HIV-1, the virus that causes AIDS, remains a potent global threat, especially in sub-Saharan Africa and other low-income areas. And while new treatments over the past 40 years have greatly improved the prognosis for those infected, prevention of HIV-1 infection by vaccines or immunoglobulins is not yet established.

That may change with a finding at the Southwest National Primate Research Center (SNPRC) in San Antonio, Texas. A team led by Dr. Ruth Ruprecht has shown for the first time that an antibody called Immunoglobulin M (IgM) can be effective in preventing infection in the mucosa after exposure to the virus. This is significant because an estimated 90% of new HIV-1 cases are caused through exposure in the mucosal cavities such as the lining of the sexual organs or rectum.

Rhesus monkeys at the SNPRC on the campus of the Texas Biomedical Research Institute were treated with a man-made version of IgM. Thirty minutes later, the same animals were exposed to simian-human immunodeficiency virus, a hybrid virus containing elements of the monkey and human immunodeficiency virus. Four of the six animals treated this way were fully protected against the virus.

“IgM can grab multiple particles like HIV-1 and SHIV very quickly and does not let go,” said Dr. Ruprecht. “Our study reveals for the first time the protective potential of IgM. It basically opens up a new area of research – IgM can do more than it has been given credit for.”

IgM, which had been thought by most scientists to have too short-lived a protective effect, may now lead the way to an effective barrier against HIV-1 infection.

The 2015-16 Zika outbreak in Brazil caused many babies to be born with severe brain abnormalities. It also prompted researchers at the Southwest National Primate Research Center into action. With a colony of 300 marmosets, they worked from findings which showed that Zika antibodies were present in wild marmosets, meaning they had become infected with the mosquito-borne illness. Specifically, male marmosets have been shown to mimic human disease when infected, leading researchers to ask whether pregnant female marmosets would show similar effects of infection. Marmosets have also shown symptoms similar to humans when infected with Lassa virus, Ebola, dengue and West Nile.

“There is strong interest in the scientific community in developing animal models to understand Zika virus with the goal of developing vaccines and therapies,” said lead author Dr. Suzette Tardif, a Scientist at Texas Biomedical Research Institute and Associate Director of Research at the Southwest National Primate Research Center. “We believe marmosets may be an especially relevant model for effects on infection in pregnancy.”

“We have a theory that the placenta may be a reservoir for the Zika virus, which would explain why there’s so much of it because we find a huge number of infected cells there,” said Dr. Jean Patterson, a researcher at Texas Biomedical Research Institute. She has proposed further studies on the impact of west Nile and other viruses in pregnant marmosets in an effort to pinpoint the link between these emerging diseases and fetal developmental problems in both marmosets and humans.

Researchers exposed pregnant marmosets to the Zika virus during the first half of pregnancy, which caused those pregnancies to end about two weeks after infection. The fetuses also showed evidence of brain abnormalities. For this reason, marmosets may be the “canary in a coalmine” for studying the effects of Zika on human pregnancy and fetal development.

Since the Zika virus epidemic of 2015, there has been a surge in the number of infants in the Americas born with small heads due to brain damage that occurred when their mothers were infected during pregnancy, a condition called microcephaly.

Scientists previously thought this condition was the primary indicator of brain damage due to Zika infection, but researchers at Washington National Primate Research Center (WaNPRC) have discovered damage may still be present when head size is normal.

“Current criteria using head size to diagnose Zika-related brain issues fail to capture more subtle brain damage that can lead to significant learning problems and mental health disorders later in life,” said Kristina Adams Waldorf, MD, FACOG, a professor of obstetrics and gynecology at the UW School of Medicine who specializes in maternal and fetal infections. “We are diagnosing only the tip of the iceberg.”

In addition to Adams Waldorf, the lead researchers were Michael Gale Jr., PhD, a professor of immunology at the UW School of Medicine and an expert on how the body responds to viruses, and Lakshmi Rajagopal, PhD, an associate professor of pediatrics at the University of Washington School of Medicine and expert on newborn infectious diseases at Seattle Children’s Research Institute and UW School of Medicine.

According to the researchers, even children with a normal head size at birth may be diagnosed with serious eye injuries or late-onset microcephaly when the head fails to grow normally. Damage may also occur in children infected during early childhood and adolescence. In addition, it’s possible undetected Zika brain damage may later lead to learning disorders, psychiatric illnesses and dementia.

In the study, researchers looked for subtle changes in the brains of five fetal macaques whose mothers had been infected with the Zika virus in pregnancy. In all but one case, the researchers found no obvious fetal abnormalities with weekly ultrasounds, a medical imaging technique that is commonly used during pregnancy to assess the health of developing fetuses.

The brains of the infected fetuses, however, did grow more slowly than normal, but they remained large enough so their smaller size did not meet the criteria for Zika virus-associated microcephaly the U.S. Centers for Disease Control and Prevention uses. Under these criteria, most children (between 91 percent to 96 percent) born in the United States whose mothers were infected with Zika during the pregnancy are also not considered microcephalic. As a result, those children might not be checked regularly for Zika-related brain injury.

Magnetic resonance imaging (MRI) scans of the fetal brains, however, were abnormal in 4 of 5 of the animals. Certain areas of the brain were not growing as quickly as others. Brain regions particularly affected were areas that generate new brain cells, including the subventricular zone in the wall of the lateral ventricle, which contains the largest number of neural stem cells in the brain. Another injured part of the fetal brain was the subgranular zone of the dentate gyrus in the hippocampus, where neural stem cells play a key role in memory and learning and continue to contribute to brain health through at least adolescence.

“The study clearly shows that cells within these brain regions are highly susceptible to Zika virus infection. The findings suggest that neural stem cells within these sites, and at specific stages of development, are unable to suppress virus replication,” noted Gale.

Gale added these findings further emphasize the urgency for an effective vaccine to prevent Zika virus infections. The researchers also concluded Zika-exposed fetuses should continue to be checked for symptoms of the disease throughout their developmental years.

“All children exposed to Zika virus in utero should be followed long-term for problems with learning and development, regardless of head size at birth,” Adams Waldorf said.

Tuberculosis (TB) is the leading cause of death in AIDS patients. Unfortunately, no one knows exactly why the disease is such a significant threat in people with immune systems compromised by the HIV virus.

But researchers at the University of Pittsburgh and the University of Wisconsin–Madison recently reported in Infection and Immunity that a new nonhuman primate model using Mauritian cynomolgus macaques may help bring scientists closer to understanding the AIDS-TB link. The immune systems of these animals are similar to humans, and they are susceptible to both SIV (the nonhuman primate version of HIV) and Mycobacterium tuberculosis (which causes TB).

The paper’s authors included Shelby O’Connor, associate professor of pathology and laboratory medicine at UW–Madison and the Wisconsin National Primate Research Center (WiNPRC), and researchers from the University of Pittsburgh and WiNPRC.

The researchers used 15 macaques in the study. Of the eight monkeys infected with only M. tuberculosis, four animals survived more than 19 weeks following infection. In stark contrast, the researchers found that that all seven animals previously infected with SIV exhibited rapidly progressive TB following co-infection with M. tuberculosis and all had to be humanely euthanized after 13 weeks.  

“Our study demonstrated that pre-existing SIV dramatically diminishes the ability to control M. tuberculosis co-infection from the start,” said Mark Rodgers, senior research specialist at the University of Pittsburgh and the study’s lead author.

Senior author Charles Scanga, research associate professor of microbiology and molecular genetics at the University of Pittsburgh, added that this finding has much larger implications for research into the AIDS-TB link.

“For the first time, we have a well-characterized nonhuman primate model that will facilitate research into vaccines or therapeutics to battle TB in people living with HIV,” he said.

The theme for the 2018 World AIDS Day (December 1) is “Saving Lives through Leadership and Partnerships,” which closely aligns with National Primate Research Center (NPRC) efforts to improve therapies to treat people who are living with HIV/AIDS and to develop a vaccine that is safe and effective against all strains of the virus.

For more than 30 years, the NPRCs have led the way toward understanding and fighting HIV. The virus infects and kills millions globally; just last year, approx. 36.9 million people worldwide were living with HIV, and the death toll from AIDS-related illnesses had reached 940,000.

HIV treatments have come a long way since the disease turned pandemic and poured into the public consciousness in the mid-1980s. Today, because of the antiretroviral drug cocktails available to treat the virus, HIV is no longer a death sentence in most developed countries. Yet the hunt for better treatments and a vaccine continues.

One potential treatment making headlines involves broadly neutralizing monoclonal antibodies (bNAbs). These antibodies are isolated from individuals who have the rare ability to neutralize a majority of evolutionarily diverse HIV-1 field isolates after years of chronic infection.

NPRC scientists are part of multiple large research collaborations working on moving these bNAbs from research labs to doctors’ offices. To achieve this, the scientists have extracted these special antibodies from human blood, grown them in lab dishes and infused them into monkeys that have simian immunodeficiency virus, or SHIV, a chimeric version of the AIDS virus.

Based on the encouraging results of the monkeys being able to control their viral loads, researchers are moving bNAbs into human clinical trials. If successful, the treatment could mean fewer lifelong medications for people with HIV. This is exciting news for the scientists who have devoted decades of basic research to gain understanding of this complex, insidious and ever-shifting virus.

The NIH Office of Research Infrastructure Programs (ORIP), which supports the NPRCs, and the National Institute for Allergy and Infectious Diseases (NIAID) have been leading supporters of animal-based AIDS research, thus making possible the NPRCs’ research involving hundreds of dedicated scientists, veterinarians, animal care personnel, technicians, students and more.

On World AIDS Day today, the NPRCs express our support for people who are living with HIV, remember those who have died from an AIDS-related illness and thank our employees for their commitment that is bringing us closer to the day when the HIV/AIDS global health challenge is a distant memory.

For most of us, getting a flu shot ranks among the least exciting annual events. But researchers at the Washington National Primate Research Center (WaNPRC) at the University of Washington (UW) are hoping to make this yearly obligation a thing of the past.

A team led by Deborah Fuller, a professor in the Department of Microbiology at the UW School of Medicine, is testing the effectiveness of a universal vaccine that protects from every strain of influenza virus, even when the viruses transform genetically from year to year. Working with cynomolgus macaques, the researchers have seen promise using a DNA vaccine that instructs skin cells to produce antigens, while inducing antibodies and T cell responses to fight flu infection.

The vaccine was created using genetic components of influenza virus that remain constant. This feature allows the vaccine to get around the genetic drift, or changes, that occur in influenza strains from year to year.

“With the immunized groups, we found that using this conserved component of the virus gave them 100 percent protection against a previous circulating influenza virus that didn’t match the vaccine,” Fuller said. “This was very exciting for us.”

The DNA vaccine is administered through the epidermis with a “gene gun” device, which injects the vaccine directly into the skin cells. The cells then produce the flu vaccine and prompt the body to actively fight infection. This is an improvement over current on-the-market vaccines, which simply repel the virus.

This approach also takes less time to produce—about three months—than the nine months required to produce the current U.S.-approved vaccine.

“We’ve been working essentially with the same vaccine (techniques) over the last 40 years,” Fuller noted. “It’s been a shake-and-bake vaccine: You produce the virus, you kill the virus, you inject it. Now it’s time for vaccines to go through an overhaul, and this includes the influenza vaccine.”

Fuller said that this kind of universal vaccine could eliminate the need for yearly flu vaccinations and be kept on-hand for rapid deployment in response to a deadly pandemic strain of the virus.

She added that DNA-based vaccines may also prove effective for different viruses, like Zika, and for other possible serious outbreaks.

Can a promising cancer drug also treat tuberculosis (TB), the world’s single deadliest infectious disease? Researchers at the Texas Biomedical Research Institute, host institution for the Southwest National Primate Research Center, think so.

The team discovered a mechanism for regulating cell death – called apoptosis – that could help control the bacterial infection that causes TB. Dr. Eusondia Arnett and her colleagues tested this concept by infecting human immune cells called macrophages with the TB bacterium, then treating those infected cells with the potential cancer treatment. The result was an 80% reduction in the growth of the TB bacterium.

“Induction of apoptosis and subsequent reduced growth of the TB bacterium should ultimately result in less inflammation and damage to the lungs, and increased control of TB,” said Dr. Arnett.

One-fourth of the world’s population is infected with TB, according to the Centers for Disease Control and Prevention, including 9,000 new cases in the United States in 2017. Up to 13 million people in America carry the latent TB infection, with 5-10% developing infectious TB in their lifetimes. (The majority of those infected were born outside the U.S. and infected prior to arriving in the country from areas of the world where TB is more common.)

TB infection also creates dense cellular structures, called granulomas, in the lungs of infected persons. Granulomas are the body’s attempt to wall off an infection it is unable to eliminate. But they also provide a niche for the bacteria to become resistant to antibiotics. Dr. Arnett’s study showed that these experimental cancer drugs also reduced TB bacteria growth in granulomas in a human model, holding promise for these drugs in humans and animals.

Dr. Larry Schlesinger, President and CEO of Texas Biomed, said this finding highlights the critical role of basic scientific research.

“When we study important host cell pathways for disease, we can find relationships we didn’t even know existed,” he explained. “We can forge new ways to use current knowledge to create novel strategies for therapy for infection to be used along with antibiotics.”

The drugs used in this study are already in Phase II of Food and Drug Administration clinical trials. The next step for testing the drugs’ effectiveness in treating TB is a mouse model, followed by nonhuman primate models and ultimately, human clinical trials.

Cytomegalovirus, or CMV, is a common virus found in almost every person on the planet. For most of them, it causes no harm and leads to no symptoms. But for newborn babies and people with compromised immune systems, it can lead to birth defects, serious illness and even death.

Now, researchers associated with the California National Primate Research Center (CNPRC) at the University of California, Davis have discovered that low levels of CMV changed microbe and immune cell populations and response to the flu vaccine in rhesus macaques. CMV infection generally increased immune activity but also diminished antibodies responding to influenza vaccination. The study also found that low levels of CMV make the body susceptible to changes in environmental conditions that could accentuate their impact.

“Subclinical CMV infection alters the immune system and the gut microbiota in the host and that impacts how we respond to vaccines, environmental stimuli and pathogens,” said Satya Dandekar, who chairs the Department of Medical Microbiology and Immunology at UC Davis and is a core scientist in the infectious diseases unit at CNPRC at UC Davis. “This study highlights the role of these silent, latent viral infections that are totally asymptomatic.”

The researchers believe that these low-level CMV infections may be one reason for the variation in response to vaccines across large populations. One possibility is that the immune system’s constant effort to control CMV might be diverting resources that it might direct to other threats.

The next step in the process will be testing other vaccines in CMV-infected animals and generally working to better understand how subclinical viruses affect the immune system.

“This highlights the impact silent viruses have to influence how the host responds to vaccines,” said Dandekar. “Can we somehow use this information to optimize our immune system? That’s the direction we would like to go to see how we can inhibit CMV to see if we can enhance the vaccine response.”

Reviewed August 2019

Global fears about Zika virus may have waned since the disease first made headlines in 2015 – but scientists at the National Primate Research Centers continue to make important discoveries to understand and prevent its adverse effects during pregnancy.

Scientists at six NPRCs across the U.S. have recently collaborated on a study that concluded Zika may be responsible for more childbirth complications than originally thought – even when women show few symptoms during pregnancy.

The study, published in the journal Nature Medicine, showed that 26% of nonhuman primates inoculated with Zika in the early stages of pregnancy experienced miscarriage or stillbirth, despite displaying few clinical signs of infection. For scientists, this indicates that Zika-associated pregnancy loss in humans may be more common than previously believed, since the illness itself often goes undetected.

“The primary conclusion from this multi-center study with important implications for pregnant women infected with Zika virus is that stillbirth and miscarriage occur more frequently in infected nonhuman primates than animals not exposed to the virus,” explained lead author Dawn Dudley, PhD, with the Wisconsin National Primate Research Center.

This discovery matches human reports of adverse outcomes in babies exposed to Zika during the first trimester, helping to solidify the connection between Zika infection and its negative effects on pregnancy, even when symptoms are mild or absent. It also underlines the importance of frequent Zika testing for pregnant women – especially in regions where the disease has been identified.

In the U.S., infections have been reported in Florida and Texas. Now, the Texas Department of State Health Services is asking OB/GYNs in the counties bordering Mexico to test pregnant patients for Zika three times during pregnancy. In addition, all pregnant women across the country are cautioned to protect themselves against mosquito bites.

The effects of Zika on an adult are upsetting enough, but the impact it can have on unborn children and newborns is heart wrenching, which is why researchers at the Yerkes National Primate Research Center have made studying Zika virus a priority.

One of the most common consequences of Zika infecting an unborn child is microcephaly – a birth defect that leaves the baby with an unusually small head and undersized brain. It can be fatal, and infants who survive usually face intellectual disabilities and developmental delays.

When researchers at the Yerkes National Primate Research Center in collaboration with colleagues at Emory University School of Medicine and Children’s Healthcare of Atlanta wondered whether contracting the disease early after birth had the same effect, they noted some small, but important distinctions. For example, the disease did not appear to affect vision or visual memory.

“This gives us hope that in our future work, we can find ways to limit Zika’s effect on the developing brain,” said Ann Chahroudi, MD, PhD, the study’s lead researcher.

For now, because there is lasting damage to the nervous system and areas of the brain, the research team recommends more than just routine monitoring for pediatric patients known to be infected with Zika.

The researchers hope further work with the monkey model will allow them to study in more detail the effects of postnatal Zika virus infection on the brain and give them opportunities to test therapies for alleviating or even preventing the neurologic consequences of Zika virus infection.