Response to dengue fever--the good, the bad, and the ugly?

Dengue may be the most widespread arboviral illness worldwide. Most patients with dengue infection have only mild disease or classic dengue fever, with influenza-like symptoms, severe headache, and aching joints and muscles. However, in a small percentage of patients — maybe half a million people every year — potentially lethal forms of dengue called dengue hemorrhagic fever and dengue shock syndrome develop. It has been known for many years that antibodies directed against either of the two surface proteins of the dengue virus (the precursor membrane protein and the envelope protein) can neutralize infectivity and confer protection, although envelope protein is known to be the more important protective antigen. Paradoxically, antibodies against either protein can also enhance infectivity, depending on their specificity, avidity, and concentration. Dejnirattisai et al.1 recently reported that after a secondary dengue infection, a large proportion of the human antibody repertoire is directed against the precursor membrane protein on immature virus particles. This observation might be pertinent to the development of inactivated dengue vaccines. Two to three billion people in tropical and subtropical climates are at risk for dengue infection, and an estimated 50 million infections occur each year, mostly in urban areas. The four dengue serotypes are transmitted by mosquitoes, and the ongoing spread of serotypes and of the vectors (mosquitoes) has now reached more than 100 countries, including the United States. The clinical picture of dengue fever is highly variable, particularly with age. Young children might simply have fever and a rash, whereas classic dengue fever is more likely to develop in older children and adults. If dengue fever progresses to dengue hemorrhagic fever at the time of defervescence, it generally manifests as a capillary leak syndrome accompanied by thrombocytopenia and abnormalities in coagulation and in liver function, potentially resulting in shock, bleeding, and organ failure. Lifelong immunity against the infecting serotype (so-called homotypic immunity) is conferred by virus-neutralizing antibodies. Antibodies induced by one serotype can cross-react with the other serotypes (heterotypic immunity), but heterotypic neutralizing titers wane over time. Below a certain threshold and depending on antibody specificity, antibodies fail to neutralize and instead opsonize; this helps the virus to infect cells bearing IgG receptors. This phenomenon, termed “antibody-dependent enhancement,” increases the number of infected cells and is thought to lead to higher virus titers and a more pronounced inflammatory response. Antibodydependent enhancement has been thought to