Highly Efficient Maternal-Fetal Zika Virus Transmission in Pregnant Rhesus Macaques

Abstract

Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated. Author summaryMaternal ZIKV infection in pregnancy is associated with severe fetal anomalies, including microcephaly. It has been shown that infection manifests differently in pregnancy than in the non-pregnant state, with prolonged maternal viremia. ZIKV is spread by mosquitos and through sexual contact and since its first detection in early 2015, has become endemic to the Americas. While much has been learned from studying infected human pregnancies, there are still many questions concerning transmission of ZIKV from mother to fetus. Investigating ZIKV infection in non-human primates could help answer these questions due to similarities in the immune system, and the tissues separating the fetus from the mother during pregnancy. Our study serves to model ZIKV transmission in early and late pregnancy, as well as study the effects of this infection on the fetus and mother at these different times in pregnancy. The data collected provides an important insight on ZIKV in pregnancy where the pregnancies have been monitored throughout the entire infection period until term, and suggests that vertical transmission may be very efficient, although severe fetal outcomes are uncommon.

Mathematical modeling of within‐host Zika virus dynamics

“…Zika virus infection of pregnant macaques (Figure A) results in prolonged maternal viremia as well as fetal pathology and ZIKV infection of the fetus, mimicking features of human infection. Similar results have also been found in marmosets .…”

“…Zika viral infection dynamics in NHP s infected during pregnancy or by alternative infection routes. ZIKV RNA concentration (A) in plasma of RM after SC infection with 10 4 PFU of a French Polynesian strain of ZIKV while pregnant, data taken from Nguyen et al . Red, circles: RM ‐infected mid‐first trimester of pregnancy.…”

CImP: Cellular Imprinting Proteomics applied to ocular disorders elicited by Congenital Zika virus Syndrome

“…However, no ocular pathologies were observed in congenitally infected mice. Female rhesus monkeys infected with ZIKV early in pregnancy (weeks 6-7 of gestation) recapitulate the CZS observed in humans and ocular dysfunctions have been described (9,11,12). Indeed, Zika virus RNA was found in fetal retina, choroid and the optic nerve (12).…”

Variations in maternal adenylate cyclase genes are associated with congenital Zika syndrome in a cohort from Northeast, Brazil

“…Despite the strong evidence for ZIKV vertical transmission, the mechanisms by which ZIKV impairs foetal development remain to be elucidated [7,8]. Virus evolution and the search for pathogenic mutations have been the focus in many studies [9,10] although, no specific viral mutations responsible for severe cases have been described [11].…”