African-lineage Zika virus replication dynamics and maternal-fetal interface infection in pregnant rhesus macaques

Abstract

Following the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The isolates responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in-vitro and in-vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titer and caused more severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here we infected four pregnant rhesus macaques with a low-passage strain of African-lineage ZIKV and compared its pathogenesis to a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-infected controls. Viral replication kinetics were not significantly different between the two experimental groups and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery in either group. However, a significantly higher burden of ZIKV vRNA was found in maternal-fetal interface tissues in the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV isolates of any genetic lineage pose a threat to women and their infants. IMPORTANCEZIKV was first identified over 70 years ago in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015-16. In its most recent update, the WHO stated that improved understanding of African-lineage pathogenesis during pregnancy must be a priority. Recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational non-human primate model. We show African-lineage isolates replicate with similar kinetics to Asian-lineage isolates and are capable of infecting the placenta. However, there was no evidence of more severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to women and their infants and the need for future epidemiological and translational in-vivo studies with African-lineage ZIKV.