Flaviviruses--such as Zika, dengue, and yellow fever--have emerged as human (and other primate) pathogens because of their ability to specifically overcome our anti-viral defenses. The 70+ known flaviviruses use diverse mechanisms to overcome interferons produced by host cells, and so the researchers were curious to find out which family member Zika most took after.

In the case of Zika (ZIKAV), researchers at the Icahn School of Medicine at Mount Sinai report in Cell Host & Microbe that one of the virus's seven non-structural proteins (NS5) is singularly responsible for blocking the action of interferons (proteins that stop viral replication) in human cells, while mouse cells are unaffected.

The shared target is STAT2, a protein that tells the cell to start making a range of antiviral genes induced by interferons. While both dengue and Zika viruses use their non-structural protein, NS5, to bind to and shut down STAT2 activity, the mechanism of degradation of STAT2 is unique for Zika virus among the flaviviruses.

How Zika NS5 has this effect is being worked out; however, there is evidence that Zika is the first known flavivirus with an NS5 protein that accumulates in specific nuclear dots, which might relate to its ability to shut down host antiviral defences.

By blocking NS5 activity, it can make the virus more susceptible to an infected cell's innate immune response. This approach could also be useful for vaccine development, although it will be important to learn how quickly NS5 could mutate, as viral resistance is always a possible issue.

ZIKV NS5 expression resulted in proteasomal degradation of the IFN-regulated transcriptional activator STAT2 from humans, but not mice, which may explain the requirement for IFN deficiency to observe ZIKV-induced disease in mice. The mechanism of ZIKV NS5 resembles dengue virus (DENV) NS5 and not its closer relative, Spondweni virus (SPOV).

However, unlike DENV, ZIKV did not require the E3 ubiquitin ligase UBR4 to induce STAT2 degradation. Hence, flavivirus NS5 proteins exhibit a remarkable functional convergence in IFN antagonism, albeit by virus-specific mechanisms.

http://www.cell.com/cell-host-microbe/abstract/S1931-3128(16)30205-0