The Structural Basis for Serotype-Specific Neutralization of Dengue Virus by a Human Antibody

The mechanism of action of a serotype-specific natural human antibody against dengue virus has been identified. Defeating Dengue Dengue virus is a major mosquito-borne viral pathogen that is transmitted through the bite of an infected mosquito. Infection can be asymptomatic, cause a self-limiting fever, or result in potentially fatal hemorrhage. There are no approved vaccines or antiviral therapies for dengue, and current treatment is restricted to fluid replacement. Thus, there is an urgent need for new treatment options for this disease. Dengue virus consists of four related but distinct serotypes, and infection is thought to elicit lifelong immunity to the infecting serotype in patients who recover but only short-term immunity against the other serotypes. Immunity is mediated by serotype-specific antibodies, but little is known about their specificity or mode of action. Now, Teoh et al. characterize a neutralizing human monoclonal antibody induced by natural dengue infection. This antibody is specific for dengue virus serotype 1 and shows little or no binding or neutralizing activity for serotypes 2, 3, and 4. The authors demonstrate that the antibody binds across two adjacent viral envelope proteins and identify the amino acids that comprise the binding site. The antiviral activity of this antibody is linked principally to a blockade of virus binding to target host cells. Treatment with this antibody results in increased survival in a mouse model of dengue virus infection. This human antibody represents a new therapeutic candidate for treating dengue serotype 1 infection. These findings also provide a structural and molecular context for understanding the nature of durable, serotype-specific immunity to dengue infection and thus have implications for the design and evaluation of vaccines against dengue. Dengue virus (DENV) is a mosquito-borne flavivirus that affects 2.5 billion people worldwide. There are four dengue serotypes (DENV1 to DENV4), and infection with one elicits lifelong immunity to that serotype but offers only transient protection against the other serotypes. Identification of the protective determinants of the human antibody response to DENV is a vital requirement for the design and evaluation of future preventative therapies and treatments. Here, we describe the isolation of a neutralizing antibody from a DENV1-infected patient. The human antibody 14c10 (HM14c10) binds specifically to DENV1. HM14c10 neutralizes the virus principally by blocking virus attachment; at higher concentrations, a post-attachment step can also be inhibited. In vivo studies show that the HM14c10 antibody has antiviral activity at picomolar concentrations. A 7 Å resolution cryoelectron microscopy map of Fab fragments of HM14c10 in a complex with DENV1 shows targeting of a discontinuous epitope that spans the adjacent surface of envelope protein dimers. As found previously, a human antibody specific for the related West Nile virus binds to a similar quaternary structure, suggesting that this could be an immunodominant epitope. These findings provide a structural and molecular context for durable, serotype-specific immunity to DENV infection.