Fetal Zika virus infection of the developing brain has a wide range of effects. Despite increased research, there are still many unknowns regarding the relationship between infection dynamics and fetal and infant development.

Now, researchers show that Zika virus infection in pregnant rhesus macaques slows fetal growth and affects how infants and mothers interact in the first month of life. The work has implications for both humans exposed to Zika virus and for other viruses that can cross the placenta, including SARS-CoV-2, responsible for the COVID-19 pandemic.

This research was published in Science Translational Medicine, in the paper, “Prenatal Zika virus infection has sex-specific effects on infant physical development and mother-infant social interactions.

In most people, Zika virus infection causes mild or no symptoms and leaves long-lasting immunity. During pregnancy, however, the virus can cross the placenta and cause damage to the nervous system of the fetus. In extreme cases, it can cause microcephaly in humans.

Researchers have previously shown that Zika virus could enter the fetal brain in pregnant macaques. This new study looked at the effects of Zika infection during the second trimester of pregnancy on infants up to a month after birth.

“Initially I thought this was a story about Zika, but as I looked at the results I think this is also a story about how fetal infections in general affect developmental trajectories,” said Eliza Bliss-Moreau, PhD, professor of psychology at the University of California, Davis.

Using a nonhuman primate model of Zika virus infection, the researchers inoculated pregnant rhesus macaques and their fetuses with Zika virus in the early second trimester of fetal development. Then, they tracked the monkeys’ health across gestation and characterized infant development across the first month of life.

Zika-infected pregnant mothers had long periods of viremia and mild changes to their hematological profiles. Although pregnant animals did not become visibly ill with the virus,  ultrasounds showed fetal growth slowed after infection, noted Florent Pittet, PhD, assistant project scientist at the University of California, Davis. At birth, Zika-exposed infants were “at the low end” of the range for head size in rhesus macaques. “They were smaller overall,” he said. Higher levels of circulating Zika virus corresponded with longer delays in growth.

After birth, the researchers tracked the development of sensory and motor skills—using tests similar to those used for human babies—and interaction with the mother.

“The trajectory was quite different,” Pittet said. Right after birth, infant monkeys spend a lot of time on their mother but start to separate after about two weeks. But the Zika infants spent much more time clinging to their mothers through the first month.

It’s not clear whether the mother or the infant is initiating this contact, Bliss-Moreau said. “We know that moms will keep hold of infants that are having challenges,” she said.

The RNA concentrations of Zika virus (an indicator of infection magnitude) “were higher in mothers whose fetuses were male, and the magnitude of ZIKV RNA in the mothers’ plasma or amniotic fluid predicted infant outcomes.” In addition, growth delays and effects on mother-infant interactions were greater in male than in female infants, although both showed delays compared to uninfected controls.

Additionally, the animals were housed in established social groups of multiple adult females (including their mother), a single male, and other male and female infants of about the same age. This allows the infants to learn from each other and from the adults, Pittet said.

“The presence of unrelated adults and infants in the social group is a critical factor for normative development,” he said. “Offering such a social rearing environment is tons of additional work but ensures a lot more relevance to developmental studies.”

The authors plan to describe the monkeys’ growth through the first two years of life in upcoming publications. Zika virus exposure during pregnancy sets off a cascade of consequences that may not appear until later in development, Pittet said.

The finding that outcomes correlate with viral load during pregnancy offers opportunities to intervene, the researchers said. A drug or vaccine would not have to completely eliminate the virus to be beneficial. This may be generally true for other infections that can affect the fetus, such as SARS-CoV-2.

“Anything you can do to reduce viral load is a good thing for infant development,” Bliss-Moreau said. A 2019 study by CNPRC scientists, in collaboration with the National Institute of Allergy and Infectious Diseases, found that an experimental Zika vaccine lowered levels of circulating viruses in pregnant macaques.

While no local transmission of the virus has been reported in the United States since 2018, the mosquitoes that carry Zika virus continue to expand their range throughout Africa, the Americas, Asia, and the Pacific.

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