While much progress has been made during the last few years in combating and preventing the deadly Zika virus, researchers are still working toward a greater understanding of how the disease affects the development of the brain in newborns.

Recently, scientists at the Yerkes National Primate Research Center (YNPRC) made a breakthrough by showing Zika virus infection, soon after birth, leads to long-term brain and behavior problems. The study is one of the first to shed light on potential long-term effects of Zika infection during infancy.

“Researchers have shown the devastating damage Zika virus causes to a fetus, but we had questions about what happens to the developing brain of a young child who gets infected by Zika,” says lead researcher Ann Chahroudi, MD, PhD, an affiliate scientist in the Division of Microbiology and Immunology at Yerkes, director of the Center for Childhood Infections and Vaccines (CCIV), Children’s Healthcare of Atlanta (CHOA) and Emory University, and an associate professor of pediatrics in the Division of Pediatric Infectious Diseases at Emory University School of Medicine.

The study followed four infant rhesus monkeys for one year after Zika virus infection at one month of age. Studying a rhesus monkey until the age of one translates to the equivalent of four to five years in human age.

Researchers found postnatal Zika virus infections led to significant changes in behavior—including reduced social interactions and increased emotional reactions—and some impairments in memory and gross motor abilities. 

“These changes corresponded with structural and functional brain changes we found on MRI scans,” says researcher Jessica Raper, PhD, research assistant professor at Yerkes. “This is especially important because it allows us to confirm the neurologic findings lead to ongoing and noticeable changes in behavior,” she continues. 

The researchers also noted this finding will give healthcare providers a greater understanding of the possible complications of Zika infection following pregnancy and birth.

“Our results shed light on potential outcomes of human infants infected with Zika virus after birth and provide a platform to test treatments to alleviate long-term neurologic consequences of Zika infection,” says Chahroudi. “Our research team encourages future studies to understand the impact of early postnatal Zika infection during later stages of life, from adolescence to adulthood.”

More than 85 countries and territories have reported evidence of mosquito-acquired Zika virus infection, for which there is no cure or treatment medications. Zika virus and the mosquitoes that transmit it have not been eliminated, and so transmission remains a risk.

Research related to the prevention and treatment of Zika at the NPRCs is ongoing. You can learn more about our studies and findings here. 

The study in this article was highlighted by the editors of Nature Communications on a dedicated webpage for brain and behavioral research.

Zika virus may be out of the headlines, but scientists are continuing to work on treatments and vaccines to address this serious threat to public health.

Now, an experimental vaccine against the virus has been shown to reduce the amount of virus in pregnant rhesus macaques and improve fetal outcomes. The study marks the first test of a Zika vaccine given before conception with exposure to the virus during pregnancy, said Koen Van Rompay, virologist at the California National Primate Research Center (CNPRC) at the University of California, Davis (UC Davis).

Zika virus infection of pregnant women is associated with a high risk of adverse fetal effects, including fetal death, microcephaly (small head) and other abnormalities, collectively termed congenital Zika syndrome. While no approved vaccine is currently available, the new study was designed to mimic a real-world scenario where women could be vaccinated months or years before becoming pregnant and be protected during pregnancy.

UC Davis researchers, alongside scientists from the National Institute of Allergy and Infectious Diseases (NIAI), injected female monkeys with candidate vaccine VRC5283. After vaccination, depending on their reproductive cycles, the female animals were housed with males and allowed to procreate. Thirteen vaccinated animals and 12 unvaccinated controls became pregnant. The investigators then exposed the pregnant animals to Zika virus at intervals representing first and second trimesters.

Two unvaccinated animals lost the fetus early in pregnancy due to Zika virus infection, but there was no early fetal loss in the vaccinated group. In addition, vaccinated females had less virus in their blood, and the virus persisted for a shorter duration after their exposure.

At the end of pregnancy, the researchers looked for Zika virus in tissues from the mothers and fetuses. It was found that 11 of 12 fetuses in the unvaccinated control group had detectable Zika virus RNA. However, no Zika virus RNA was detected in the 13 fetuses from the vaccinated group—suggesting that the vaccine prevented transmission of virus to the fetus. The results also indicate that VRC5283 may prevent mother-to-fetus transmission of Zika virus in humans, Van Rompay said.

The candidate vaccine is currently in trials, and results from the animal studies could help support the case for approving the vaccine.

Want to know more about the ongoing fight to eliminate Zika? Here are some additional ways NPRC scientists across the country are making progress against this disease.

Children born to HIV-positive mothers are susceptible to contracting the disease themselves, but scientists at Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University (OHSU) have new evidence suggesting that newborn infection may be entirely preventable.

The researchers successfully demonstrated, in a non-human primate model, that a single dose of an antibody-based treatment given after virus exposure can prevent HIV transmission from mother to baby, provided that dose is given at the correct time. 

The study found that rhesus macaque newborns did not develop the monkey form of HIV (known as SHIV), when they received a combination of two antibodies 30 hours after being exposed to the virus. This is the first time a single dose of broadly neutralizing antibodies given after viral exposure has been found to prevent SHIV infection in nonhuman primate newborns.

However, when the antibody treatment was delayed until 48 hours after exposure, half of the baby macaques developed SHIV, even when given four smaller doses of the same antibody. 

Previous research by this group has shown that four doses of antibodies started 24 hours after exposure also prevented SHIV infection, and the current ONPRC study suggests that a three-week course of antiretroviral therapy given after virus exposure could also prevent HIV transmission to newborns.

“These promising findings could mean babies born to HIV-positive mothers can still beat HIV with less treatment,” said Nancy Haigwood, PhD, ONPRC director and a professor of pathobiology and immunology at the OHSU School of Medicine.

Antibodies aren’t toxic and can be modified to last a long time in the body, which reduces treatment frequency. This means antibody treatments may also help prevent negative side effects from the drug combination currently given to infants born to HIV-positive mothers.

Next, ONPRC scientists plan to see if different antibodies, or a combination of antibodies and antiretroviral therapy, could be even more effective. They also hope to find out whether the antibodies actually eliminate HIV or only prevent it from replicating.combination. This suggests that there is a 30-hour limit for the successful use of antibodies to prevent HIV transmission to newborns.

While antiviral medications limit the impact of the disease on daily life, human immunodeficiency virus (HIV) continues to infect 1.7 million people annually and cause some 770,000 deaths each year, which makes research on the virus a high priority.

Recently, a team that includes researchers from the Yerkes National Primate Research Center (YNPRC) at Emory University showed a new HIV vaccine is better at preventing infection and also lasts longer.

According to the researchers, the new vaccine’s improved protection lies in the combination of two types of immune responses: “neutralizing” antibodies and cellular immunity, a process involving the activation of T cells.

”Most efforts to develop an HIV vaccine focus on activating the immune system to make antibodies that can inactivate the virus, so-called neutralizing antibodies,” said Eric Hunter, PhD, professor of pathology and laboratory medicine at Emory, and a researcher at the Emory Vaccine Center (EVC) and YNPRC. “We designed our vaccine to also generate a strong cellular immune response that homed in on mucosal tissues so the two arms of the immune response could collaborate to give better protection,” he continues.

In the study, the researchers inoculated three groups of 15 monkeys during a 40-week period.

The first group received Env, a protein on the virus’ outer surface known for stimulating antibody production, plus an adjuvant, a chemical combination often used in vaccines to enhance immune response.

The second group received the same, plus additional injections of three different attenuated (weakened) viruses modified to contain the gene for an HIV viral protein, Gag, which is known to stimulate cellular immunity.

A third, the control group, received injections containing only the adjuvant.

Following the 40-week regimen, all animals rested for 40 weeks, and then the researchers gave them booster shots of just the Env inoculation. After resting four more weeks, the researchers gave the animals 10 weekly exposures to SHIV, the simian version of HIV.

The results revealed animals in the two experimental groups experienced significant initial protection from viral infection if their immune system had a strong showing of neutralizing antibodies. Even more notable, say the researchers, was several of the Env-plus-Gag animals—but none of the Env animals—remained uninfected even though they lacked robust levels of neutralizing antibodies.

This outcome is exceptional because the potency of neutralizing antibodies has previously been thought to be crucial to a vaccine’s effectiveness. What’s more, when the researchers rechallenged the protected animals six months after the first challenges, the Env-plus-Gag animals but not the Env animals maintained protection, which shows the protection is durable.

“These results open exciting opportunities for HIV vaccines,” said Rama Amara, PhD, a Yerkes and EVC researcher and professor of microbiology and immunology at Emory. We now know it’s possible to achieve durable protection against HIV with a low response of neutralizing antibodies as long as the vaccine induces T cells.”

The team will use these results to refine the way it approaches vaccine development, noting a similar approach could possibly be feasible for other pathogens, including influenza, tuberculosis, malaria and COVID-19.

As the search for a cure continues, scientists across the NPRC network are working to discover new ways of treating and preventing HIV. Learn more about similar studies here.

In the midst of the novel coronavirus (COVID-19) outbreak, scientists at the National Primate Research Centers (NPRCs) have initiated research programs to better understand and diagnose as well as develop potential treatments and vaccines for the disease. NPRC animal colonies will be key in moving SARS-CoV-2 infection/COVID-19 research from cell models to studies in whole living systems so researchers can determine treatment safety and effectiveness.

Since the virus began to spread at the end of 2019, more than 3 million people have been infected worldwide as of April 28, 2020, with numbers growing daily. The coordinated efforts of the scientific community will be crucial to slow the spread of COVID-19, lower the risk of transmission and treat those who have the disease.

NPRC COVID-19 Research

Several of the NPRCs have made public announcements that research is under way, including California NPRC, Southwest NPRC, Tulane NPRC and Wisconsin NPRC. Others, including Oregon, Washington and Yerkes NPRCs, are also beginning research, and Oregon and Yerkes are accepting applications for COVID-19 pilot projects, which facilitate research collaborations and provide important preliminary data.

California NPRC researchers have already isolated, characterized and cultured COVID-19 from a patient treated at UC Davis, the first community-acquired case in the U.S. Next, they plan to make diagnostic tests in-house.

The Southwest NPRC scientists are proposing research projects to establish a nonhuman primate model to study the development and transmission of the disease, test new detection methods and partner with others in the scientific community.

At Tulane NPRC, researchers plan to create a nonhuman primate model to study the disease’s clinical progression, how it is transmitted through the air and how it specifically affects aging populations. The scientists are aiming to answer many questions, including why older individuals are more susceptible to complications and death from COVID-19.

In Wisconsin NPRC researchers have developed a coalition of scientists to combat the disease, drawing heavily from their firsthand experience during the Zika virus outbreak in 2016.

Yerkes NPRC researchers have begun initial research, and the center’s goals include understanding immunity and antibody response to SARS-CoV-2, and developing diagnostics, key reagents, antiviral therapies and vaccines.

COVID-19 Research Safety

The NPRCs are well-positioned to conduct SARS-CoV-2 infection/COVID-19 research because of our expertise in infectious diseases and collaborations internally at each NPRC as well as across NPRCs and with colleagues worldwide. Also, we can conduct such research safely in our Biosafety Level 3 (BSL3) facilities specifically designed to keep personnel, the research and the environment safe. Examples of BSL3 safety features include additional training and oversight for employees, directional air flow and filtered ventilation systems, and specialty equipment to contain the virus isolates used in the research and to decontaminate the lab space and research equipment and supplies.

News Stories about NPRC COVID-19 Research

News articles by The Scientist and ABC News provide more information about the NPRC studies and the critical role of research with animals.

As we have more information to share about NPRC COVID-19 research, we’ll post information at NPRC.org/news and tweet from @NPRCnews. In the meantime, here are a few helpful COVID-19 resources we’re following.

Cells that harbor HIV, even while a person is on antiretroviral drugs, are referred to as the “reservoir”. Some of these cells might be able to self-renew/proliferate, thus continually replenishing the virus reservoir. The elusive task of “drying up” this reservoir is key in uncovering a cure.

Researchers at Yerkes National Primate Research Center (YNPRC) recently tested the possibility to block the reservoir self-renewal, working with macaques infected with SIV (Simian immunodeficiency virus) and targeting the Wnt/beta-catenin pathway during antiretroviral therapy. 

Wnt is a common signaling pathway, and beta-catenin is a central protein in that pathway. Beta-catenin regulates the balance between self-renewal and differentiation (changing to another cell type, more mature and shorter-lived) of memory T cells.

The team used PRI-724, a molecule that blocks interaction between beta-catenin and another protein beta-catenin needs to turn on genes. The researchers noted decreased proliferation of long-lived memory T cells and signs of more differentiation into shorter-lived cells that are more prone to die. However, short-term treatment with PRI-724 alone didn’t significantly reduce the size of the overall viral reservoir.

The scientists noted, though, it may be possible PRI-724 or a similar drug could be combined with other approaches for a longer time to make a greater impact.

They also pointed out this technique differs from the “shock and kill” approach that activates dormant infected T cells to trigger an immune system response. NPRC scientists are testing this approach in separate, ongoing studies.

The way that HIV—the virus that causes AIDS—spreads and progresses over time varies among people.

A recent study by scientists at Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute shows this variance may be at least partially explained by a genetic mechanism, a discovery that could open the door for more targeted treatments.

A team of scientists led by Assistant Professor Smita Kulkarni, PhD, and Mary Carrington, PhD, conducted the study, which revealed that a specific long “noncoding” RNA molecule influences a key receptor involved in HIV infection and progression. Dr. Kulkarni said that until the last decade or so, scientists thought many of these particular RNAs were “junk.” Thanks to recent developments in technology and genomics, however, the scientific community has been able to examine them further.

The team of researchers showed that the long non-coding RNA molecules impact the genes encoding an HIV co-receptor known as CCR5. Since CCR5 is critical for the HIV virus to enter the cell, its various expressions can affect the infection’s outcome. Genomic DNA from various groups, including Hispanics, African Americans and Japanese, showed that this is present across many ethnicities, which means it can likely be explained by a single functional mechanism.

“Finding functional mechanisms of the disease-associated gene regions will increase our understanding about how they regulate disease-associated genes and pathways,” Kulkarni explained. “We may be able to find selective targets for (HIV) therapy.”

Kulkarni further stated that these discoveries may have implications for the progression of other infectious diseases as well.

“There are many ways we can use the techniques we have learned through this study—what we have established in our lab,” she said. “We can apply it to many other pathogens currently being studied by scientists at Texas Biomed and at many other institutions.”

Understanding these mechanisms is just part of the equation in fighting HIV. See how other ongoing research at the NPRCs is helping purge HIV “reservoirs” from the body.

While no true cure for HIV/AIDS exists, patients can suppress the virus through a continuous regimen of medication. But now, scientists have discovered a new approach to dealing with HIV infection—one which could eliminate the need for such ongoing treatment.

The study was conducted at the Wisconsin National Primate Research Center (WiNPRC) with the University of Miami (UM) Miller School research team, the Frederick National Laboratory for Cancer Research in Maryland and the Gene Therapy Center at the University of Massachusetts Medical School.

In the study, researchers used an adeno-associated virus (AAV) to deliver gene products into the muscle cells of nonhuman primates, turning the cells into “factories” which produce genetically engineered antibodies indefinitely.

One primate in the study had an exceptionally positive response to the new approach. After receiving a single injection of the AAV-delivered antibodies, its HIV viral load immediately dropped below the limit of detection and has remained undetectable for more than three years.

According to Ronald C. Desrosiers, PhD, professor of pathology at UM and a longtime HIV researcher, this result provides proof of concept that this approach can deliver a functional cure for HIV.

“Our goal is to be able to deliver these potent broadly neutralizing antibodies with one shot so the patient is good for life,” he explained. “But more research needs to be done.”

While such a technique—known as anti-retroviral drug therapy— may suppress viral replication in HIV-infected humans, or SIV- or SHIV-infected monkeys, the study’s authors say it is not a cure. Removal of antiviral drugs results in a rebound of plasma viral loads in the vast majority of individuals. Because of this, repeated infusions are needed to maintain a protective concentration.

In addition, while two other monkeys in the study also maintained long-term viral suppression, the AAV delivery method triggered a defensive immune system response which inactivated the antibodies. The muscle cell-produced antibodies were seen as foreign antigens, resulting in an anti-drug reaction, which can also occur in some patients receiving antibodies for treating Crohn’s disease, rheumatoid arthritis or other conditions.

“Now, we have to solve this anti-drug antibody problem so that we can generate a robust response in virtually all humans,” said Desrosiers, noting this could be a significant breakthrough for world health. “One advantage to this AAV approach is that it could be readily applied throughout the developing world, where antiretroviral therapies are not readily available. An easy ‘one-shot’ approach could make a huge difference in addressing this global epidemic.”

Rhesus macaques have long been considered the prime model for AIDS vaccine research because these monkeys’ immune systems are analogous to humans.

In fact, most medications approved to treat HIV in humans to date have resulted from biomedical research with macaques, much of it performed at the National Primate Research Centers.

Now, for the first time, scientists have used a genetically engineered herpesvirus to achieve significant vaccine protection against the AIDS virus in monkeys. Only live attenuated strains of simian immunodeficiency virus (SIV) – the monkey version of HIV – have previously provided similar protection.

This finding, supported by multiple NIH grants, comes from research at the University of Miami and the Wisconsin National Primate Research Center (WiNPRC). Lead researcher Mauricio Martins is an assistant professor working with long-time AIDS vaccine research experts and NPRC collaborators Ron Desrosiers and David Watkins in the Department of Pathology, Miller School of Medicine, University of Miami.

Although several approaches to an AIDS vaccine show promise, molecularly cloned SIVmac239 is difficult for antibodies to neutralize, just as HIV-1 is in human infection, and a variety of approaches have had great difficulty achieving protective immunity against it, the authors reported.

“These latest results demonstrate for the first time significant protection against acquisition of SIVmac239 by any vaccine regimen other than live-attenuated SIV vaccines,” said Martins.

Four out of six vaccinated monkeys were protected against infection following repeated viral injections over four months, whereas five out of six control animals became infected over the same time span — and those five acquired it the most quickly of all the animals. Animal care and humane euthanasia were administered throughout this study by WiNPRC veterinarians as needed and under the guidelines of the American Veterinary Medical Association.

The herpesvirus used in the study was rhesus monkey rhadinovirus (RRV). The genetically engineered strain, rRRV-SIVnfl, produced not only replicating RRV, but noninfectious SIV, both working together to elicit a safe and strong enough response to fight off SIV infection. It is crucial for any prophylactic vaccine to recognize and kill all virus particles before they invade T-helper cells, take over their machinery and create more viruses. In AIDS, when those viruses eventually burst out, they kill their host cells, destroy the rest of the immune system and eliminate the body’s defenses against lethal opportunistic infections.

Further work is needed, the authors say, to define the critical components necessary for eliciting this protective immunity, evaluate the breadth of the protection against a variety of strains, and explore how this approach may be extended to humans.

Photo credit: National Institute of Allergy and Infectious Diseases

Is it possible to reverse the effects of a life-threatening poison? In the case of one such toxic substance, it very well may be.

A recent study at the Tulane National Primate Research Center (TNPRC) showed for the first time that an experimental drug can save nonhuman primates exposed to deadly ricin toxin. Ricin is derived from the seeds of the castor oil plant, and a single dose of purified ricin powder the size of a few grains of table salt can kill an adult. Due to its toxicity and the availability of its source material, it is considered a leading bioterrorism threat.

It’s also difficult to counter the effects of the lethal toxin once a person has been exposed to it.

“Clinically, there is no treatment that can be administered currently to save someone in the event of an exposure to this toxin,” said study first author Chad Roy, PhD, director of infectious disease aerobiology and biodefense research programs at TNPRC.

In the study, researchers at TNPRC, Mapp Biopharmaceutical Inc., University of Texas Southwestern Medical Center and the New York State Department of Health used a drug comprised of humanized monoclonal antibodies against the toxin. This drug was developed from research of a successful ricin vaccine that was originally tested at TNPRC, and it was engineered to look very similar to the structure of antibodies that were generated from vaccinated nonhuman primates.

“Our study shows proof of concept in a near-clinical animal model, the nonhuman primate, that we finally have a life-saving treatment against one of the world’s most notorious toxin agents,” noted Roy.

Researchers also found the drug was much more effective four hours after exposure as opposed to 12 hours after exposure, indicating a short time window for successful treatment. They plan to develop a stronger version that would “expand the therapeutic window” for effective treatment longer after exposure, Roy said.

Additionally, the scientists hope to develop the drug as a possible preventative therapeutic that emergency workers or members of the military could take before they enter areas contaminated with ricin. The research is part of ongoing federal efforts to develop effective countermeasures against bioterrorism agents.

Reviewed: June 2020