Flying under the radar: mosquito-borne virus uses nonoptimal codons to infect host

Researchers have found that dengue virus infects mosquito and human hosts using nonoptimal synonymous codons, potentially to avoid triggering an antiviral response.

Researchers at the Stowers Institute for Medical Research (MO, USA) have discovered that dengue virus, in addition to hundreds of other viruses, replicates in mosquito and human hosts using nonoptimal, less efficient codons. This strategy is thought to make the viruses less easily detected by the host, preventing an antiviral response. However, now that their strategy has been revealed, this breakthrough could aid the development of vaccines and novel antivirals against the most prevalent mosquito-borne viral disease in the world.

Viruses don’t contain the machinery necessary to replicate; therefore, they rely on host cells’ protein-making machinery to transform their RNA code into proteins that allow for viral propagation. This viral genetic code is composed of codons, the optimality of which is of key interest to the researchers of the current study.

Codons are sequences of three nucleotides that encode an amino acid. There are 64 codons encoding 20 amino acids; those codons that encode the same amino acid are referred to as synonymous codons. However, just because these codons encode the same amino acid, it doesn’t mean they don’t have distinct effects on cellular efficiency. A certain synonymous codon can be optimal and efficient in one species and nonoptimal in another; this is called codon optimality.

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Using RNA-seq to create endogenous mRNA decay profiles, the team discovered that mosquitoes exhibit codon optimality, much like how humans do. They went on to find that dengue viruses often use synonymous codons that are nonoptimal in their mosquito and human hosts, which they worked out by calculating the relative synonymous codon usage (RSCU) fold change as the ratio of viral RSCU to host RSCU. This was not what they expected: “Viruses accumulate mutations during infection of their hosts. We were surprised to find that mutations in the dengue virus genome toward these less efficient codons increased dengue virus fitness in both mosquito and human cells,” reported Ryan McNamara, co-author of the study.

They calculated the correlation between RSCU fold change and human codon stability coefficient for 483 other human-infecting viruses, finding that many – including HIV and SARS-CoV-2 – also use less efficient codons relative to humans.

This viral preference for using nonoptimal synonymous codons appears to be an evolutionarily conserved characteristic, indicating that having an inefficient genome is a benefit for the virus. The team hypothesized that this characteristic could have evolved to avoid triggering an antiviral response. “In the future, we hope to better understand the mechanism by which viruses are benefitting from using these inefficient codons, and which molecules viruses may be manipulating to gain control,” concluded first author Luciana Castellano.

This research provides much-needed insights into virus evolution as well as host–pathogen relationships. As mosquitoes and mosquito-borne viruses become more widespread, it is essential that we understand the mechanisms underlying infection so we can develop novel antivirals and vaccines.