Since first making waves in 2015, news coverage of Zika virus and Zika fever infections has decreased in major news outlets. A concomitant decrease in Google searches for “Zika” (see figure, right) suggests the emerging disease has moved to the further corners of public consciousness (at least until the weather warms up and mosquitos resume biting). Though Zika may not make the headlines like it did during the 2016 Olympics, it remains a serious issue that scientists continue to study in order to devise treatment and prevention strategies. Many different areas of study have been forwarded in recent months through the hard work of these researchers, and ASM Journals have been proud to publish a number of their recent studies.
Population Genetics and Epidemiology
Tracking the mutations and diversity of circulating strains helps researchers understand Zika virus populations as well as where in the world the virus is found. A Genome Announcements study demonstrated that isolate diversity decreases after the patient-derived virus is grown in cell culture; within a patient, single-nucleotide polymorphisms appear common.
Portable Zika virus sequencing, a potential diagnostic tool to differentiate it from viral infections with similar symptoms, increased with the publication of two Nanopore-derived viral genomes isolated from Ecuadorian patients, also in Genome Announcements. These are the first two confirmed Zika cases in Ecuador, which doesn’t share a border with Brazil. Neither patient had recently visited Brazil, so the question remaining is how the virus migrated across South America.
Antiviral targets and strategies
The crystal structure of Zika Virus NS5-MTase may help in future drug design. Source.
The race is on for an effective antiviral to treat those infected with Zika virus. Deciphering the structure of viral proteins necessary for replication allows fine-tuning of inhibitors of these necessary processes. A Journal of Virology study revealed the structure of the Zika NS5 protein (see figure, right), a methyltransferase (MTase) that methylates the viral mRNA cap, a required process for viral replication. As with many Zika studies, the authors were able to apply findings from Dengue virus studies, by investigating Dengue virus MTase inhibitor effects on Zika MTase. Almost all inhibitory compounds inhibited Zika MTase activity and thus its replication, suggesting this mechanism may not treat Zika and Dengue but may act as a pan-Flavivirus therapeutic strategy.
The search for effective antiviral molecules requires synergy from many different studies, however, and these studies are nicely summarized in an Antimicrobial Agents and Chemotherapy minireview. This includes a number of compound library studies, repurposed FDA-approved drugs, and broad-spectrum antiviral targeting common structures like the NS5 gene listed above. The review compiles the latest research on directly antiviral compounds, therapeutic antibodies, and host-targeting molecules that target host cell factors involved in the Zika virus life cycle.
Similarities between the Zika and dengue viruses have led to incorrect diagnoses, and because both viruses can circulate in the same populations, accurate diagnostic tests have been hard to design. An ELISA assay specific for antibodies against Zika NS1 protein has been promising, with a recent Journal of Clinical Microbiology study demonstrating nearly 80% sensitivity up to 3 years post-symptom onset (though this was observed for only 1 patient). The ability to track exposure over long periods of time will greatly help scientists to diagnose infections as well as understand exposure patterns from those in Zika-affected areas.
Areas where neither Zika nor dengue are prevalent also face challenges in diagnostics. A New York study looked at the first 80 cases of Zika diagnosed in the state, using molecular methods to test for the presence of viral RNA. The study found that often only a single genetic sequence could be detected by RT-PCR, and that positive samples required sampling of various patient samples, including urine. The researchers conducting the study suggest the expanded testing eligibility changes, such as changing the two-target-positive requirement and changing the time frame eligibility for testing, made possible the positive diagnoses and advocate for further study to improve molecular testing for Zika infection.
Tools for future studies
A novel reverse genetics system based on a 2015 Puerto Rican isolate was promoted in a Journal of Virology report. The new cloning system allows easy manipulation of a cDNA-generated viral sequence transcribed in vitro into RNA that can be electroporated into model host cell cultures. The scientists who developed the system showed that the cloned Zika virus has similar in vitro cell line replication kinetics, mosquito infectivity rate, and disease pathogenesis in mice to the parental viral strain, setting the stage for using this genetic system to interrogate molecular determinants of disease.
The optimal animal model for Zika depends on the aspect of its biology one wishes to study. Source.
A Journal of Virology minireview covers another important aspect of studying infectious disease: animal models. A number of animal models have been used to investigate viral transmission, tissue dissemination, and pathogenesis of infection. Because of the congenital birth defects associated with Zika infection during pregnancy, it’s been especially important to establish models to study placental transmission of the virus. Though the current Zika epidemic came to light less than two years ago, several mouse and nonhuman primate models have been developed. Each model helps scientists study different aspects of the virus biology (see figure, right) and these will undoubtedly continue to be crucial.
The rapid response to the Zika epidemic shows what the scientific community can accomplish in a relatively short time frame. Advances in basic virology, pathogenesis, and treatment are making their way toward clinical applications, and nearly a dozen vaccines are in clinical trials, with a promising candidate already moving into Phase II clinical trials. While Zika may not make major news headlines as frequently as it once did, scientists remain vigilant in understanding and eliminating this still-present disease.