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Study shows Zika infection longer in pregnancy

Research with monkeys has shown that a first infection with the Zika virus protects against future infections. But with pregnancy, Zika stays in the body a drastically long time.

Led by David O'Connor PhD, Professor of Pathology at the University of Wisconsin-Madison (UW-Madison), researchers published their work in the journal Nature Communications.

Working with an established colony of rhesus macaque monkeys at the Wisconsin National Primate Research Center as their model animals, they studied the way Zika infections progress. The UW-Madison team worked in collaboration with Duke University scientists. The joint teams included specialists in emergent and insect-borne diseases, genetics, immunology, pediatrics and pregnancy.

"What we've shown in the monkey model matches a lot of what people have observed in epidemiological studies of humans — that if you can clear viremia (infection by the Zika virus) within a week, you are protected from future infections by the same virus."

Emma Mohr PhD, Pediatric Infectious Disease fellow, UW-Madison and first author on the study along with Matthew Aliota, School of Veterinary Medicine, and Dawn Dudley, School of Public Health, UW-Madison.

According to the researchers, rhesus monkeys are often employed in brain research as models for humans. Researchers infected the monkeys with the Zika virus strain causing the current epidemic, first apparent in South America in 2015. They found the monkeys could resist re-infection by that same Zika strain 10 weeks later.

"This is good news for vaccine design as it suggests the sort of immunity that occurs naturally is sufficient. If you can mimic that in a vaccine, you'll likely have a very successful vaccine," adds David O'Connor, whose work is funded by the National Institutes of Health. "You may have to follow children for five years or longer to tell whether there is cognitive impairment in their development," says Aliota, whose research has focused on Zika's spread in Colombia. "But it's something you can answer with macaques relatively quickly, and that speed is very important in the context of an epidemic."

The findings, however, uncovered a stark contrast between the length of infection in pregnant monkeys versus that in males and non-pregnant females.

Non-pregnant animals in the study were free of Zika virus within 10 days of infection. But, the virus persisted in the blood of pregnant monkeys for another 30 to 70 days.

The prolonged infection period in pregnant monkeys has implications for the severe impacts of Zika virus during pregnancy. Zika has been tied to neurological problems in babies such as microcephaly, a particularly grim birth defect that results in underdeveloped brains and small heads.

"We have good news for most people: If you are not pregnant and not at risk of becoming pregnant, you probably don't need to be worried about Zika," O'Connor says. "But my concern for Zika virus in pregnancy is much higher now than it was six months ago."

One possible explanation for the persistence of the virus in pregnancy is that the mother's immune system is too compromised, and she simply can't clear the virus as fast as a non-pregnant infected person.

Though researchers have been performing ultrasounds on Zika-infected pregnant monkeys and collecting amniotic fluid, they can't yet say whether the still-growing fetuses themselves are infected or whether any of them are developing microcephaly.

"For human pregnancies, we have very refined growth charts, lots of historical information, lots of high-end diagnostic technologies that can be used to ask what's happening," O'Connor says. "While some of those things are in development in macaques, they are far less mature and far less detailed. So we can't draw conclusions yet."

But the results also show that one infection primes the immune system to protect against future infection and could provide some peace of mind for millions left in the wake of the Zika epidemic.

"In Africa where the virus has been circulating for an extended period of time, they haven't seen these adverse outcomes in pregnancy. That seems to be because people are primarily exposed early in life, develop immunity, and then are protected later in life when they have children."

Matthew T. Aliota PhD, Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA

In a different mother-fetus infection loop — first proposed earlier this year by Johns Hopkins University obstetrician Rita W. Driggers in an analysis of Zika infection in a pregnant woman — could provide an opportunity to track the risks to a developing fetus without resorting to inherently risky invasive tests.

O'Connor: "A more provocative hypothesis is that it's infection in the fetus. And, what we're observing in the maternal bloodstream is the shedding of virus by the fetus back into the mother's bloodstream. If that happens to be the case, it would suggest there is a prolonged infection of the fetus that lasts much longer than infection in the mother."

"... measuring the viral load on a Zika-infected pregnant woman on a weekly or biweekly basis could provide an indication for the likely degree of damage to the fetus. If a pregnant woman comes into a clinic with Zika virus, but a week later shows no more evidence of infection, that could be a good indication that the fetus is unlikely to be affected."

David H. O’Connor PhD, Department of Pathology and Laboratory Medicine, and the Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA

Measuring the amount of virus in the blood of pregnant monkeys or women might also provoke ideas for treatments to protect babies from neurological damage as their infection progresses.

However, no one now can really predict the range of outcomes for children affected by Zika virus during pregnancy.

"In Brazil, where the oldest children born to women infected with Zika are only about one year old, we don't have any idea whether some of the children who look apparently normal are going to have issues that only manifest later in life."

David H. O’Connor PhD

Infection with Asian-lineage Zika virus (ZIKV) has been associated with Guillain–Barré syndrome and fetal abnormalities, but the underlying mechanisms remain poorly understood. Animal models of infection are thus urgently needed. Here we show that rhesus macaques are susceptible to infection by an Asian-lineage ZIKV closely related to strains currently circulating in the Americas. Following subcutaneous inoculation, ZIKV RNA is detected in plasma 1 day post infection (d.p.i.) in all animals (N=8, including 2 pregnant animals), and is also present in saliva, urine and cerebrospinal fluid. Non-pregnant and pregnant animals remain viremic for 21 days and for up to at least 57 days, respectively. Neutralizing antibodies are detected by 21 d.p.i. Rechallenge 10 weeks after the initial challenge results in no detectable virus replication, indicating protective immunity against homologous strains. Therefore, Asian-lineage ZIKV infection of rhesus macaques provides a relevant animal model for studying pathogenesis and evaluating potential interventions against human infection, including during pregnancy.

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