A Viral Trojan Horse

Viruses Are Cool #3
Click here to read the introduction to this series.

A recent Nature article entitled "Dengue Fever Climbs the Social Ladder" has brought attention to a viral disease that is endemic in many tropical countries, but is little known here. The article discusses how the increasing wealth of dengue fever patients in Asia is driving new efforts by drug companies to develop a vaccine, and highlights some troubling, if not surprising, issues regarding how drug companies (and indeed, governments) select the diseases in which to invest research dollars and effort.

Whether development of vaccines should be determined primarily by potential benefit or potential return--i.e., how many people would benefit from the vaccine versus how much people would pay for it--is certainly a topic worth discussing. But this post will focus on the viral agents of dengue fever, which provide an interesting example of how our own immune responses can sometimes be our downfall.

Dengue fever is a mosquito-borne disease characterized by high fever, headache, and muscle and joint pain. There are ~100 million cases of dengue fever a year worldwide, but it is rarely fatal and patients typically recover completely. In contrast, the related dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), of which there are ~450,000 cases annually, have fatality rates ranging from 1-10% depending on the availability and quality of medical care. The odd thing about dengue fever and DHF/DSS is that they are both caused by dengue virus infection. So why do some people get dengue fever while others develop the much more severe DHF/DSS?

Dengue virus, a positive-sense single-stranded RNA virus from family Flaviviridae and genus flavivirus, actually exists in four distinct serotypes known as dengue-1, -2, -3, and -4. The serotypes differ in their antigens; in other words, they "look different" and can be distinguished from each other by our immune system. During infection, our immune system develops antibodies specific to the antigens of the infecting serotype. These antibodies are capable of neutralizing virus of that serotype, and thereby protect us from future infection with that serotype. For example, someone who has a primary infection with dengue-1 virus may develop dengue fever, and upon recovery, will have lifelong immunity to dengue-1.

Epidemiological evidence indicates that risk of developing DHF/DSS increases when someone with pre-existing immunity to one serotype subsequently becomes infected with virus of a different serotype. Our exemplar patient who has lifelong immunity to dengue-1 is much more likely to develop DHF/DSS upon secondary infection with dengue-3, for example, than someone with a primary infection. This is believed to be due to a phenomenon called antibody-dependent enhancement. The dengue-1-specific antibodies do not recognize dengue-3 well enough to neutralize it, but because of similarities between dengue-1 and dengue-3 antigens, the dengue-1 antibodies can bind dengue-3 virus to some extent. The coating of virus with antibodies causes it to be "eaten" by immune cells such as macrophages through a process called phagocytosis.

Phagocytosis of antibody-coated foreign particles by macrophages is exactly what our immune system is supposed to do. But in this case, unfortunately, there is a twist in the storyline: dengue virus likes to replicate in macrophages. So by facilitating uptake of the virus into macrophages, our antibodies essentially carry the viral Trojan horse into our own fort. This results in increased viral replication and viral load, which contributes to the pathogenesis of DHF/DSS. It's a lose-lose situation for the immune response--generation of neutralizing antibodies exacerbates disease upon secondary infection, but without those antibodies, there would be no immunity to reinfection.

Antibody-dependent enhancement in secondary dengue virus infection is one of the reasons development of a vaccine has been complicated. An effective vaccine would have to generate complete immunity to all four serotypes to avoid increased incidences of DHF/DSS. Two strategies currently being explored are use of a live attenuated mixture of all four viral serotypes, and generation of a chimeric virus containing antigenic regions from all four serotypes. Until there is a vaccine on the market, our best defense against dengue infection is prevention through mosquito control.

References

• Knipe, D.M. & Howley, P.M., eds. Fields Virology. Philadelphia: Lippincott, 2001.
• Nat Rev Microbiol 5:518-28

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