When Zika swept across Latin America in 2015, a couple of alarming developments quickly followed: microcephaly in fetuses and a murky association with Guillain-Barré Syndrome. Despite ongoing research, much about the virus remains a mystery, including many details of how it spreads.
Mosquitoes are the most obvious vector, but as far back as 2011, virologists suspected that Zika might also be transmitted sexually, a hunch that was confirmed last year. Still, researchers had no idea how easily the virus could be passed through sexual contact.
Now, a pilot study offers new insights about this hard-to-research transmission route, which could potentially spread the virus to new areas. In the study, 12 out of 16 monkeys exposed to Zika through sexual routes tested positive for the virus.
It’s been nearly impossible to identify sexually transmitted cases in outbreak regions because they’re masked by mosquito-transmitted cases, which has made the potentially important vector practically invisible. On top of that, 80% of Zika infections are asymptomatic, meaning that people may not even know they have the disease and thus might be excluded from data about infection rates.
“The study provides a starting point to where we can start gauging risk,” said lead author Andrew Haddow of the United States Army Medical Research Institute of Infectious Diseases. To see how transmission rates had been studied in the past, Haddow said his team looked to HIV/AIDS research. As with that research, this initial model will need to be refined to truly understand human risk, he said.
“This is really big news,” said Enbal Shacham, an associate professor of behavioral science and health education at Saint Louis University, who was not involved in the study. Shacham said that because so little is known about how—and how efficiently—Zika is transmitted sexually, any new information is valuable.
The study involved 16 monkeys: eight rhesus and eight cynomolgus macaques. For each group, the researchers exposed four monkeys to Zika by delivering the virus to the vagina and the other four by delivering it to the rectum.
Researchers anesthetized the animals and, using a lubricated feeding tube, administered a single dose of the virus that was comparable to the highest amount reported in human semen. The method was specifically intended to be nontraumatic, avoiding microtears in the tissue. “We wanted to see what happened in an ideal situation,” Haddow said.
Four of the eight monkeys inoculated vaginally became infected (two of each species), while all eight of the individuals inoculated rectally were infected.
“We were pretty surprised by that,” Haddow said, adding that he and his team expected maybe one in four monkeys to become infected.
The new research provides “important proof” that primates can be infected through vaginal and rectal mucous membranes, said Akiko Iwasaki, a professor of immunobiology and molecular, cellular and developmental biology at Yale School of Medicine.
Despite the infections, none of the animals showed symptoms of the disease. Based on the amount and duration of infectious virus in the macaques’ blood, Haddow’s team thinks humans infected through sexual transmission may be capable of infecting mosquitos with the virus.
Haddow and his coauthors conclude that sexual transmission could be a way for the virus to maintain itself in the absence of mosquito transmission, and it might increase the likelihood of Zika spreading into new areas. “The possibility exists that you could have silent transmission, where somebody gets Zika sexually and has no idea,” Haddow said.
Researchers know that animal models have their limitations, though. John Brooks, a medical epidemiologist with the Centers for Disease Control and Protection (CDC), said we should be “very circumspect” when translating data from research animals to what it means for humans. Nonetheless, he pointed out that both groups of monkeys in Haddow’s research showed detectable virus in their blood for about the same amount of time it stays in humans.“To me that’s saying, okay, it’s behaving in this animal model like it’s behaving in humans,” Brooks said.
Still, he’s not worried about Zika spreading through sexual transmission alone. “Despite everyone’s concern that Zika could be spreading quietly through the country through sexual transmission, we’re just not seeing it,” Brooks said. “And people would have begun to recognize that by now.”
In the United States, the CDC knows of about 50 couples among whom sexual transmission of Zika has occurred. Researchers think those cases are the tip of an iceberg, Brooks said, adding, “I don’t know how big that iceberg is.”
Based on rough estimates of the number of travelers arriving in the United States from active Zika regions, the CDC estimates that 200,000 affected men could enter the country per year. Brooks says that’s a lot of opportunity for the virus to transition and to be sustained, but that hasn’t been observed. (While Zika can be transmitted from women to men, that’s far less common than men transmitting it to their partners, and there is only one known case of woman-to-man transmission.)
One reason that Zika outbreaks in the U.S. haven’t been traced to sexual transmission could be that, unlike some sexually transmitted diseases which remain infectious until treated (and even after), Zika clears from the system fairly quickly, Brooks said.
“In Zika, your body mounts a really effective immune response,” he said. Within about a month after infection, 50% of men will no longer have Zika in their semen, he said. After 81 days, that number rises to 95%.
While the dose of virus used in Haddow’s study is comparable to what can be found in human semen, Brooks said, “men don’t stay at that level for very long.” The level of Zika in semen declines “rapidly and steadily,” he added, although researchers don’t know at what point someone is no longer infectious. But, he points out, the known cases of sexual transmission in the United States have shown that people who infect their partners generally do so early in their illness—something researchers can determine by the timing of the second person’s illness.
For men who have traveled to an area with active Zika transmission, the CDC recommends abstaining from sex or using a barrier protection method (like a condom) for six months after leaving the area. For women who have traveled, the recommendation is eight weeks.
Haddow’s latest research builds on the legacy of his grandfather—who was one of the discoverers of Zika—as well as his own groundbreaking work. It was Haddow who pieced together clues that Zika might be sexually transmitted.
Despite the new research, the unknowns surrounding Zika extend far beyond its sexual transmission rate. Iwasaki, who has studied Zika in mice, said it can cause shrinking of testes and reduced sperm count in those animals. “Zika virus may be a silent disease with significant reproductive impact in humans for years to come,” she said.
Brooks said it took about 20 years to get the necessary data about HIV to run current models to assess both per-act risk of HIV transmission through various routes and the impact of prevention strategies on specific kinds of transmission.
Additionally, Haddow says there’s a possibility of a so-called sylvatic cycle of Zika, in which monkeys transmit the virus to each other sexually. In this scenario, animal populations could serve as a reservoir of the virus, keeping it alive without human hosts.
“It’s going to take years to investigate this stuff,” Haddow said.
Image credit: David Goodsell (CC BY 4.0)