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Zika Virus Sequence Analysis Reveals Structural Change to Key Viral Protein

NEW YORK (GenomeWeb) – An analysis of Zika virus sequences has revealed that the virus has undergone both nucleotide and protein sequence changes during the past 50 years.

Researchers from Brazil, China, and the US examined the phylogenetic relationships between 41 Zika virus strains collected from the current outbreak in South America, as well as from previous outbreaks in Polynesia, Malaysia, and Nigeria. As they reported today in Cell Host & Microbe, the researchers found genetic changes specific to the African and Asian viral lineages in addition to amino acid substitutions that appear to lead to structural changes in a key viral protein in the Asian strain that could affect virulence.

"We believe these changes may, at least partially, explain why the virus has demonstrated the capacity to spread exponentially in the human population in the Americas," senior author Genhong Cheng, a professor at the University of California, Los Angeles, said in a statement. "These changes could enable the virus to replicate more efficiently, invade new tissues that provide protective niches for viral propagation, or evade the immune system, leading to viral persistence."

Chen and his colleagues examined the nucleotide sequences of 41 strains —including 30 human, one monkey, and 10 mosquito isolates — of the Zika virus. The virus, they noted, is a single-stranded RNA flavivirus whose 10,800-base-pair genome is made up of one open reading frame from which multiple proteins are generated. The strains the researchers studied included newly reported ones as well as ones that had previously circulated in Africa or Asia.

Using maximum likelihood mapping based on the full ORF sequences, the researchers generated a phylogenetic tree reflecting the relationships among the viral isolates. As expected, the tree reflected two Zika virus lineages, African and Asian.

All the strains from the recent South American outbreaks exhibited greater similarity with the 1966 Malaysian strain than the 1968 Nigerian one, suggesting that the current outbreak strains have evolved from the Asian lineage. Further, the outbreak strains are more similar to the 2013 French Polynesian strain than the 2007 Micronesian strain. This, the authors added, indicates that these two strains likely evolved in parallel from a common ancestor.

Intriguingly, eight of the mosquito-derived isolates belonged to the African lineage and one to the Asian lineage. The researchers also noted that the Zika virus has yet to be isolated from a mosquito in the current outbreak.

By focusing on four human strains isolated from patients whose clinical data was available, Chen and his colleagues searched for nucleotide changes that could potentially account for the virus's seemingly increased recent clinical impact. Each of these four isolates, obtained from patients, harbored between 13 and 15 nucleotide changes that led to between one and three amino acid-level changes, as compared to other Asian-lineage viruses

When the researchers compared the amino acid sequences of the African and Asian lineages, they noted 59 amino acid variations that were shared by members of the same lineage but not by the other lineage. As compared to the Asian mosquito isolate, the current outbreak strains harbored 34 amino acid changes.

The researchers traced about 10 percent of the amino acid changes between the Asian human and African mosquito strains to the pr region of the prM protein, which plays a key role in viral assembly, maturation, secretion, and virulence. Through modeling, they predicted that these changes would lead to dramatic structural changes, though they also noted that the consequences of these changes are as yet unclear.

"Our modeling studies suggest that these sequence variations could mediate specific changes in the prM protein, which could play a role in virulence or improved fitness," Chen and his colleagues wrote. However, they added that further studies are needed to assess which substitutions may be responsible for such increased virulence or fitness.