Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus

Abstract

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

Infection of the maternal-fetal interface and vertical transmission following low-dose inoculation of pregnant rhesus macaques (Macaca mulatta) with an African-lineage Zika virus

“…However, we did find evidence of vertical transmission in 3/9 pregnancies and pathology in the decidua. Two out of the three pregnancies that had vertical transmission were inoculated at gd 30, this is consistent with previously published studies demonstrating that ZIKV inoculation at gd 30 results in a high rate of vertical transmission compared to inoculation at gd 45 [ 39 ]. We saw vertical transmission in one of the cases inoculated at gd 45, this is somewhat unexpected as the Crooks study found that ZIKV-DAK inoculation at gd 34 with approximately 200 times more virus did not result in vertical transmission [ 18 ].…”

“…ZIKV was vertically transmitted in three pregnancies, as evident by infectious virus in the amniotic fluid. The amniotic fluid is absorbed by the embryo/early fetus prior to skin keratinization [ 39 ], thus the embryo/early fetus has no barrier protecting it from infectious ZIKV in the amniotic fluid. Later in gestation the fetus also swallows amniotic fluid [ 38 ], this would be another way that ZIKV in the amniotic fluid can infect the fetus, however the fetuses in the current study have not yet developed the ability to swallow.…”

Comparative Infections of Zika, Dengue, and Yellow Fever Viruses in Human Cytotrophoblast-Derived Cells Suggest a Gating Role for the Cytotrophoblast in Zika Virus Placental Invasion

“…Congenital malformations associated with ZIKV have been attributed only to the Asian lineage ( 3 , 4 ). However, our findings agree with previous reports using human placental trophoblasts, animal cell lines, mosquitoes, mouse models, and, more recently pregnant higher primate models, which all evidenced the higher capacity for transmission, replication, and virulence of the African over the Asian lineage ( 38 – 40 ). Thus, our data add to the accumulating evidence that African lineage ZIKV strains may be more virulent and more pathogenic to pregnancy than Asian lineage strains, generating early miscarriages and preventing advanced fetal development ( 41 ).…”

Vertical transmission of African-lineage Zika virus through the fetal membranes in a rhesus macaque (Macaca mulatta) model

“…To minimize the variability in vertical transmission, we inoculated all dams at PLOS PATHOGENS Vertical transmission of ZIKV-DAK in rhesus macaques approximately gd 30, during the late embryonic stage (term = gd 165). Inoculation at this gestational age has been shown to result in a high rate of vertical transmission [28]. Details on the gestational age of each dam at the time of inoculation can be found in S1 Table . Blood was collected from the dams prior to inoculation, during the first two weeks after inoculation, and intermittently up to 87 days post-infection (dpi) or until euthanasia.…”