# African strains of Zika virus resist ISG-mediated restriction

## TL;DR

African strains of Zika virus are more resistant to the body's antiviral defenses than Asian strains, which may explain their faster replication but not their lower epidemic potential.

## Contribution

The study reveals that African Zika virus strains resist ISG-mediated antiviral activity more effectively than Asian strains.

## Key findings

- African ZIKV strains are more resistant to ISG-mediated restriction than Asian ZIKV strains.
- ISGs like SHFL, RTP4, and IFI6 inhibit Asian ZIKV but have little effect on African strains.
- Resistance in African strains is due to evasion of ISG activity, not enhanced IFN signaling inhibition.

## Abstract

Zika virus (ZIKV) is a neurotropic Orthoflavivirus transmitted by mosquito vectors, which has evolved into two lineages, namely African and Asian. ZIKV from the Asian lineage has been responsible for epidemics in the Pacific and the Americas, the largest of which occurred in Brazil in 2015 and was associated with severe neurological disorders, including cases of microcephaly and other congenital fetal malformations. Although never implicated in human epidemics, African strains exhibit faster replication, higher virus production, and greater virulence in animal models compared to their Asian counterparts. A key feature that may account for the better fitness of African ZIKV strains compared to Asian ones is the fact that they are more resistant to interferon (IFN). IFN response is a major host defense mechanism against viral infections, which culminates in the induction of hundreds of IFN-induced genes (ISGs) whose products inhibit viral replication. By screening an array of ISGs known for their antiviral activity, we show that African ZIKV strains are globally more resistant than their Asian counterparts to ISG-mediated restriction. In particular, SHFL, RTP4 and IFI6, which were the three most active ISGs against Asian viruses, had little or no effect on the replication of African ZIKV strains. These observations therefore suggest that if African strains are more resistant to the antiviral effect of IFN than Asian strains, this is not because they have greater capacity to inhibit IFN signaling, but rather because they are able to escape ISG-mediated restriction. Our results provide an explanation as to why viruses of African origin spread more rapidly and efficiently in vitro than their Asian counterparts as repeatedly demonstrated. However, it remains unclear why, despite their greater virulence and resistance to cellular antiviral defenses, ZIKV strains of the African lineage have never been identified in large-scale epidemics.

Interferons (IFNs) are secreted antiviral cytokines, which commonly exert their activity by inducing an antiviral state, conferred by antiviral factors encoded by IFN-stimulated genes (ISGs). Collectively, ISGs can inhibit the replication of all known viruses, although some have developed resistance mechanisms. In this study, we compared the sensitivity to ISGs of different strains of Zika virus (ZIKV), a neurotropic arbovirus that exists as two distinct lineages, African and Asian. The Asian lineage of ZIKV has been responsible for major epidemics associated with severe neurological and congenital disorders, while the African lineage of ZIKV has not been reported to be responsible for epidemics or severe disease so far. In this study, we demonstrate that African ZIKV strains are more resistant than their Asian counterparts to the antiviral activity of IFN, and that ISGs that inhibit replication of Asian viruses have little or no effect on strains of African origin. While our results explain why African ZIKV strains propagate better than Asian ones, as demonstrated in various cellular and animal models, they do not provide an explanation for the higher pathogenicity and epidemic propensity of the Asian lineage.