Studying the Zika virus in rhesus macaques
The 2016 Olympic Games are due to begin in Rio de Janeiro this weekend. In the lead-up to this year’s Games, the Zika virus has never been far from the headlines. A number of top golfers and basketball players have decided to pull out and other athletes have also expressed their concerns, despite the risk to anyone who is not pregnant being minimal. As it is not currently mosquito season in Brazil, experts say the Olympics will not accelerate the spread of the virus.
It is thought the epidemic has reached its peak in Latin America and will slowly burn out over the next few years. Still, there have been over 60,000 confirmed cases of the Zika virus in Brazil since the outbreak began in early 2015 and the virus has reached Europe, with the first baby with Zika-related microcephaly born in Spain. Mosquitoes in Florida have now also been seen to transmit the virus, and the Centers for Disease Control and Prevention (CDC) in the US have issued a travel warning for Florida.
The Zika virus remains a prominent public health concern and a priority for the biosciences. In March, EARA spoke to Dr Koen van Rompay, who helped to develop and test the anti-viral drug tenofovir, which is currently the most frequently used HIV drug in the world. We interviewed him on the day before he and his team at the California National Primate Research Center (CNPRC), USA, infected two female rhesus macaques with Zika virus to understand how the disease progresses. We asked him about his current study on the Zika virus, why he uses primate models in his work and how he responds to critics of animal research.
EARA: The WHO has declared the Zika virus to be a public health emergency. How worried should we be about the Zika virus? Dr. Van Rompay: I think we should be alert, but not over-panic. Only about one in five adults who get infected develop symptoms. As far as we know now, the main danger is really for women who are pregnant. For them it will be very important to avoid getting infected by taking necessary precautions. That means staying away from areas where the mosquito that transmits Zika virus is present, and also to avoid sexual exposure to somebody who may have travelled to any of those regions.
In non-pregnant adults it has also been described, especially in French-Polynesia, that a very small percentage develops the Guillain-Barré Syndrome. This is another kind of immune syndrome that affects the peripheral nervous system – but it seems that most of those people recover from it. Overall, I think it is very important to create good awareness. It is important that we do not overreact, but it is important to get the facts right, especially for pregnant women – they are our main concern.
What does your current work on the Zika virus entail? We are starting studies tomorrow; we are going to infect two animals with virus from Brazil. We are going to monitor these monkeys by taking blood samples every single day. If we see that this virus can infect the monkeys, then in the next step we will infect some pregnant animals. This will allow us to see if the virus can also infect the foetus, and if it causes microcephaly or some of the other abnormalities that have been described in humans. Such findings would show very conclusively the link between Zika virus and microcephaly and those other diseases. Once we have that model available, we can use it to test interventions such as vaccines and drugs.
How did you end up studying this virus? For the past 26 years at the CNPRC my main research topic has been HIV and AIDS. About two months ago I was reading the stories about the Zika virus. It sparked my interest, so I decided to get a team together. I got into contact with the Primate Center in Wisconsin and learned that they were also starting studies. For the past few months we have been gathering the best team of experts from different disciplines – virology, neuroscience, mosquito-borne diseases – to design the best experiments.
What are the benefits of using animal models in research into the Zika virus? An animal model can be useful to, in a very short time sometimes, show proof of concept – of how the virus transmits, or how it causes disease – but also if you want to test interventions. It is difficult to test interventions that are focused on preventing infection in humans. Especially with HIV, but also with Zika virus, you would have to monitor a very large population of humans to see if an intervention can be effective. In monkeys we can do very controlled studies in a very small number of animals to see if some intervention works. By showing proof of concept, we can provide guidance to clinicians who want to test these interventions in humans.
While your team is working on developing a primate model, what other models are being used in the study of the Zika virus? Other researchers at other institutions are developing mouse models. We know that mice can get infected; in early studies, 60 years ago, they were able to show that if you inject the Zika virus in the brain of adult mice, they would develop neurological disease. As far as I know, nobody has been able to show that if you infect a pregnant mouse with a healthy immune system not directly in the brain but, for example, under the skin, this causes any disease. I also do not think anyone has shown that in mice the Zika virus affects the developing foetus.* Other groups are working on these and other questions. Whenever they get results, we will also learn how we can optimise our non-human primate studies. So we can all learn from each other as fast as possible.
What makes non-human primates so valuable as a model in Zika research? Monkeys are very valuable because they are much more similar to humans. Monkeys and humans have very similar foetal and brain development and placenta formation. Also, pregnancy in mice progresses very differently. If we find something that can prevent or treat infection in monkeys, it is much more likely that it can be translated into humans.
Where do you see the future of Zika research going? I have good hopes that in the next, say, six months to a year we will understand a lot better what the virus is doing, how it causes infection of the foetus and how it affects the brain. I have high hopes that a vaccine can be developed, because vaccines have been developed against other viruses of the same family, for example yellow fever. Also, we know that Zika virus infection in adults is very acute. Adults make a good immune response that controls the virus. All the data suggests that if you can mimic the natural immune response to Zika virus, such a vaccine should be sufficient to be effective. In the next year we can hopefully start testing vaccines in monkeys.
As your work takes place in primates, do you notice any criticism of your institution or other researchers around you from, for example, animal rights activists? Yes, sometimes we do get criticism from animal rights activists. What we do is try to be open about the research that we do. We are planning to make our data available as much as possible, and I think it is very important for the public to be educated about what we do, and that people can see in an objective way the research that we do.
There are good animal welfare activists, but there are also extremists who I do not really trust. Those are the ones who distort the facts, who take things out of context. We really care about animal welfare, and we try to be transparent, to show what we really do, how well we take care of our animals, including by doing outreach work. I often go to schools to talk about the research. We have tours where people can see our facilities and some of the research that goes on here.
You started your career in Belgium. Have you noticed any differences in working in the US as compared to Europe? In the US we often have more resources available. Here at the CNPRC we have our own breeding colony. Most of our animals live outdoors in large colonies, so they have quite natural conditions. We are self-sustaining: we do not have to import monkeys from the wild anymore. I think in Europe most of the primate centres are much smaller; they do not have such a breeding colony, partly because of the climate, so they are much more dependent on importing animals. Of course that comes with extra expenses, but it also risks animals bringing in new diseases. There is a lot more need for quarantine and other preventative measures. In Europe the laws have made it a lot more difficult to do research in monkeys. I think here in the US right now, the law makes it more practical, as long as, of course, we follow the very strict laws and regulations about animal welfare.
There is criticism of using non-human primates in research from around the globe. What would you say to opponents of primate research? Non-human primates only make up a very small fraction of animals in biomedical research: it is less than 0.25%. Most animals used in biomedical research are other species, especially mice and rats. We only use monkeys if we feel that it is crucial in order to make progress, to learn more about a disease and to develop interventions. Monkey research is very expensive, and even when we decide that it is the only thing that can be done to gain that knowledge, we also follow the principles of the 3Rs: reduction, refinement, replacement. We do our best to limit the number of animals that we have to use, we also do our best to minimise the discomfort that animals have. We give our animals the best medical care that is available; our animals are being monitored every single day. We try to keep them happy with environmental enrichment, and the health of our animals in general is much better than the health of most animals in the wild.
You can follow the progress of Dr Van Rompay’s Zika study on the CNPRC website, where the team publishes their scientific findings in as close to real time as possible.
*In the time since this interview took place, some groups have been able to show foetal abnormalities in Zika-infected mice that were made immunocompromised. Dr Van Rompay is not aware of any report of foetal abnormalities in healthy mice yet. Continue reading