Researchers from the A*STAR Singapore Immunology Network and Institute for Infocomm Research have shown how a virus can re-emerge as an epidemic after laying dormant for more than 20 years by mutating to avoid detection by the immune system.
Chikungunya virus is a mosquito-borne virus that causes fever, headache, nausea and vomiting, often accompanied by severe muscle pain that can last several years. The virus infected some 100,000 people in Africa and Asia between the 1960s and 1980s (Fig. 1) before becoming inactive.
Recently, however, a more virulent strain of chikungunya virus that can enter the brain and cause fatal haemorrhaging has emerged. Outbreaks have infected millions in Southeast Asia and the Pacific, but why the virus has re-surfaced after more than 20 years has remained unclear.
To examine genetic diversity of the virus and how it has changed over time, lead investigators Lisa Ng and Victor Tong compared chikungunya virus DNA and protein sequences obtained from individuals who were infected in different parts of the world between the 1950s and the present.
The analysis revealed that viruses isolated from individuals in India, Mauritius and Senegal since 1983 had accumulated up to seven different mutations within a specific region of a structural protein called E2. It also revealed numerous mutations in the genes encoding other structural proteins.
The researchers used mathematical and statistical techniques, called bioinformatics, to predict how the mutations might affect binding of human leukocyte antigen (HLA) molecules — key components of the human immune system — to the virus. This showed that 62 of the mutations resulted in the inability of all 41 known HLA molecules to bind to the structural virus proteins.
The mutated region of the E2 protein is normally recognized by HLA molecules, which then ‘present’ it to the cells that produce antibodies, so that a stronger defense can be mounted. The immune response itself may therefore be the driving force behind virus evolution.
Mutation of the E2 domain thus enables the virus to evade the immune system, making it more virulent. The researchers speculate that changes in E2 structure prevent HLA binding, or interfere with the immune response in other ways. The mutations may also increase transmission of the virus, and enable it to replicate more efficiently within its mosquito carriers.
“We are currently tracking new outbreaks of chikungunya virus and constantly updating our databases with the newly added information,” says Ng, adding that their findings will become “important baseline data which could be used for vaccine designs.”
This work is part of an A*STAR Joint Council Office (JCO) Grant project. The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network and the Institute for Infocomm Research.