Antibody response to dengue virus

+

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63

MICINF4171_proof ■ 13 August 2014 ■ 1/10

MODEL

Microbes and Infection xx (2014) 1e10 www.elsevier.com/locate/micinf

Antibody response to dengue virus Q4

Leticia Cedillo-Barr
on a,*, Julio García Cordero a, Jos
e Bustos-Arriaga b, Mois
es Le
on Ju
arez c, Benito Guti
errez-Casta~ neda d a

Departamento de Biomedicina Molecular, CINVESTAV IPN, Av. IPN # 2508, Col. San Pedro Zacatenco, CP 07360 M
exico, D.F., Mexico b Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, 20892 MD, USA c Departamento de Inmunobioquímica, Instituto Nacional de Perinatología, Montes Urales #800, Col. Lomas de Virreyes, 11000, Mexico d Laboratorio de Inmunología, Facultad de Estudios Superiores Iztacala, Universidad Aut
onoma de M
exico, Tlalnepantla, Estado de M
exico, Mexico Received 3 April 2014; accepted 28 July 2014

Abstract In this review, we discuss the current knowledge of the role of the antibody response against dengue virus and highlight novel insights into targets recognized by the human antibody response. We also discuss how the balance of pathological and protective antibody responses in the host critically influences clinical aspects of the disease. © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Keywords: Dengue virus; Antibody response; Antibody-enhanced infection

1. Introduction Dengue disease is caused by the bite of mosquito (Aedes aegypti or Aedes albopictus), infected with dengue virus (DENV) serotypes 1e4, which belong to the Flavivirus genus. These four serotypes cause dengue fever (DF) and more severe disease manifestations, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). DF is a febrile, acute disease characterized by headache, myalgia, arthralgia, and severe retro-orbital pain. In contrast, DHF presents with hemorrhagic manifestations, thrombocytopenia, and plasma leakage, which may lead to hypotensive shock (DSS) and death. Approximately 50e100 million cases of DF are reported every year, and 2.5e3 billion people are at risk of acquiring DF throughout the world. Indeed, DF represents an important public health problem in all tropical and subtropical regions of Asia and the Americas [1].Considerable efforts have been * Corresponding author. Tel.: þ52 57473800x5021. E-mail addresses: [email protected], [email protected] (L. Cedillo-Barr
on).

directed toward developing a safe vaccine, and several strategies have focused on the development of DENV recombinant vaccine subunits expressed in different expression systems. Moreover, different strategies have been implemented to develop carrier molecules that elicit a robust immune response [2,3]. However no effective vaccine for dengue is currently available [4,5]. After a mosquito bites a human host, different resident cells present in the skin may be infected with DENV, including Langerhans cells, keratinocytes, and fibroblasts. While the roles of the latter two cell types in DENV remain to be elucidated, dendritic cells have been shown to spread the infection from the skin to the lymph nodes, where monocytes, macrophages, or resident dendritic cells become infected. The virus possesses a lipid envelope and a positive-strand RNA genome of 10.7 kb, which encodes a polypeptide precursor that is proteolytically cleaved into structural proteins, i.e., capsid (C), pre-membrane (prM), and envelope (E) proteins, and non-structural proteins, i.e., NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. After infection, the virus enters into the cell through receptor-mediate endocytosis [6,7].Under acidic pH in the endosomal vesicles, the protein E of the virus

http://dx.doi.org/10.1016/j.micinf.2014.07.011 1286-4579/© 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128

MICINF4171_proof ■ 13 August 2014 ■ 2/10

2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

L. Cedillo-Barr
on et al. / Microbes and Infection xx (2014) 1e10

undergoes conformational changes to promote fusion with the endosomal membrane. The virus is then uncoated, and the single-stranded RNA (ssRNA) escapes into the cytoplasm and initiates translation and simultaneous genome replication in the membrane vesicles of the endoplasmic reticulum (ER). Viral RNA then associates with C protein and assembles with prM and E proteins in membranes derived from the ER. Immature virions bud into the lumen of the ER and are transported through the secretory pathway [6,8e10].When the immature virus arrives in the trans-Golgi, the protease furin, encoded by the host genome, cleaves prM protein into the membrane (M)protein and pr-peptide, yielding mature virions [9,11,12].DENV also induces the remodeling and redistribution of distinct membrane structures to obtain a platform for viral RNA replication, assembly, and spreading [8,11]. According to the oligomeric state and arrangement of E proteins on the surface of the virion, virus particles can be classified as immature or mature. Immature virions (spiky) contain the prM protein, which is about 600 Å, and this protein must be proteolytically processed in the Golgi, yielding mature particles that, combined with the E protein, provide the virus with a smooth outer layer. Interestingly, both immature and mature virions are observed during viral propagation [12,13]. Recent studies using electron tomography have demonstrated that viral replication occurs on double-membrane vesicles adjacent to the ER. Furthermore, image analyses have shown physical linkages between the sites of DENV replication and assembly [8,14]. 2. Initiation of the immune response against DENV Both the innate and adaptive immune responses participate in the control of dengue disease. Thus, the skin participates in the rapid initiation of innate host defenses, and this event may prevent DENV infection. In the skin, both infiltrating cells (such as macrophages, neutrophils, dendritic cells, and lymphocytes) and resident cells (such as keratinocytes and fibroblasts), which are abundantly localized in the epithelium, participate in the production of various types of cytokines, establishing a pro-inflammatory microenvironment with antimicrobial activity against arthropod-borne pathogens, such as DENVs [15]. Little is known about the events that occur in the skin in the very early stages after mosquito feeding. However, cumulative data have shown that DENV is sensed by both Tolllike receptors (TLRs) TLR3 and TLR7 [16]. Wang et al. demonstrated that plasmacytoid dendritic cells (pDCs) constitutively express TLR7 and elicit responses through interferon (IFN) regulatory factor IRF7, leading to IFN-a/b production in response to DENV [17]. In contrast, human umbilical vein endothelial cells (HUVECs) and U937 cells infected with DENV produce interleukin (IL)-8 and IFN-a/b after viral recognition through TLR3 [18].Cytoplasmic molecules, such as retinoic acid-inducible gene 1 (RIG-1) and melanoma differentiation-associated protein 5 (MDA5) have been shown to play an important role in sensing different

flaviviruses, including DENV, as demonstrated by Bustos et al. [15]. The IFN response is one of the early mechanisms of host defense that contributes significantly to innate immunity. The IFN system includes cells that synthesize IFN in response to viral infection. Thus induction of IFN-a/b is one of the early events following viral infection and is widely accepted as the most immediate and important antiviral host response to many viral infections [19]. The adaptive immune response also plays an important role in DENV infection, working to resolve infection and prevent re-infection. However, the antibody response to DENV infection is very complex and unpredictable and can either benefit or harm the host. Multiple studies have established that protection against DENV is mediated by neutralizing antibodies; thus, infection with anyone of the four DENV serotypes induces a strong, long-lasting antibody response against the homologous serotype, but only short-term protection against heterologous viruses. Furthermore, during a secondary infection by different serotypes of DENV, heterotropic immunity may promote acquisition of the severe forms of dengue, which is associated with antibody-enhanced infection (ADE)or the cytokine storm [20,21], (i.e., preformed polyspecific IgM antibodies that are not shaped by somatic hypermutation or class switching). 3. Antigenic DENV proteins and structure DEN V is a small virus of approximately 50 nm and is composed of C protein, which associates with viral RNA and the lipid envelope where the E and prM proteins are associated. When the virus infects the host and viral replication starts the proteins that are immediately in contact with the host are the E and prM proteins. Thus, the main targets of the immune response in individuals infected with DENV are the E and prM proteins [22]. After replication, NS1 is expressed and becomes a target of the immune system. However, these three proteins (i.e., E, prM, and NS1; Fig. 1) seem to be involved in both protection and pathogenesis. Immune responses have also been shown to target other non-structural proteins, albeit with reduced intensity and frequency [23]. The E glycoprotein has a molecular weight of about 55 kDa and is present in all four serotypes of DENV. It is compound of 495 amino acids and contains two transmembrane helixes and 12 conserved cysteine residues, which form a dimer. The amino acid residues of the E protein are well conserved, with high similarities (between 90% and 96%) among the four different serotypes. The amino acid sequence of this protein defines each DENV serotype. The E protein performs critical functions such as mediating interactions with the host cell and fusion of viral and cellular membranes during viral entry. The mature virion contains 90 homodimers of the E protein, arranged in a head-to-tail orientation on the surface of the virion [8,11,12]. Based on crystallography studies, the monomeric E protein folds itself into three distinct structural and functional domains, with residues1e395 forming the ectodomain. The

Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

MICINF4171_proof ■ 13 August 2014 ■ 3/10

L. Cedillo-Barr
on et al. / Microbes and Infection xx (2014) 1e10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

3

Fig. 1. The main Dengue virus targets for the human antibody response. Dengue virus posses a single ORF to encode a polyprotein which is processed by viral and host proteases to give yield 10 proteins: 3 structural and 7 non-structural proteins. The primary and secondary immune responses for each protein are marked with crosses.

domain located in the center of the folded protein (domain I) contains the N-terminus and possesses glycosylation sites. This domain is flanked by domain II, which contains a conserved fusion loop that actively participates in the structural rearrangements occurring under conditions of low pH, when the virus fuses with an endosomal membrane. Domain II has several overlapping immune dominant epitopes that stimulate small amounts of neutralizing antibodies. These epitopes are clustered at the tip of domain II, in the hinge region between domains I and II. The final domain, domain III, is located on the other side of the protein. Domain III is an immunoglobulin-like domain and is exposed on the surface of the virion [24].Domain III forms a b-barrel-type structure composed of six anti parallel b-strands in Japanese encephalitis virus (JEV) or 10 anti- parallel b-strands in DENV-2 [25].Domain III has also been shown to define the DENV serotype-specific, sub complex-specific and complex-specific epitopes. Furthermore, domain III also participates in receptor binding and is the major target of neutralizing antibodies, which correlate with protection against infection [25]. 4. The prM protein and its immunogenicity Besides the E protein, the prM protein has also received much attention in the study of DENV. This protein is a small protein of 166 amino acids (molecular weight of 19 kDa). The structure of prM has been determined and does not differ according to changes in pH. During viral morphogenesis, prM is cleaved by furin and releases an N-terminal fragment of 91 amino acids (called the pr-peptide), yielding an ectodomain from amino acids 92e166 (called the M protein). The prpeptide covers the hydrophobic fusion loop as a lid, protecting the fusogenic peptide present in E protein and thus helping to avoid premature fusion with intracellular membranes in the immature virion. Before maturation of the virion, prM is associated with the E protein, forming a heterodimer. The prM protein has only one fold and possesses six conserved cysteine residues. Only three of these residues form disulfide bridges [26,27]. The prM protein is an essential component of the DENV present in the virion and a good inductor of the immune

response. Previous work in mice immunized with recombinant prM and M proteins demonstrated that these proteins induced a protective response [28]. Furthermore, serum samples from 69 convalescent patients with primary and secondary infections showed specific recognition of the pr and M proteins. Thus, this protein had been included in many recombinant vaccines; however, the results of these studies were contradictory with recent data obtained using a panel of human monoclonal antibodies targeting prM, which revealed high cross-reactivity between the four DENV serotypes. Interestingly, such monoclonal antibodies do not neutralize infections at high concentrations, but may strongly induce ADE infections over a broad range of concentrations [29].Furthermore, some monoclonal antibodies obtained from memory B cells immortalized from individuals with primary or secondary DENV infections are reactive to prM, although they have low neutralizing activity, and exhibit distinctive cross-reactivity among the four DENV serotypes [30,31].Furthermore, D29 Fab-IgG, a DENV cross-reactive monoclonal antibody against prM protein, was found to have high affinity for a conformational epitope on prM and was capable of restoring the infectivity of virtually non-infectious immature DENV in K562 cells [31,32](Fig. 2). 5. Structural characteristics and antigenicity of NS1 protein NS1 is another highly immunogenic protein associated with both protection and pathogenesis. NS1 is a glycoprotein with a variable molecular weight (due to the level of glycosylation) of 46e55 kDa and can be anchored on the infected cell surface, associated with intracellular vesicular compartments, or secreted as oligomers [33].While NS1 has been shown to colocalize with viral RNA or the replication complex in DENV, its role in this process has not yet been fully elucidated [34]. NS1 has been shown to induce protection against natural infections and in experimental models [35]. For example, inoculation of mice with specific monoclonal antibodies against NS1 confers protection against lethal viral challenge. Interestingly, a direct correlation was noted between

Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

MICINF4171_proof ■ 13 August 2014 ■ 4/10

4 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

L. Cedillo-Barr
on et al. / Microbes and Infection xx (2014) 1e10

Interestingly, researchers also reported the production of a truncated NS1 protein that induces antibodies with lower platelet-binding activity than antibodies induced by full-length NS1 [40]. Despite these controversial results regarding the immune response, NS1 protein has become a highly useful molecule in diagnostics because secreted NS1 has been detected in the circulation at very early stages of dengue infection [41]. 6. The antibody response and the E protein

Fig. 2. Schematic representation of the two more immunogenic proteins E and PrM. The immature virions are represented with spiky complex of 60 trimmers of PrM-E. When prM protein is cleavage a new organization of 90 dimmers are observed for E protein giving smoothly surfaced appearance particles. Viral protein-antibody complexes in mature and immature particles during ADE are shown in the figure. The structural and functional domains of E protein are represented in color red domain I; domain II in yellow and in blue domain III.

monoclonal antibodies that fixed complement and those that conferred protection, probably via complement-mediated lysis of infected cells following antibody recognition of cell surface-bound NS1 [36].Furthermore,anti-NS1 antibodies generated in infected individuals are able to fix complement components, leading to elimination of infected cells [37]. In addition, a recent report demonstrated that recombinant DENV-2 NS1 fused to a monoclonal antibody could targetNS1 to dendritic cells (DEC205þ). Administration of this monoclonal antibody to mice induced anti-NS1 immune responses and conferred protection to mice challenged with DENV serotype 2 [38]. However, NS1is also involved in pathogenic immune responses [39]; indeed, some antibodies against NS1 protein cross-react with different host proteins, including ATP synthase, vimentin, or monocyte chemotactic protein 1 [34,39].A recent study by Chen et al. showed that there is a crossreactive motif located within the C-terminal region of NS1.

Responses due to both T and B cells can play a protective or pathogenic role in dengue. Currently, antibodies are known to be crucial in the protection against viral infections, such as acute cytolytic viruses. This protective function is possible because the antibody blocks the interaction between the virus and target cell or interferes with the fusion mechanism of the enveloped virus. In addition to neutralization, antibodies can recruit effectors cells or complement, leading to the killing of infected cells. However, additional mechanisms may contribute to protection. In general, DENV can also be controlled through neutralizing antibodies, as humoral protection against this virus correlates with induction of the neutralizing antibody response [42,43]. When DENV enters into the circulation, it will encounter natural antibodies produced by B-1 cells derived from the innate B cell population, which is abundant in the peritoneum. These cells produce poly-specific IgM, which does not undergo class switching or somatic hypermutation. This IgM is present in the circulation and can bind to and neutralize the virus at very early stages, thereby controlling the infection [44]. The dengue E protein is the most exposed structural glycoprotein in flaviviruses and is the principal target of neutralizing antibodies. Furthermore, it is considered the primary candidate target of subunit vaccines [6,7]. Many studies have attempted to elucidate the antigenic map of DENV. Mouse models have provided important information in this regard, demonstrating that the most effective neutralizing antibodies are directed to domain III and are specific for each serotype [45]. Work performed with monoclonal antibodies has demonstrated that important neutralizing antibodies recognize amino acids 307, 330, and 332or 383 and 384of domain III [46,47]. With regards to domain II, Modis et al. [24] developed a monoclonal antibody that efficiently binds to virus particles exposed to low pH (5.0) and defined residues at positions 98e110 (viral fusion sequence),which is epitope characteristic of the flavivirus group. Furthermore, Deng et al. [48] described another monoclonal antibody, 2A10G6, directed to the same fusion loop, but with neutralizing activity. Thus, strong evidence indicates that antibodies directed to domain II of the E protein can affect fusion of the virus in the endosomal compartment by generating changes in structural integrity. Moreover, Chan et al. isolated and characterized cross-reactive antibody D29, that recognizes a cryptic epitope of the E protein located in the junction of domains I and II. This epitope is inaccessible in mature viral particles, but exposed if the E protein is incorrectly folded [44].

Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

MICINF4171_proof ■ 13 August 2014 ■ 5/10

L. Cedillo-Barr
on et al. / Microbes and Infection xx (2014) 1e10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Interestingly Messer and collaborators transferred DENV 4 hinge (domain I/II) into a recombinant DENV-3 and demonstrated that this complex conformational epitope was the main target of the long-term, type-specific neutralizing antibody response in humans and primates. Furthermore, the authors suggested that this effect may result from blocking of the structural transition of E protein during membrane fusion [49]. The most surprising pieces of data are related to the plasticity of the structure of flavivirus particles, which are highly dynamic. Indeed, constant temperature shift results in the exposure of apparent cryptic antigenic sites. Another remarkable discovery in humans revealed that the most abundant antibodies during a primary infection are crossreactive with domain II, and fewer antibodies target domain III of the E protein. Beltramello et al. [30] immortalized memory B cells from patients after primary or secondary infections Monoclonal antibodies against E domain III were found to be cross-reactive and highly neutralizing, while antiprM monoclonal antibodies were poorly neutralizing and showed equal cross-reactivity against the four serotypes. In another study, in Thai children with primary or secondary DENV infection they shown, DENV E-specific B cells were highly serotype-specific after primary DENV infection, while most E-specific B cells in patients with secondary infections were cross-reactive with different serotypes and secreted antibodies with higher avidity to heterologous DENV serotypes [42].Moreover, anti-prM antibodies have been shown to increase dissemination of DENV by increasing the infectivity of immature particles. Interestingly, the ADE pattern in immature particles is different between anti-prM and anti-E antibodies; ADE is only observed at higher antibody titers in anti-E opsonized immature particles, but is observed at lower titers with anti-prM antibodies [32].

5

reactive. Moreover, this screening revealed that highly neutralizing or serotype-specific antibodies were poorly represented in the isolated clones [52]. In this regard, some evidence suggests that the attenuated DENV vaccine candidatesrDEN1D30 may be capable of inducing memory immunity similar to that of wild-type DENV [55]. The vaccine and natural infection raised weakly neutralizing antibodies, which dominated the response. Antigen specificities were very similar, with a slightly greater percentage of antibodies targeting E protein domain I/II than domain III [55]. During secondary infection, large numbers of plasma blasts (CD20CD19dimCD138þ/) are observed 6e7 days after the onset of fever [56,57].Long-lived plasma cells provide a persistent antibody titer in the blood and represent an important fraction of the total humoral memory of the immune system, which is independent of the continuous presence of the antigen and can last for a lifetime [58]. Additionally, Xu et al. isolated circulating plasmablasts from two patients that secrete antibodies specific for E protein, with high neutralizing activity. However, the authors concluded that these antibodies were not representative of the serum antibodies secreted by long-lived plasma cells in the memory phase [59]. All these studies suggested that the specific memory B cells exhibited rare serotype-specificity, potent neutralizing specificities, which may be the primary determinants of protection against severe disease in humans. However, the roles of these cells with respect to highly represented cross-reactive antibodies during heterologous infection are not known. Thus, these antibodies, while not providing sterile immunity, may be reducing viral loads earlier in secondary infections [60].Based on these data, it is obvious that more studies are needed to characterize the elements involved in the establishment of the humoral memory response to DENV infection.

7. Humoral memory response induced by dengue infection

8. Dengue infection and the role of ADE

Studies of the humoral response during primary and secondary infections with DENV have greatly improved our understanding of the pathogenic processes of the disease. Several reports have established that a primary infection with DENV is characterized by the presence of IgM antibodies followed by an IgG-type response, mainly IgG1 and IgG3. Some reports have suggested that immunological memory against DENV infection persists for at least for 60 years [50,51]. The elements involved in the selection of epitopes that determine the repertoire of memory B cells have been studied in some detail. Several studies have suggested that specificity to the B-cell epitope is selected during acute infection and that the repertoire increases after successive exposure to the virus. Parameswaran et al. performed a 6-month longitudinal study from onsetin60 patients with acute DF and observed increased expansion of B-cell clones, with higher overall clonality in secondary infection [52e54]. Smith and collaborators isolated memory clones from 12 patients several years after primary or secondary infection and found that memory clones are directed against E or prM proteins, which are broadly cross-

Fortunately, severe forms of the disease, such as DHS and DSS, are rare, but tend to occur more frequently in young people. Nevertheless, other factors also contribute to the development of severe clinical forms of Dengue, such as genetic susceptibility, which affects the disease outcome, viral replication rates, and environmental exposures, and the human immune response, which also affects various disease characteristics. Indeed, variability of the host immune response plays an important role in the severe forms of the disease [61].Several groups have studied antibody dynamics during the natural progression of the disease. DENV infection by one serotype induces a strong and long-lasting antibody response against the same serotype virus (homotypic response) and is accompanied by a short-term cross-reactive antibody response against other serotypes of DENV (heterotypic response). Moreover, despite the elevated repertoire of antigen specificities, antibodies can only prevent infection with the homologous serotype [61e63]. This phenomenon promotes the ADE due to the dramatic increase in infected cells bearing FcgR receptors or complement receptors in the presence of sub

Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

MICINF4171_proof ■ 13 August 2014 ■ 6/10

6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

L. Cedillo-Barr
on et al. / Microbes and Infection xx (2014) 1e10

neutralizing concentrations of antibody, suggesting that the weakly neutralizing antibodies from the first infection bind to the heterologous serotype and enhance the infection of FcgRbearing myeloid cells, such as monocytes and macrophages. The process of ADE involves the binding of antibodies to DENV, forming antibody-DENV immune complexes, and the binding of the complexes to FcR [64,65]. ADE is mediated by FcRs [66,67]. The FcR family consists of three classes (I, II, and III) with class III proteins exhibiting higher binding affinities. However, FcgRIIA (i.e., alpha and beta), the alpha isoform is more involved in the development of ADE than the beta isoform due to its ability to bind strongly to the antibody. All ADE-associated cellular changes are induced before late endosome viral escape [68]. As mentioned before, the pediatric population is at higher risk of severe dengue disease in endemic areas because neutralizing antibodies can be acquired passively through breast milk. The levels of these antibodies then decrease after about 1 year, and protection decreases accordingly. Furthermore sub neutralizing antibody titers may remain, and children become susceptible to enhanced DENV infection [69e71]. Anders et al. [72] performed a study where they evaluated anti-DENV antibodies acquired from breast milk and found a strong association between non-neutralizing antibodies and viral titers related to the child's age. Additionally, in studies performed in older Thai children who presented secondary infections, dengue RNA titers correlated with disease severity [73,74]. ADE infections have also been shown to be associated with exacerbated cytokine release by infected macrophages. This process is known as the “cytokine storm” and has been reported to occur in patients with vascular permeability syndrome following the release of pro-inflammatory cytokines, such as interleukin (IL-6 and tumor necrosis factor (TNF)), and the production of interferon IFN-I by macrophages and mature DCs, which are modulated by primary or secondary ADE infections [20,75](Fig. 3). Puerta-Guardo et al. [76] showed that U937 cells infected with DENV in the presence of enhancing concentrations of a humanized monoclonal antibody showed strong induction of pro-inflammatory cytokines. These supernatants are able to disrupt tight junctions in MDCK cells, in contrast to U937 cells infected in absence of antibodies. Interestingly, immature DCs do not undergo ADE when treated with DENV immune sera. However, mature DCs are more susceptible to developing ADE, likely due to the higher expression of the Fc gamma receptor CD32 in mature DCs [66]. In order to study the ADE phenomenon, many cellular systems and animal models such as human peripheral blood mononuclear cells [64,77], human acute monocyticleukemia cells (THP1), human myelogenous cells (K562), and mouse macrophages (PD3881) [78]. Although the reproducibility of ADE patterns has been reported previously using established cell lines, the amount of infectious virus required to infect FcgR-expressing hematopoietic cell lines varies among DENV isolates. Moi et al. developed an assay to measure ADE using BHK cells that stably express human FcgR [79].

The lack of an adequate animal model has slowed progress towards production of a licensed vaccine. Moreover, development of an appropriate animal model would provide tools for evaluating immune responses to different viral antigens. However, the use of existing murine or nonhuman primate models has provided invaluable knowledge regarding the immune response and protection. For example, Harris et al. used an IFN receptor-deficient mouse model (AG129), which was adapted to a DENV-2 strain, and evaluated DENV immunopathogenesis [75].Additionally, studies conducted have shed light on the role of IFN in an IFN-g-immuno deficient mouse reconstituted with human hematopoietic stem cells [80]. The use of nonhuman primate models has helped enormously such as Rhesus macaques, which present lymphadenopathy, lymphocytosis and leucopenia. Therefore, the use of these models in the study of pathogenesis/immunopathogenesis is relevant. Recently, Onlamoon et al. reported that infection of Rhesus monkeys with DENV via the intravenous (i.v.) route resulted in hemorrhage and petechiae on day 3e5 of primary infection [81]. Further standardization of virus strains or other experimental conditions will be an important promise to have a reliable model [82]. 9. Variability of the immune response in the different clinical presentations of dengue disease As mentioned above, dengue-specific antibodies in the serum can be, but are not necessarily, protective. It is not yet clear which subset of pathogen-specific serum immunoglobulin (Ig) contributes to protection or humoral memory. When compared with natural antibodies, the half-life of secreted antibodies is relatively short, i.e., a few days [83,84].Likewise, secondary DENV infections have been associated with increased risk of developing DHF. One of the most accepted explanations for this is ADE, which has been shown to occur in response to DENV antibodies in cell cultures and animal models [62]; however, there is not enough evidence to conclude whether these mechanisms also work in human disease. Furthermore, strong evidence has demonstrated that CD4þ and CD8þ T cell activation are substantially increased in patients with DHF rather than in patients with DF [85]. The quality of the adaptive response may be influenced by several viral and host factors. Viral factors include the viral population infecting the host and viral load introduced from the mosquito bite. Host factors include early soluble factors produced in response to the presence of the virus in the skin, intensity of the initial innate immune activation by the virus, and host-related variation, such as HLA molecules or functional polymorphisms in immune-related proteins (e.g., PRRs, signaling proteins, Ss, cytokines, etc.). Regarding this phenomenon, some groups have compared the soluble mediators present in sera from patients with DF during different stages of the disease. In a group of 221 patients, pro-inflammatory cytokine profiles were evaluated, and the levels of IFN-g were higher in patients with DF, whereas IL-6and IL-8 levels were higher in patients with DHF [86]. Bozza et al. in Cuba

Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

MICINF4171_proof ■ 13 August 2014 ■ 7/10

L. Cedillo-Barr
on et al. / Microbes and Infection xx (2014) 1e10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

7

Fig. 3. Dengue infection and the role of antibody-dependent enhancement (ADE). Dengue virus infects a cell by interacting with a cellular receptor. The virus particle is internalized through receptor-mediated endocytosis. Conformational changes occur in the envelope protein allowing the fusion of the viral membrane with the membrane of the endosome, releasing the viral genome into the cytoplasm (1). The genome then replicates and this allows the production and maturation of new viral particles (2). The infected cell starts an immune response, promoting the activation and maturation of antibody-producing B cells (3). These antibodies are specific for the virus, by promoting the neutralization of the viral particles (4). Immune cells such as macrophages or monocytes eliminate the captured virusantibody complex, which cannot escape the endocytic vacuole and end up destroying the virus (5). When a person is infected with a different serotype (6), memory B cells created during the first infection are reactivated and the antibodies produced by these cells are specific to the serotype of the primary infection (7). These antibodies bind with lower affinity to the serotype of a secondary infection (8). As a result, these virus-antibody complexes of low affinity are captured by macrophages or monocytes to promote the escape of virus in the endosome, promoting ADE of viral infection and replication within these cells (9).

and Becquart et al. in Africa found increases in IL-13, IL-7, granulocyte macrophage colony-stimulating factor, and IFN-a in patients with severe disease, while patients with mild DF exhibited increasedMIP-1b levels [87,88]. Srikiatkhachorn et al. analyzed samples from patients with DHS in Thailand and found that secondary DENV-2 infections mounted an alternate immune response, with lower IFN-a levels 3e7 days after the onset of symptoms associated with DHF [89].Furthermore, Anusyahand et al. compared the cytokine profiles of 44 patients with DF classified by the World Health Organization (WHO) 2009 guideline as dengue with warning signs, dengue without warning signs, and severe dengue during febrile, defervescent, and convalescent stages. Thus, the above results suggest that the massive secretion of cytokines is due to the activation of T cells, monocytes, and endothelial cells. They found that the dynamics of the soluble signals

varied with the stage and severity of the disease. Interestingly, dengue infection generally induces low levels of cytokines involved in isotype switching, such as IL-4, IL-5, and IL-13 [90]. Thus, the apparent contradictory data presented in different studies could be explained. If the number of DENV susceptible cells increases as a consequence of ADE, the intracellular signaling events occur through inhibition of the antiviral response, such as via IFNI, or by the induction of anti-inflammatory cytokines, such as IL-10, coupled with suppression of pro-inflammatory cytokines, such asIL-12 and TNFa [68,91]. Clearly, the number of cytokines and the level of cytokine increase depend on the severity and type of dengue disease, which vary with the genetic background and the rate of viral replication. However, cumulative studies have revealed that the so-called cytokine storm may participate in the immunopathology of the disease.

Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

MICINF4171_proof ■ 13 August 2014 ■ 8/10

8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Q1 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 Q2 52 53 54 55 56 57 58 59 60 61 62 63 64 65

L. Cedillo-Barr
on et al. / Microbes and Infection xx (2014) 1e10

10. Conclusion It is not clear whether the differences in the cytokine environment and other elements of the immune system influence the type or quality of the humoral immune response to DENVs. Some soluble mediators associated with increased affinity of the antibody response have been found in patients with DENV; usually one or two of these mediators are found within a patient and are present at modest concentrations. In this case, the maturation of the immune response may take longer to establish or may never reach optimal levels. Thus, the immune response is strongly influenced by the host genetic background, and studies have not elucidated a specific phenotype that provides balanced protective and pathological immune responses in DF and related disease. More studies are needed to determine the requirements for stimulation of an efficient, cross-protective, long-lasting humoral response to DENVs. So far, the understanding of the immune response against dengue in humans is only starting since clearly denguespecific antibodies in the serum can be, but are not necessarily, protective. It is not yet clear which subset of pathogenspecific serum immunoglobulin (Ig) contributes to humoral memory, as compared to natural antibodies. Thus, several candidates are currently in clinical trial and it is likely that we are close to an effective vaccine that may solve the problem of dengue; however, more exhaustive work performed in humans is necessary regarding the magnitude of response and memory involving domains I and II and prM protein. This knowledge will help researchers design vaccines and adjuvants that elicit an effective immune response to protect and resolve infection with DENV. Acknowledgments This work was supported by the National Council for Science and Technology (CONACyT) Grant CB-2010-01/ 0154270.Additionally, LCB is member of the National System of Researchers, SNI. References [1] PAHO. Dengue regional information: number of cases. PAHO; 2011. http://newpahoorg/hq/index/php?option¼com_ content&task¼view&id¼264&Itemid¼363. [2] Garcia-Machorro J, Lopez-Gonzalez M, Barrios-Rojas O, FernandezPomares C, Sandoval-Montes C, Santos-Argumedo L, et al. DENV-2 subunit proteins fused to CR2 receptor-binding domain (P28)-induces specific and neutralizing antibodies to the dengue virus in mice. Hum Vaccin Immunother 2013;9:2326e35. [3] Coconi-Linares N, Ortega-Davila E, Lopez-Gonzalez M, GarciaMachorro J, Garcia-Cordero J, Steinman RM, et al. Targeting of envelope domain III protein of DENV type 2 to DEC-205 receptor elicits neutralizing antibodies in mice. Vaccine 2013;31:2366e71. [4] Durbin AP, Whitehead SS. Next-generation dengue vaccines: novel strategies currently under development. Viruses 2011;3:1800e14. [5] Anez G, Morales-Betoulle ME, Rios M. Circulation of different lineages of dengue virus type 2 in Central America, their evolutionary time-scale and selection pressure analysis. PloS One 2011;6:e27459.

[6] Li L, Lok SM, Yu IM, Zhang Y, Kuhn RJ, Chen J, et al. The flavivirus precursor membrane-envelope protein complex: structure and maturation. Science 2008;319:1830e4. [7] Heinz FX, Stiasny K. Flaviviruses and their antigenic structure. J Clin Q3 Virol 2012;55:289e95. [8] Bartenschlager R, Miller S. Molecular aspects of dengue virus replication. Future Microbiol 2008;3:155e65. [9] Urcuqui-Inchima S, Patino C, Torres S, Haenni AL, Diaz FJ. Recent developments in understanding dengue virus replication. Adv Virus Res 2010;77:1e39. [10] Lindenbach BD, Rice CM. Molecular biology of flaviviruses. Adv Virus Res 2003;59:23e61. [11] Murray CL, Jones CT, Rice CM. Architects of assembly: roles of flaviviridae non-structural proteins in virion morphogenesis. Nat Rev Microbiol 2008;6:699e708. [12] Kuhn RJ, Zhang W, Rossmann MG, Pletnev SV, Corver J, Lenches E, et al. Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 2002;108:717e25. [13] Elshuber S, Allison SL, Heinz FX, Mandl CW. Cleavage of protein prM is necessary for infection of BHK-21 cells by tick-borne encephalitis virus. J Gen Virol 2003;84:183e91. [14] Welsch S, Miller S, Romero-Brey I, Merz A, Bleck CK, Walther P, et al. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. Cell Host Microbe 2009;5:365e75. [15] Bustos-Arriaga J, Garcia-Machorro J, Leon-Juarez M, Garcia-Cordero J, Santos-Argumedo L, Flores-Romo L, et al. Activation of the innate immune response against DENV in normal non-transformed human fibroblasts. PLoS Neglected Trop Dis 2011;5:e1420. [16] Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4:499e511. [17] Wang JP, Liu P, Latz E, Golenbock DT, Finberg RW, Libraty DH. Flavivirus activation of plasmacytoid dendritic cells delineates key elements of TLR7 signaling beyond endosomal recognition. J Immunol 2006;177:7114e21. [18] Warke RV, Xhaja K, Martin KJ, Fournier MF, Shaw SK, Brizuela N, et al. Dengue virus induces novel changes in gene expression of human umbilical vein endothelial cells. J Virol 2003;77:11822e32. [19] Seo YJ, Hahm B. Type I interferon modulates the battle of host immune system against viruses. Adv Appl Microbiol 2010;73:83e101. [20] Rothman AL. Dengue: defining protective versus pathologic immunity. J Clin Invest 2004;113:946e51. [21] Halstead SB, Simasthien P. Observations related to the pathogenesis of dengue hemorrhagic fever. II. Antigenic and biologic properties of dengue viruses and their association with disease response in the host. Yale J Biol Med 1970;42:276e92. [22] Roehrig JT, Bolin RA, Kelly RG. Monoclonal antibody mapping of the envelope glycoprotein of the dengue 2 virus, Jamaica. Virology 1998;246:317e28. [23] Lazaro-Olan L, Mellado-Sanchez G, Garcia-Cordero J, EscobarGutierrez A, Santos-Argumedo L, Gutierrez-Castaneda B, et al. Analysis of antibody response in human dengue patients from the Mexican coast using recombinant antigens. Vector Borne Zoonotic Dis 2008;8:69e79. [24] Modis Y, Ogata S, Clements D, Harrison SC. A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc Natl Acad Sci U S A 2003;100:6986e91. [25] Bressanelli S, Stiasny K, Allison SL, Stura EA, Duquerroy S, Lescar J, et al. Structure of a flavivirus envelope glycoprotein in its low-pHinduced membrane fusion conformation. EMBO J 2004;23:728e38. [26] Yu IM, Zhang W, Holdaway HA, Li L, Kostyuchenko VA, Chipman PR, et al. Structure of the immature dengue virus at low pH primes proteolytic maturation. Science 2008;319:1834e7. [27] Lorenz IC, Allison SL, Heinz FX, Helenius A. Folding and dimerization of tick-borne encephalitis virus envelope proteins prM and E in the endoplasmic reticulum. J Virol 2002;76:5480e91. [28] Lu H, Xu XF, Gao N, Fan DY, Wang J, An J. Preliminary evaluation of DNA vaccine candidates encoding dengue-2 prM/E and NS1: their immunity and protective efficacy in mice. Mol Immunol 2013;54:109e14.

Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

MICINF4171_proof ■ 13 August 2014 ■ 9/10

L. Cedillo-Barr
on et al. / Microbes and Infection xx (2014) 1e10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

[29] Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, et al. Cross-reacting antibodies enhance dengue virus infection in humans. Science 2010;328:745e8. [30] Beltramello M, Williams KL, Simmons CP, Macagno A, Simonelli L, Quyen NT, et al. The human immune response to dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity. Cell Host Microbe 2010;8:271e83. [31] Chan AH, Tan HC, Chow AY, Lim AP, Lok SM, Moreland NJ, et al. A human PrM antibody that recognizes a novel cryptic epitope on dengue E glycoprotein. PloS One 2012;7:e33451. [32] Rodenhuis-Zybert IA, van der Schaar HM, da Silva Voorham JM, van der Ende-Metselaar H, Lei HY, Wilschut J, et al. Immature dengue virus: a veiled pathogen? PLoS Pathog 2010;6:e1000718. [33] Flamand M, Megret F, Mathieu M, Lepault J, Rey FA, Deubel V. Dengue virus type 1 nonstructural glycoprotein NS1 is secreted from mammalian cells as a soluble hexamer in a glycosylation-dependent fashion. J Virol 1999;73:6104e10. [34] Kanlaya R, Pattanakitsakul SN, Sinchaikul S, Chen ST, Thongboonkerd V. Vimentin interacts with heterogeneous nuclear ribonucleoproteins and dengue nonstructural protein 1 and is important for viral replication and release. Mol BioSyst 2010;6:795e806. [35] Henchal EA, Henchal LS, Schlesinger JJ. Synergistic interactions of antiNS1 monoclonal antibodies protect passively immunized mice from lethal challenge with dengue 2 virus. J Gen Virol 1988;69(Pt 8):2101e7. [36] Chung KM, Nybakken GE, Thompson BS, Engle MJ, Marri A, Fremont DH, et al. Antibodies against west Nile virus nonstructural protein NS1 prevent lethal infection through Fc gamma receptordependent and -independent mechanisms. J Virol 2006;80:1340e51. [37] Lin CF, Wan SW, Cheng HJ, Lei HY, Lin YS. Autoimmune pathogenesis in dengue virus infection. Viral Immunol 2006;19:127e32. [38] Henriques HR, Rampazo EV, Goncalves AJ, Vicentin EC, Amorim JH, Panatieri RH, et al. Targeting the non-structural protein 1 from dengue virus to a dendritic cell population confers protective immunity to lethal virus challenge. PLoS Neglected Trop Dis 2013;7:e2330. [39] Chuang YC, Wang SY, Lin YS, Chen HR, Yeh TM. Re-evaluation of the pathogenic roles of nonstructural protein 1 and its antibodies during dengue virus infection. J Biomed Sci 2013;20:42. [40] Chen MC, Lin CF, Lei HY, Lin SC, Liu HS, Yeh TM, et al. Deletion of the C-terminal region of dengue virus nonstructural protein 1 (NS1) abolishes anti-NS1-mediated platelet dysfunction and bleeding tendency. J Immunol 2009;183:1797e803. [41] Muller DA, Young PR. The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antivir Res 2013;98:192e208. [42] Mathew A, West K, Kalayanarooj S, Gibbons RV, Srikiatkhachorn A, Green S, et al. B-cell responses during primary and secondary dengue virus infections in humans. J Infect Dis 2011;204:1514e22. [43] Corti D, Lanzavecchia A. Broadly neutralizing antiviral antibodies. Ann Rev Immunol 2013;31:705e42. [44] Chan KR, Ong EZ, Tan HC, Zhang SL, Zhang Q, Tang KF, et al. Leukocyte immunoglobulin-like receptor B1 is critical for antibodydependent dengue. Proc Natl Acad Sci U S A 2014;111:2722e7. [45] Gromowski GD, Barrett AD. Characterization of an antigenic site that contains a dominant, type-specific neutralization determinant on the envelope protein domain III (ED3) of dengue 2 virus. Virology 2007;366:349e60. [46] Nybakken GE, Oliphant T, Johnson S, Burke S, Diamond MS, Fremont DH. Structural basis of west Nile virus neutralization by a therapeutic antibody. Nature 2005;437:764e9. [47] Sukupolvi-Petty S, Austin SK, Purtha WE, Oliphant T, Nybakken GE, Schlesinger JJ, et al. Type- and subcomplex-specific neutralizing antibodies against domain III of dengue virus type 2 envelope protein recognize adjacent epitopes. J Virol 2007;81:12816e26. [48] Deng YQ, Dai JX, Ji GH, Jiang T, Wang HJ, Yang HO, et al. A broadly flavivirus cross-neutralizing monoclonal antibody that recognizes a novel epitope within the fusion loop of E protein. PloS One 2011;6:e16059. [49] Messer WB, de Alwis R, Yount BL, Royal SR, Huynh JP, Smith SA, et al. Dengue virus envelope protein domain I/II hinge determines long-

[50]

[51] [52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61] [62] [63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

9

lived serotype-specific dengue immunity. Proc Natl Acad Sci U S A 2014;111:1939e44. Imrie A, Meeks J, Gurary A, Sukhbaatar M, Truong TT, Cropp CB, et al. Antibody to dengue 1 detected more than 60 years after infection. Viral Immunol 2007;20:672e5. Sabin AB. Research on dengue during world war II. Am J Trop Med Hyg 1952;1:30e50. Smith SA, Zhou Y, Olivarez NP, Broadwater AH, de Silva AM, Crowe Jr JE. Persistence of circulating memory B cell clones with potential for dengue virus disease enhancement for decades following infection. J Virol 2012;86:2665e75. Sierra B, Garcia G, Perez AB, Morier L, Rodriguez R, Alvarez M, et al. Long-term memory cellular immune response to dengue virus after a natural primary infection. Int J Infect Dis 2002;6:125e8. Parameswaran P, Liu Y, Roskin KM, Jackson KK, Dixit VP, Lee JY, et al. Convergent antibody signatures in human dengue. Cell Host Microbe 2013;13:691e700. Smith SA, de Alwis R, Kose N, Durbin AP, Whitehead SS, de Silva AM, et al. Human monoclonal antibodies derived from memory B cells following live attenuated dengue virus vaccination or natural infection exhibit similar characteristics. J Infect Dis 2013;207:1898e908. Wrammert J, Onlamoon N, Akondy RS, Perng GC, Polsrila K, Chandele A, et al. Rapid and massive virus-specific plasmablast responses during acute dengue virus infection in humans. J Virol 2012;86:2911e8. Balakrishnan T, Bela-Ong DB, Toh YX, Flamand M, Devi S, Koh MB, et al. Dengue virus activates polyreactive, natural IgG B cells after primary and secondary infection. PloS One 2011;6:e29430. Manz RA, Lohning M, Cassese G, Thiel A, Radbruch A. Survival of long-lived plasma cells is independent of antigen. Int Immunol 1998;10:1703e11. Xu M, Hadinoto V, Appanna R, Joensson K, Toh YX, Balakrishnan T, et al. Plasmablasts generated during repeated dengue infection are virus glycoprotein-specific and bind to multiple virus serotypes. J Immunol 2012;189:5877e85. Tricou V, Minh NN, Farrar J, Tran HT, Simmons CP. Kinetics of viremia and NS1 antigenemia are shaped by immune status and virus serotype in adults with dengue. PLoS Neglected Trop Dis 2011;5:e1309. Halstead SB. Neutralization and antibody-dependent enhancement of dengue viruses. Adv Virus Res 2003;60:421e67. Halstead SB, O'Rourke EJ. Antibody-enhanced dengue virus infection in primate leukocytes. Nature 1977;265:739e41. Kliks SC, Nisalak A, Brandt WE, Wahl L, Burke DS. Antibody-dependent enhancement of dengue virus growth in human monocytes as a risk factor for dengue hemorrhagic fever. Am J Trop Med Hyg 1989;40:444e51. Littaua R, Kurane I, Ennis FA. Human IgG Fc receptor II mediates antibody-dependent enhancement of dengue virus infection. J Immunol 1990;144:3183e6. Kontny U, Kurane I, Ennis FA. Gamma interferon augments Fc gamma receptor-mediated dengue virus infection of human monocytic cells. J Virol 1988;62:3928e33. Boonnak K, Slike BM, Donofrio GC, Marovich MA. Human FcgammaRII cytoplasmic domains differentially influence antibody-mediated dengue virus infection. J Immunol 2013;190:5659e65. Rodrigo WW, Jin X, Blackley SD, Rose RC, Schlesinger JJ. Differential enhancement of dengue virus immune complex infectivity mediated by signaling-competent and signaling-incompetent human Fcgamma RIA (CD64) or FcgammaRIIA (CD32). J Virol 2006;80:10128e38. Boonnak K, Slike BM, Burgess TH, Mason RM, Wu SJ, Sun P, et al. Role of dendritic cells in antibody-dependent enhancement of dengue virus infection. J Virol 2008;82:3939e51. Libraty DH, Acosta LP, Tallo V, Segubre-Mercado E, Bautista A, Potts JA, et al. A prospective nested case-control study of dengue in infants: rethinking and refining the antibody-dependent enhancement dengue hemorrhagic fever model. PLoS Med 2009;6:e1000171. Kliks SC, Nimmanitya S, Nisalak A, Burke DS. Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am J Trop Med Hyg 1988;38:411e9.

Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

MICINF4171_proof ■ 13 August 2014 ■ 10/10

10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

L. Cedillo-Barr
on et al. / Microbes and Infection xx (2014) 1e10

[71] Chau TN, Hieu NT, Anders KL, Wolbers M, Lien le B, Hieu LT, et al. Dengue virus infections and maternal antibody decay in a prospective birth cohort study of Vietnamese infants. J Infect Dis 2009;200:1893e900. [72] Anders KL, Nguyen NM, Van Thuy NT, Hieu NT, Nguyen HL, Hong Tham NT, et al. A birth cohort study of viral infections in Vietnamese infants and children: study design, methods and characteristics of the cohort. BMC Public Health 2013;13:937. [73] Laoprasopwattana K, Libraty DH, Endy TP, Nisalak A, Chunsuttiwat S, Vaughn DW, et al. Dengue virus (DV) enhancing antibody activity in preillness plasma does not predict subsequent disease severity or viremia in secondary DV infection. J Infect Dis 2005;192:510e9. [74] Vaughn DW, Green S, Kalayanarooj S, Innis BL, Nimmannitya S, Suntayakorn S, et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 2000;181:2e9. [75] Balsitis SJ, Williams KL, Lachica R, Flores D, Kyle JL, Mehlhop E, et al. Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog 2010;6:e1000790. [76] Puerta-Guardo H, Raya-Sandino A, Gonzalez-Mariscal L, Rosales VH, Ayala-Davila J, Chavez-Mungia B, et al. The cytokine response of U937derived macrophages infected through antibody-dependent enhancement of dengue virus disrupts cell apical-junction complexes and increases vascular permeability. J Virol 2013;87:7486e501. [77] Kou Z, Lim JY, Beltramello M, Quinn M, Chen H, Liu S, et al. Human antibodies against dengue enhance dengue viral infectivity without suppressing type I interferon secretion in primary human monocytes. Virology 2011;410:240e7. [78] Boonnak K, Dambach KM, Donofrio GC, Tassaneetrithep B, Marovich MA. Cell type specificity and host genetic polymorphisms influence antibody-dependent enhancement of dengue virus infection. J Virol 2011;85:1671e83. [79] Moi ML, Lim CK, Kotaki A, Takasaki T, Kurane I. Detection of higher levels of dengue viremia using FcgammaR-expressing BHK-21 cells than FcgammaR-negative cells in secondary infection but not in primary infection. J Infect Dis 2011;203:1405e14.

[80] Mota J, Rico-Hesse R. Dengue virus tropism in humanized mice recapitulates human dengue fever. PloS One 2011;6:e20762. [81] Onlamoon N, Noisakran S, Hsiao HM, Duncan A, Villinger F, Ansari AA, et al. Dengue virus-induced hemorrhage in a nonhuman primate model. Blood 2010;115:1823e34. [82] Clark KB, Onlamoon N, Hsiao HM, Perng GC, Villinger F. Can nonhuman primates serve as models for investigating dengue disease pathogenesis? Front Microbiol 2013;4:305. [83] Koraka P, Murgue B, Deparis X, Setiati TE, Suharti C, van Gorp EC, et al. Elevated levels of total and dengue virus-specific immunoglobulin E in patients with varying disease severity. J Med Virol 2003;70:91e8. [84] Thein S, Aaskov J, Myint TT, Shwe TN, Saw TT, Zaw A. Changes in levels of anti-dengue virus IgG subclasses in patients with disease of varying severity. J Med Virol 1993;40:102e6. [85] Rothman AL. Immunology and immunopathogenesis of dengue disease. Adv Virus Res 2003;60:397e419. [86] Priyadarshini D, Gadia RR, Tripathy A, Gurukumar KR, Bhagat A, Patwardhan S, et al. Clinical findings and pro-inflammatory cytokines in dengue patients in western India: a facility-based study. PloS One 2010;5:e8709. [87] Bozza FA, Cruz OG, Zagne SM, Azeredo EL, Nogueira RM, Assis EF, et al. Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity. BMC Infect Dis 2008;8:86. [88] Becquart P, Wauquier N, Nkoghe D, Ndjoyi-Mbiguino A, Padilla C, Souris M, et al. Acute dengue virus 2 infection in Gabonese patients is associated with an early innate immune response, including strong interferon alpha production. BMC Infect Dis 2010;10:356. [89] Srikiatkhachorn A, Ajariyakhajorn C, Endy TP, Kalayanarooj S, Libraty DH, Green S, et al. Virus-induced decline in soluble vascular endothelial growth receptor 2 is associated with plasma leakage in dengue hemorrhagic fever. J Virol 2007;81:1592e600. [90] Rathakrishnan A, Wang SM, Hu Y, Khan AM, Ponnampalavanar S, Lum LC, et al. Cytokine expression profile of dengue patients at different phases of illness. PloS One 2012;7:e52215. [91] Ubol S, Phuklia W, Kalayanarooj S, Modhiran N. Mechanisms of immune evasion induced by a complex of dengue virus and preexisting enhancing antibodies. J Infect Dis 2010;201:923e35.

Please cite this article in press as: Cedillo-Barr
on L, et al., Antibody response to dengue virus, Microbes and Infection (2014), http://dx.doi.org/10.1016/ j.micinf.2014.07.011

39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76