South American Zika Strain May Have Asian Ancestor

A commentary in press at the journal Cell Host and Microbe presents the findings of a phylogenetic and genetic analysis as well as the targeted structural modeling of all known, full-length open reading frames (ORFs) of the Zika virus available to date, revealing numerous sequence variations between the African and Asian lineages of the virus, as well as different strains of the Asian lineage, and highlighting a potential role for these variations in disease virulence.

The international team of researchers from UCLA, the Evandro Chagas National Institute of Infectious Diseases and the Oswaldo Cruz Foundation in Rio de Janeiro, and the Center for Systems Medicine/Institute of Basical Medical Sciences at the Chinese Academy of Medical Sciences in Beijing write that “the rapid expansion of geographic range and increase in severe pathogenicity first noted in the 2015-2016 Brazilian outbreak has raised questions regarding the molecular evolution of this virus.” They analyzed nucleotide sequences from 41 strains (30 human isolates, including two newly identified by the team), 10 mosquito isolates, and one monkey isolate), first identifying the phylogenetic relationships for all full-length ORF sequences by using maximum likelihood (ML) mapping method with 1,000 replicates.

They found that the African lineage contained eight mosquito isolates, compared to only one (P6-740 or Malaysia/1966) in the Asian lineage, and that all contemporary human strains share greater sequence homology to P6-740 than IbH-30656 (Nigeria/1968), which suggests that the virus strains in the most recent outbreak in the Americas are evolved from the Asian lineage. Their analysis also revealed that all of the human strains identified in the ongoing epidemic appear to be more closely related to the H/PF/2013 strain (French Polynesia/2013) than the FSM strain (Micronesia/2007), which may mean that these two variants have evolved “in parallel from a common ancestor.”

In addition, compared to the mosquito strain of the Zika virus, the authors identified 435 and 446 nucleotide changes in FSM and H/PF/2013, respectively, and that, among them, 344 nucleotides are identical. This could mean that the two Asian sub-lineages have diverged from a common ancestor, arrived in Malaysia, established niches, and later dispersed to South America.

“The goal of our study was to see whether there were genetic changes in the viral sequence that could explain why Zika was thought to be a benign disease until now,” study co-author Stephanie Valderramos, MD, PhD, Department of Microbiology, Immunology and Molecular Genetics and Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA told Contagion. “We found that there are have been significant mutations in the virus since its discovery in 1947. Next steps are to determine which, if any, of these mutations could have made the virus more capable of causing the severe disease that we see today.”

The authors also compared the amino acid sequences between eight African strains (seven from mosquitos and one from a monkey) and 25 Asian strains isolated from humans and found that there were 59 amino acid variations located throughout the viral polyprotein sequence that are shared among the individual strains within the African or Asian lineages but are different between these two major lineages.

In their concluding remarks, the authors wrote, “It is unclear why the ZIKV strain that already existed in 1966 in Malaysia did not have a significant clinical impact until 50 years later in Oceania. A more rigorous analysis of the potential relationship between the genetic changes and epidemiological topography is required, which will be possible as we gain further sequence information on currently circulating clinical strains and their associated pathology… Our phylogenic analysis builds upon prior studies by the addition of the most recent human strains to the analysis and further supports the existence of two divergent African and Asian lineages.”

“We have a lot to learn about Zika,” Dr. Valderramos added. “From a clinical perspective, we need to improve our ability to diagnose Zika infection, and learn more about the spectrum of disease that is caused by Zika. We also need research [to improve] understanding the various modes and kinetics of viral transmission, and how to block the cycle. And of course treatment with antiviral agents or prevention of disease with a vaccine would be the ultimate goal.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.