A lineage of type 1 dengue virus found in Brazil is able to prevail over another even though it multiplies less in vector mosquitoes and infected human cells. This discovery was made under the scope of a Thematic Project supported by the São Paulo Research Foundation – FAPESP involving several Brazilian institutions as well as a university in the United States.
According to the study, the lineage activates a weaker immune response in the patient and is less strongly combated. As a result, the virus is able to multiply more in the organism and is more likely to be transmitted to others via infected mosquitoes, so that this lineage supersedes the other owing to its significantly greater overall capacity to multiply in mosquitoes and patients.
The researchers studied lineages 1 and 6 (L1 and L6) of type 1 dengue, which affect the population of São José do Rio Preto, São Paulo State, Brazil. Their findings showed that while L1 had a superior capacity to multiply in mosquitoes and cells, L6 was able to minimize and even deactivate the human immune response, so that this lineage ended up replacing L1.
"There were three approaches to investigating the situations in which dengue virus multiplies and to explain why one lineage supersedes another. Our research brought to light a new phenomenon that explains how a virus survives in a population," said Maurício Lacerda Nogueira.
Production of dengue vaccines
The study produced vital new knowledge for the production of dengue vaccines. "A global understanding of how the virus interacts with the population helps us understand how vaccines work and is fundamental to our ability to design them," he said.
Type 1 dengue virus has been circulating in Brazil since the mid-1980s. Three lineages (L1, L3 and L6, all belonging to the same genotype) were introduced at different times.
L1 was expected to display a higher capacity to multiply in cells and in the vector mosquito, Aedes aegypti, since it arrived after L6 and its viral fitness appeared to be superior to that of L6. L1 was therefore expected to replace L6 as the dominant strain, but it began to decline in 2013 and eventually disappeared.
This fact contradicted existing scientific knowledge about the prevalence of one lineage over another – a phenomenon called clade replacement (a clade is a branch of a phylogenetic tree comprising all organisms that have evolved from a common ancestor).
Clade replacement occurs if a lineage multiplies more in human cells after being introduced than another lineage that was already living in the same environment, or if a lineage that arrives later multiplies more in the mosquito. In both cases, the lineage that supersedes the other is said to have a higher level of viral fitness.
"Based on the information available at the time, it was assumed that L6 multiplied better and therefore became dominant, but when we looked at contaminated human and monkey cells, we found that L1 multiplied ten times more on average than L6," said the coordinator for the FAPESP Thematic Project.
The next hypothesis was that L6's higher viral fitness might be due to its higher multiplication rate in the mosquito. The researchers therefore infected captive mosquitoes (bred for use in scientific experiments) orally, having them feed by biting a membrane that contained mouse blood contaminated with dengue virus L1 and L6. "Again, L1 multiplied ten times better than L6 in the mosquito," Nogueira said.
"Using epidemiological, phylogenetic, molecular and immunological analysis, the authors of the research showed that differences in the host's immune response determine the dynamics of circulation in two lineages of dengue virus found in the city, suggesting that the factors that influence the dynamics of dengue transmission are far more complex than was previously thought," Vasilakis said.