The role of antibodies to DI/DII is less clear as they tend to be more cross-reactive and less potent in neutralization ( Crill and Chang, 2004 Goncalvez et al., 2004 Oliphant et al., 2006). DIII-reactive antibodies produced by mice immunized with virus and boosted with recombinant E protein are largely serotype-specific and do not neutralize all the genotypes within a given serotype ( Shrestha et al., 2010). The most potent neutralizing antibodies against DENV, or other flaviviruses such as West Nile Virus (WNV), bind to DIII and have been shown in some cases to be effective as passive prophylaxis or therapy in rodents ( Beasley and Barrett, 2002 Goncalvez et al., 2008 Gromowski et al., 2008 Kaufman et al., 1987 Oliphant et al., 2005 Sanchez et al., 2005 Shrestha et al., 2010 Sukupolvi-Petty et al., 2007). Partially mature virions also express varying levels of prM protein on their surface, which is normally cleaved by a furin-like cellular protease to generate the mature virion ( Stadler et al., 1997). Domain I (DI) participates in the conformational changes required for viral entry and nucleocapsid escape from the endosomal compartment, domain II (DII) contains the fusion loop, and domain III (DIII) has been suggested to bind cellular receptors ( Bhardwaj et al., 2001 Chin et al., 2007 Chu et al., 2005 Rey et al., 1995). The E protein is structurally conserved among flaviviruses and consists of three distinct domains. The 10.7 Kb RNA genome of DENV encodes three structural proteins, the capsid protein (C), a membrane-associated protein (prM), and an envelope protein (E), and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). The difficulty of balancing immunity to the four serotypes and minimizing incomplete response and the risk of ADE are major hurdles in the development of a tetravalent vaccine against DENV ( Whitehead et al., 2007). The role of antibodies in severe dengue is supported by epidemiological studies showing that infants with waning levels of maternal antibodies (age 6–9 months) are most vulnerable to severe DENV disease ( Halstead et al., 2002 Nguyen et al., 2004), and that serum from these infants enhances DENV infection in vitro ( Chau et al., 2008 Kliks et al., 1988). Poorly neutralizing cross-reactive antibodies raised in response to a previous serotype are believed to contribute to pathogenesis of severe dengue by promoting virus entry via Fcγ receptors (FcγR) and infection of myeloid cells ( Halstead, 2003), leading to antibody-dependent enhancement (ADE) of infection. Classical epidemiologic studies suggested that immunity to one of the four DENV serotypes can increase disease severity upon subsequent challenge with a different serotype leading, in some cases, to severe dengue, a disease characterized by plasma leakage and hemorrhagic manifestations ( Halstead, 1970). A primary infection is believed to provide effective, durable and possibly life-long protection against re-infection with the same serotype, but only short-term protection against other serotypes ( Rothman, 2004). Our findings reveal an unexpected degree of cross-reactivity in human antibodies against DENV and illustrate the potential for an antibody-based therapy to control severe dengue.ĭengue virus (DENV) is a mosquito-borne Flavivirus responsible for tens of millions of human cases of dengue annually, including 500,000 hospitalizations and 20,000 deaths ( Gibbons and Vaughn, 2002), with an economic burden rivaling that of malaria. Three mAbs targeting distinct epitopes on the four DENV serotypes and engineered to prevent FcγR binding did not enhance infection and neutralized DENV in vitro and in vivo as postexposure therapy in a mouse model of lethal DENV infection. All mAbs enhanced infection at subneutralizing concentrations. DI/DII- or viral membrane protein prM-reactive mAbs neutralized poorly and showed broad cross-reactivity with the four DENV serotypes. MAbs to envelope (E) protein domain III (DIII) were either serotype specific or cross-reactive and potently neutralized DENV infection. We immortalized memory B cells from individuals after primary or secondary infection and analyzed anti-DENV monoclonal antibodies (mAbs) thus generated. Antibodies protect against homologous Dengue virus (DENV) infection but can precipitate severe dengue by promoting heterotypic virus entry via Fcγ receptors (FcγR).
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