virus-specific antibodies are considered antiviral and play an important role in the control of virus infections in a number of ways. However, in some instances, the presence of specific antibodies can be beneficial to the virus.

Antibody-Dependent Enhancement: A Challenge for Developing a Safe Dengue Vaccine

Antibody-dependent enhancement ADE has been proposed as a mechanism to explain dengue hemorrhagic fever DHF in the course of a secondary dengue infection. Very recently, Dejnirattisai et al. The complexity of ADE in the context of a secondary dengue infection is discussed here. A rapid increase in dengue reports has been observed in the last three decades.

Today, dengue infections are a serious cause of morbidity and mortality in most tropical and subtropical regions of the world: an estimated 50— million people are infected annually and over 2.

These are transmitted to humans by Aedes mosquito bites, and Aedes aegypti is the main vector. Two types of virions are recognized: mature extracellular virions contain M protein, while immature intracellular virions contain prM, which is proteolytically cleaved during maturation to yield M protein.

The envelope of the virus contains the viral surface proteins E and M. The E glycoprotein has important functional roles in virus attachment to cells and fusion with membranes, and is the major target for neutralizing antibody.

It contains the main epitopes recognized by neutralizing antibodies virus-specific and cross-reactive epitopes [ 5 , 6 ]. This protein has three structural and functional domains: domain II contains the internal fusion peptide responsible for the fusion of flaviviruses to their target cells and domain III the cellular receptor-binding motifs [ 7 , 8 ].

Domains I and III contain predominantly subcomplex- and type-specific epitopes, whereas domain II contains the major flavivirus group and subgroup cross-reactive epitopes [ 9 — 11 ].

M protein may be found in two forms. In cell-associated immature virions, prM the precursor of M protein is observed, which forms a heterodimer with the E protein prM-E heterodimer. Apparently, prM serves as a chaperone for the E protein, protecting it from irreversible inactivation during transport of virions to the cell surface in acidic post-Golgi vesicles [ 12 , 13 ].

Through this association, prM participates in the viral assembly and budding into the lumen of the endoplasmic reticulum. Intracellular virions remain non-infectious until release when they are converted to infectious form through the cleavage of prM into the soluble pr peptide and the particle associated M protein by a host-cell-derived furin-like protease [ 14 ].

Uncleaved prM prevents the E protein from undergoing the structural changes that are required for low-pH-induced membrane fusion of DENV.

Therefore, fully immature DENV is essentially non-infectious [ 15 ]. Depending on the extent of prM cleavage, the extracellular particles may contain varying proportions of prM and M. The charged residues surrounding the furin consensus sequence at the prM cleavage junction could partially explain lower or higher cleavage efficiency; in addition, structural differences inherent to flaviviruses at prM junction affect prM cleavability [ 18 ].

Single-serotype natural infections result in lifelong immunity to the infecting serotype but only short-term cross-protection against heterotypic serotypes [ 21 ]. The humoral response to dengue infection is important for controlling infection and virus dissemination. Despite antigenic relatedness of viruses in the dengue complex, two or more serotypes may sequentially infect one individual. Specific neutralizing IgG antibody against the infecting DENV lasts decades, while cross-reactive neutralizing activity declines over time [ 22 , 23 ].

Preliminary reports also suggest that in human beings there is a continuous selection process of populations of dengue-virus neutralizing-antibodies with increasing homologous reactivity and concurrent decrease in heterotypic cross reactions [ 24 ]. These first observations were confirmed in a different setting.

The DENV 2 epidemic of preceded by a mild epidemic of DENV 1 in reported in Cuba, supported secondary infection as a main risk factor for the severe forms of dengue infection. They were born after the epidemic and, consequently, in , they were at risk only of primary DENV infection [ 29 ].

ADE has been described for several viruses including DENVs, measured by in vitro enhancement of cell infection [ 36 — 38 ]. Also, monkeys passively immunized concurrently with a DENV infection developed a higher viremia than control animals [ 39 ].

More recently, Goncalvez et al. In humans, indirect evidence of ADE has been reported. ADE was observed in vitro in sera from mothers whose infants developed DHF after a primary dengue infection [ 41 ].

This study demonstrated that maternal antibody to DENV declines at a constant rate and passes in time through three functional states: neutralization, enhancing virus growth and antibody degradation. This early study suggested that as anti-dengue antibody to a first infection wanes, some individuals will experience an interval during which their antibody level will drop below its protective capacity, acquiring the power to enhance infection.

In another study, Kliks et al. Evidence suggests that enhancing and cross-reactive neutralizing antibodies regulate dengue epidemics and disease severity.

In this sense, epidemiological and serological observations made during the Cuban dengue epidemics support the role of secondary infection and ADE even 20 or more years after primary dengue infection. A marked increase in severity associated with the longer of the two intervals 20 years versus four years between an initial DENV1 infection and a secondary DENV 2 Asian genotype infection has been reported [ 43 ].

Cross-reactive antibodies lacking neutralizing activity are induced during a primary dengue infection. In secondary infection, these antibodies bind to the second infecting virus.

A higher viremia in infected patients and consequent greater severity has been hypothesized [ 49 ]. Studies reported by Vaughn et al. Also in Taiwanese patients it was observed that dengue RNA titers even after defervescence, correlated with disease severity [ 52 ].

In a more recent study, Cameron et al. An in vitro study with Ross River virus showed that viral entry via the FcR pathway could suppress antiviral genes and enhance IL production, while entry via the normal mechanism does not change the antiviral environment [ 54 ]. These observations suggest that ADE of DENV infection not only facilitates the virus entry process but also could modify innate and adaptive intracellular antiviral mechanisms [ 55 ].

Studies using monoclonal antibodies have demonstrated that enhancing antibodies are directed to E and prM proteins [ 56 ]. Although both proteins seem to be involved in neutralization and the ADE mechanism, more studies have been designed to evaluate the role of E protein. Greater understanding of the antibody-neutralization mechanisms could shed light on their likelihood of promoting ADE.

Flavivirus neutralization is a multiple-hit phenomenon requiring engagement by more than one antibody. Neutralization occurs when the number of antibodies bound to an individual virion exceeds a required threshold, antibody affinity and accessibility of epitopes on virus particles playing an important role [ 57 ].

These E-specific antibodies appear to be pivotal, mediating homologous protection against dengue reinfection; however, in mice, prM vaccine has also been shown to protect against the lethal DENV challenge [ 59 ]. Neutralization at low occupancy requires lower antibody concentrations and can occur with lower-affinity antibodies, while those antibodies specific to poorly accessible epitopes require relatively high concentrations.

Most epitopes have the capacity to elicit antibodies capable of promoting ADE [ 60 ]; however, antibodies specific to poorly accessible epitopes are more likely to promote ADE over a wide range of concentrations [ 61 , 62 ].

Recently, Lok et al. Despite the large body of work with mouse monoclonal antibodies, little has been done to characterize the binding properties of human dengue immune sera and to understand the relationship between human antibody binding, neutralization and ADE [ 64 ]. Wahala et al. In addition, in another report these authors suggest that type-specific epitopes on domain III are not conserved between strains of DENV3 [ 66 ]. Previous investigations support large differences in neutralization titers when comparing different genotypes of the same virus [ 67 , 68 ].

Recently, Dejnirattisai et al. They observed that a antibodies to prM were a major component of the response, highly cross-reactive among the dengue serotypes, and b these antibodies have potent ADE activity and low neutralization capacity. Considering these results, the authors propose that partial cleavage of prM reduces antigen density availability for viral neutralization, leaving the viruses susceptible to ADE by antibody to prM.

Previously, a host-protective effect of anti-prM was reported for DENV; however, how these antibodies would exert their effect was not clear [ 18 , 59 , 69 — 71 ]. It has been proposed that weak neutralization of dengue infectivity by some anti prM monoclonal antibodies and anti-prM peptide sera could be due to their cross-reactivity with E protein [ 18 , 70 , 71 ].

However, similar levels of enhancing activity by strongly enhancing anti-E monoclonal antibodies have been previously reported [ 56 , 72 ]. Some studies report enhancement of infection presumably due to the presence of uncleaved prM in virus preparations, but also with DENV particles containing high levels of prM after cell treatment with chloroquine [ 72 , 73 ]. Apparently, infection enhancement and lack of potent neutralization are common properties of anti-prM antibodies, suggesting that prM constitutes another target for infection-enhancing antibodies but also that extracellular dengue virions containing prM could be infectious [ 18 ].

Previous studies have shown that immature particles are non-infectious, since the presence of prM obstructs the low-pH-induced conformational changes in the E protein required for membrane fusion of the virus [ 15 , 74 ].

However, very recently, Rodenhuis-Zybert et al. They showed that lack of infectivity of immature particles in the absence of antibodies was related to inefficient binding of immature virions to cell surfaces, but if binding is facilitated through anti-prM antibodies, immature particles become highly infectious, presumably due to efficient intracellular processing of prM to M by furin activity within the target cell.

These antibodies facilitate efficient binding and cell entry by immature particles into Fc-R- expressing cells [ 75 ]. Together, these observations suggest that immature viral particles have the potential to be highly infectious and hence may contribute to development of the severe disease during secondary infection [ 75 ].

Consequently, it is important to define the possible in vivo effects of maintaining prM on the virion surface but also the viral and host factors involved in the efficiency of prM cleavage. It has been suggested that alteration of furin target sequence in the prM junction can affect virus export [ 76 ]. Also, several studies have suggested that the multiplication of flaviviruses is not self-reliant and that the viruses subvert cellular proteins to become part of their replication strategy [ 77 , 78 ].

Of interest is that Dejnirattisai et al. Previous reports recognized that the main response is directed to E protein, but also support that anti-prM antibodies are generated during dengue infection in humans [ 79 — 81 ].

It cannot be excluded that these apparently dissimilar observations depend on the characteristics of the tested samples and the employed methodologies. CryoEM images have shown that WNV and DENV preparations contain a mixture of immature, partially mature and mature viral particles, most likely due to incomplete processing by furin during maturation [ 82 ].

Cherrier et al. These observations can also be extended to anti prM antibody. Schematic representation of viral populations and anti-E and anti-prM antibodies involved in neutralization and ADE mechanism. Immature , partially mature , mature viral particles, neutralizing anti-E antibodies , cross-reactive non-neutralizing anti-E antibodies and cross reactive anti-prM antibodies.

However, secondary infection is considered the main risk factor for disease severity. The dengue antibody somehow modulates subsequent infection with an enhancing or neutralizing role that up- or down-regulates dengue infection of mononuclear phagocytes Figure 1 [ 92 ].

Immune complex infection suppresses cellular immune responses, increasing intracellular infection and generating inflammatory cytokines and chemokines that together contribute to the development of severe disease [ 48 ].

The elegant work published by Dejnirattisai et al. Smit for her useful comments and suggestions. National Center for Biotechnology Information , U. Journal List Viruses v. Published online Dec 8. Maria G. Author information Article notes Copyright and License information Disclaimer.

This article has been cited by other articles in PMC. Abstract Antibody-dependent enhancement ADE has been proposed as a mechanism to explain dengue hemorrhagic fever DHF in the course of a secondary dengue infection.

Keywords: dengue, dengue hemorrhagic fever, prM, ADE, neutralization, cleavage. Introduction A rapid increase in dengue reports has been observed in the last three decades.

Antibody-Dependent Enhancement of Virus Infection and Disease

The pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response. Host factors such as antibody-dependent enhancement ADE , memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity as well as genetic factors are major determinants of disease susceptibility. Genomic variation of dengue virus and subgenomic flavivirus RNA sfRNA suppressing host immune response are viral determinants of disease severity. Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. This review article highlights the various factors responsible for the pathogenesis of dengue and also highlights the recent advances in the field related to biomarkers which can be used in future for predicting severe disease outcome. Dengue infection is a major public health problem and has been reported from the Americas, Africa, Southeast Asia, Europe, Western Pacific, and Eastern Mediterranean regions.

Metrics details. Antibodies are critical responses to protect the host from dengue virus DENV infection. Antibodies target DENV by two pathologic mechanisms: virus neutralization and infection enhancement. A total of pair serum samples from adult healthy volunteers were obtained during the dengue season in Ha Noi in for evaluation of neutralizing and infection-enhancing activity. Additionally, 20 serum samples from acute secondary DENV infection patients were also used as the patient group in this study. Out of residents, positive neutralizing antibodies N. A were found in

Request PDF | On Mar 29, , Tadahiro Sasaki and others published Dengue virus neutralization and antibody-dependent enhancement activities of and/or human monoclonal antibodies (MAbs) specific to viral surface.

The Complexity of Antibody-Dependent Enhancement of Dengue Virus Infection

Antiviral antibodies constitute an important component of the host immune response against viral infections and serve to neutralize and reduce infectivity of the virus. However, these antibodies, intended to protect the host, may sometimes prove beneficial to the virus, by facilitating viral entry and replication in the target cell. The internalized immune complexes then modulate host immune response so as to enhance viral replication and aggravate disease severity. The possibility of induction of ADE remains a concern in the development and implementation of viral vaccines and immunotherapeutics. Antibody-dependent enhancement ADE of infection represents a paradoxical phenomenon in host—pathogen biology, in which, antibody, an important pillar of the host defense against invading pathogen, actually allows entry of the pathogen into host territory.

Mayra R. Montecillo-Aguado, Alfredo E. IPN Col. This represents a major health concern, given the high homology between these two viruses, which can result in cross-reactivity.

Antibody-dependent enhancement ADE has been proposed as a mechanism to explain dengue hemorrhagic fever DHF in the course of a secondary dengue infection. Very recently, Dejnirattisai et al. The complexity of ADE in the context of a secondary dengue infection is discussed here. A rapid increase in dengue reports has been observed in the last three decades.

Antibody-Dependent Enhancement of Viral Infections

Current Understanding of the Pathogenesis of Dengue Virus Infection

The challenges associated with whole DENV-based vaccine strategies necessitate re-focusing our attention toward the designed dengue vaccine candidates, capable of inducing predominantly type-specific immune responses. The generation of type-specific antibodies to each of the four DENV serotypes by the designed vaccines could avoid the immune evasion mechanisms of DENVs. For the enhanced vaccine safety, all dengue vaccine candidates should be assessed for the extent of type-specific minimal ADE vs. The type-specific EDIII antibodies may be more directly related to protection from disease in the absence of ADE promoted by the cross-reactive antibodies.

Dengue virus DENV is the cause of dengue fever. It is a mosquito -borne, single positive-stranded RNA virus of the family Flaviviridae ; genus Flavivirus. Dengue virus has increased dramatically within the last 20 years, becoming one of the worst mosquito-borne human pathogens with which tropical countries have to deal.


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