Autism Spectrum Disorder (ASD), which impacts communication and interaction abilities, affects 1 in every 54 children in the United States. In order to understand the biological basis of these types of human disorders, scientists must turn to translational animal models—research with animals that closely reflects the same processes in humans.    

Until now, there hasn’t been an effective way to identify which animals were ideal candidates for ASD research. But Kate Talbot, PhD, and her colleagues in the Neuroscience and Behavior Unit at the California National Primate Research Center (CNPRC) have optimized a screening tool—based on an ASD diagnostic tool used in humans—to do just that.  

ASD is classified by the National Institute of Mental Health as a developmental disorder that affects communication and behavior. It is a spectrum disorder, which means autism can present differently in symptoms and severity across individuals. This variability is part of what makes treatment of ASD more complicated. Rather than a primary treatment for ASD, doctors and patients have to work together to develop specific treatment programs.  

Talbot pointed out that studying disease biology directly in ASD patients is difficult in other animal models because they fundamentally lack the complex social cognitive abilities that are impaired in people with autism. But there is a subset of rhesus monkeys within the natural population illustrating low-social behavior similar to what is observed in humans with ASD. The difficult part is identifying enough of these animals early in their development to conduct the necessary translational research. 

Talbot and her team made a breakthrough in that area. The original macaque social responsiveness scale (mSRS) was a 36-item observation-based instrument similar to the Social Responsiveness Scale originally developed for human children. The mSRS was developed using a relatively small sample mostly composed of females, but due to the sample size and the fact that ASD is a particularly male-biased disorder (four males for every one female), the mSRS was difficult to translate to the human screening tool.  

Talbot and colleagues refined the mSRS by applying it to hundreds of male rhesus macaques across their development. They could then compare experimenter responses to the questionnaire directly to behavioral data collected on the animals throughout their lives. Now, the revised tool can determine with 96% accuracy which monkeys qualify as particularly low-social animals compared to their peers.   

“This instrument will be indispensable for advancing the field’s understanding of the developmental trajectory of core autistic symptomology in rhesus and other macaque monkeys, and it can be used as a primary outcome measure in fast-fail preclinical therapeutic testing efforts,” Talbot explained. 

Understanding autism and other neurological conditions is a primary goal of NPRC research. Find out more about our ASD-related studies by visiting this link.  

Researchers at Yerkes National Primate Research Center (YNPRC) have discovered a way to use cancer immunotherapy treatments to reliably shrink the size of the viral “reservoir” in simian immunodeficiency virus (SIV)-infected nonhuman primates treated with antiviral drugs.

In humans, antiviral drugs can suppress human immunodeficiency virus (HIV) to the point of being undetectable in blood, but the virus embeds itself in the DNA of specific immune cells (T cells). Each reservoir consists of T cells that continue to harbor the virus even during antiviral drug treatment.

According to the researchers, chronic viral infection and cancer produce similar states of “exhaustion.” T cells that could fight virus or cancer are present but unable to respond. In long-term HIV or SIV infection, T cells harboring the virus display molecules on the cell surface that make them targets for checkpoint inhibitors (cancer immunotherapy drugs designed to counteract the exhausted state).

In this study, researchers combined two cancer immunotherapy treatments to block the surface molecules CTLA-4 and PD-1 in nonhuman primates. In subjects that received both CTLA-4- and PD-1-blocking agents, researchers noted a stronger activation of T cells compared to only a PD-1 blockade.

“We observed that combining CTLA-4 and PD-1 blockade was effective in reactivating the (SIV) virus from latency and making it visible to the immune system,” said Mirko Paiardini, PhD, an associate professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at YNPRC.

In previous studies, shrinkage of the viral reservoir has been limited and inconsistent when researchers use single checkpoint inhibitors or other immune-stimulating agents. During this study, however, combination-treated animals showed a consistently measurable and significant reduction in the size of the viral reservoir.

Despite these findings, the combination treatment does not prevent or delay viral rebound once antiviral drugs are stopped. Paiardini suggested the approach may have greater potential if combined with other strategies, for example a therapeutic vaccine, or it could be deployed in a target-rich environment, for example during ART interruption when the immune system is engaged in intercepting and fighting the rebounding virus. Other HIV researchers have started to test those tactics, he indicated.

It is also noteworthy the equivalent combination of CTLA-4 and PD-1 blockade in humans has been tested in the context of cancer treatment, and while the two drug types can be more effective together, patients sometimes experience adverse side effects like severe inflammation, kidney damage or liver damage. Fortunately, the combination-treated animals in this study did not experience comparable events.

Finding a complete HIV cure is still critically important because problematic issues, like social stigma and the long-term toxicity and cost of antiretroviral drugs, remain. 

To learn more about how NPRC scientists are working toward effective treatments—and ultimately a cure—visit this link.

Research with animals is crucial to improving human and animal health. Animals in research provide unique insights not available with other scientific models, and they help scientists determine safety and effectiveness of preventions, treatments and cures. During the COVID-19 pandemic, animals in research have been especially important in accelerating the development COVID-19 vaccines as well as better diagnostics and additional treatment options.

At the NPRCs, we’re helping fill a critical role in halting COVID-19 by leading NIH-funded studies at our centers. We’re also participating in the public-private partnership ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) to develop treatments and vaccines by sharing our knowledge, resources and animals, including conducting preclinical studies with NPRC monkeys for some of the leading industry vaccine candidates.

Scientific collaboration is especially important during a pandemic when time is of the essence and, in this case, animal resources are limited. At the onset of the pandemic, monkey importation was halted, putting increasing demands on the NPRC animal colonies, which were already limited in quantity and availability. The NPRCs account for only 1 in every 5 nonhuman primates (NHPs) used in U.S.-based research, so the limited supply at a time of high demand impacts NPRC COVID-related studies as well as pre-pandemic studies under way at the NPRCs and those in planning stages.

The NPRCs remain dedicated to our other areas of study, including research into HIV/AIDS and other infectious diseases, the neurosciences, cardiovascular and respiratory health, genetics and transplant medicine. 

We are also committed to meeting the future needs of animals for NIH-funded research. We are already growing our on-site breeding colonies when time, space and funding permit, strategically assigning animals to research protocols, harmonizing across centers for efficient use of animals and increasing rigor and reproducibility to facilitate collaboration and consistency across research labs. These strategic steps now further position the NPRCs for the translation of our research advancements from cell and animal models to humans, and are indicative of our commitment to help people across generations and the world live longer, healthier lives. 

To learn more about the NPRCs’ ongoing efforts to combat COVID-19, visit this page.

Editor’s Note, 2/22/21: The New York Times covered the research monkey shortage in today’s issue. Read the story here.

Tuberculosis (TB) and HIV are two of the world’s deadliest infectious diseases, and they’re far worse when they occur together. Now, Southwest National Primate Research Center (SNPRC) researchers at Texas Biomedical Research Institute have pinpointed an important mechanism that could lead to a new mode of treatment for this co-infection.

It’s been long-assumed the reason people with HIV are more likely to develop TB is a depletion of specific immune cells. However, SNPRC scientists showed other effects of viral co-infection play a crucial role in this process.

Using data from nearly 40 rhesus macaques, the research team found lung-specific chronic immune activation is responsible for the progression of TB. Chronic immune activation is a dysfunction of immune pathways that create molecules (cytokines and chemokines) that fight off pathogens such as bacteria, viruses and fungi.

Professor and SNPRC Director Deepak Kaushal, PhD, used an analogy to explain what this dysfunction caused by an HIV infection does in the body.

“It’s like all the taps and faucets in your house are turned on full blast all the time,” he said. “You are going to lose a lot of water. With this dysfunction, all cytokines and chemokines are constantly being produced to the highest levels. This dysregulates the body’s ability to fight off other infections.”

Even with antiretroviral therapy (ART) for people with HIV, chronic immune activation still persists. Kaushal said this study shows, “we need to develop approaches to target chronic immune activation,” perhaps with a drug that would be an additional therapy to ART.

Kaushal said he is hopeful new treatment strategies could reach the clinic within a decade, and the effects could be huge. Up to a fourth of the world’s population is infected with TB, and this co-infection is considered a global syndemic, meaning the diseases are pandemics infecting people all around the world, and they promote each other.

Understanding TB is a priority for NPRC scientists, and this study is a continuation of the groundbreaking research being done across the organization. Just last year, researchers explored the possibility of treating the disease using a cancer drug.

Could a promising discovery about viral latency help scientists effectively combat human immunodeficiency virus (HIV)?

The primary obstacle to a cure for HIV infection is the reservoir, or immune cells that harbor the inactive virus when someone is being treated with antiretroviral drugs. One of the leading research strategies for eliminating HIV from the body is “shock and kill,” which involves activating a dormant virus from within these immune cells where it hides, then eliminating it. A key challenge, however, has been finding a safe way to “wake up” the virus from its latent state.

In two complementary studies—one from the Yerkes National Primate Research Center (YNPRC) of Emory University and another from the University of North Carolina at Chapel Hill—researchers report they have come closer to that goal.

The studies relied on two animal models of HIV infection. Each took a different approach, but both yielded promising results, bringing the virus out of its hiding places even in the presence of antiretroviral drugs that stopped it from replicating for months.

“If our goal is to cure HIV/AIDS, then we have to disrupt viral latency,” said Guido Silvestri, MD, chief of microbiology and immunology at the YNPRC. “What we’re doing now is a new combination approach that provides unprecedented levels of virus reactivation.”

Both approaches were tested at the YNPRC in monkeys infected with SIV, a close relative of HIV, and treated with antiretroviral drugs. At UNC, tests were also conducted in mice transplanted with human immune cells. The results represented the first occurrence of a successful systemic HIV induction in humans or an animal model with human cells that was then replicated in a completely different species infected with a different virus.

In one study, 12 monkeys were treated with the drug AZD5582, and just one experienced a temporary fever and loss of appetite—a promising sign. In the other study, researchers stimulated the cells that are the main viral hosts (CD4+ T cells) while also depleting another kind of immune cell (CD8+ T cells), which normally keeps the virus in check. The scientists indicated both the stimulation and depletion components were necessary to see SIV re-emerge.

Neither intervention mentioned above, however, reduced the size of the viral reservoir. Once the animals were taken off antiretroviral drugs, viral levels rebounded. The scientists indicated that in future studies, the initial viral reactivation needs to be combined with other modes of treatment, such as antibodies directed against the virus itself.

Want to learn more about how researchers are working toward a cure for HIV? Take a look at some other related studies from the NPRCs, including this one about reducing the viral reservoir.

Talking about animals in research may not be part of everyday conversations – unless you work in research, are learning more about it or want to stop it. But if everyone knew how critical animals have been in 2020 to fast-track a safe and effective COVID-19 (coronavirus) vaccine, would that change?

Earlier this year, the National Institutes of Health (NIH) called upon the National Primate Research Centers (NPRCs) – as NIH has for HIV/AIDS, Ebola, Zika and other infectious disease threats – to identify animal species for studying the SARS-CoV-2 virus and developing safe and effective vaccines to block it.

The NPRCs went to work and within a few months had discovered how valuable nonhuman primate models (NHPs), especially macaques, are for studying SARS-CoV-2. The NPRCs found the virus infects rhesus, pigtail and cynomolgus macaques, so these animals were included in research programs that resulted in several vaccine candidates in the pipeline by summer’s end. In addition, other key models for SARS-CoV-2, such as mice and hamsters, contributed to the broadening knowledge of how best to tackle the disease in humans. This rapid pace of discovery was possible due to the NPRC researchers applying their expertise fighting other viruses, especially HIV/AIDS.

As with those other viruses, the NPRC researchers closely studied SARS-CoV-2 transmission routes and pathogenesis – this time focusing on the respiratory virus’ activity in the lungs and its impact on cells, tissues and organs. The researchers also conducted detailed genetic studies on the virus to help pharmaceutical researchers use pieces of the virus’ genetic code to fashion vaccine candidates and test them for safety and effectiveness in macaques.

Translating the biomedical research findings into the human population requires going from up to a few dozen monkeys in research to thousands of human volunteers in clinical trials; for COVID-19, more than 200,000 volunteers have enrolled in four promising clinical trials. As announced in November 2020, the Moderna and Pfizer mRNA vaccines tested on rhesus macaques were more than 90 percent effective in preventing COVID-19 in widespread (Phase 3) human clinical trials and are now on track for emergency FDA approval.

Research with animals connects these vaccines with other SARS-CoV-2 scientific advancements just as it has made connections among NPRC HIV/AIDS studies, the results from which facilitated the rapid pace to COVID-19 discoveries. Improving human and animal health – that’s what NPRC research with animals does, and that’s worth talking about any day.

Learn more about research with animals scientific advancements here.

Could a recent discovery about the body’s natural defenses be a stepping stone toward combating kidney-related health issues? Scientists say yes.

Macrophages are a type of white blood cell central to the immune system that detect and engulf harmful pathogens, like viruses, bacteria and fungi, serving as helpful scavengers to fight infections. They also cause or suppress inflammation and secrete molecules that allow communication between different cell types, all of which provide a healthy immune response in fighting infection and disease.

Scientists have long known the origins of different types of macrophages found in the brain, gut, heart and liver. The origins of those found in kidney tissue, however, are not as well understood. Until now, researchers hadn’t known if these macrophages had traveled from elsewhere in the body or if they were produced during embryonic development. As it turns out, both theories are correct.

In a recent study, Tulane National Primate Research Center (TNPRC) scientists Xuebin Qin, PhD, professor of medicine, and Fengming Liu, PhD, assistant professor of microbiology and immunology, made a new discovery about renal (kidney) macrophages that fundamentally changes the understanding of how these cells populate.

Using a new rapid cell ablation (destruction) technique created by Qin, the team discovered that in a mouse model, half of renal macrophages originate during the embryonic state and the other half derive from bone marrow. They also showed that embryo-derived renal macrophages have a stronger immune response than their bone marrow-derived counterparts. 

“These findings advance our current understanding of tissue-resident macrophages and may lead to promising new directions for the development of new therapeutics for kidney diseases,” explained Qin.

The implications of this discovery are important because while the kidneys help control the volume of blood in the body and maintain the proper concentrations of proteins and electrolytes, they are also subject to infection and disease. The role of macrophages in clearing any infection and supporting kidney function could prove key to future treatments of kidney disease and even infectious diseases that are associated with kidney failure, like human immunodeficiency virus (HIV) and coronavirus (COVID-19).

NPRC scientists across the country are working to combat infectious diseases through a variety of research projects. You can learn more about NPRC’s infectious disease studies at this link, as well as coronavirus-specific studies at this link.

It’s been 25 years since University of Wisconsin-Madison scientist James Thomson, VMD, PhD, was the first in the world to isolate and culture primate embryonic stem cells. He accomplished this breakthrough with nonhuman primates (NHPs) at the Wisconsin National Primate Research Center (NPRC) in 1995, using rhesus monkey cells, and again in 1996 with marmoset cells. Thomson then published his world-changing breakthrough on human embryonic stem cell derivation in Science Nov. 6, 1998.

From these early discoveries, stem cell research has advanced to human clinical trials for treating both age-related and juvenile macular degeneration, heart disease, blood and immune system cancers, skin wounds, hearing disorders, spinal cord injury, graft-versus-host disease and more. Just as Thomson predicted in the 1990s, NHPs, which were instrumental to basic stem cell research 25 years ago, are now in demand for a wealth of preclinical studies necessary before human clinical trials can begin.

Thanks to advances in pluripotent stem cell research and also gene-editing, researchers are also making progress in understanding the underlying causes of Parkinson’s disease, diabetes, pregnancy disorders, sickle-cell anemia, autoimmune diseases, cartilage regeneration and much more. Universities and medical institutions today have well-established stem cell and regenerative medicine centers to help bring researchers and resources together to advance the field and educate the next generation of stem cell scientists, doctors, educators, business people and policy makers.

The main uses of stem cells today include basic research to understand the human body, discovering the genetic origins of disease, growing new cells and tissues for transplant medicine, and growing cells and tissues for testing pharmaceuticals in the lab before animal and human trials begin. Stem cell research is helping animals, too. Pets as well as research animals at the NPRCs naturally get cancer, diabetes, arthritis and other diseases that stem cell therapies may be able to treat.

It’s important to make sure therapies are based on well-designed and thorough clinical trials. The Federal Food and Drug Administration (FDA) recently cracked down on a number of rogue stem cell clinics that have offered untested, unapproved and even potentially dangerous medical interventions. Only a licensed physician with a patient under his or her direct care should recommend any stem cell therapy or other medical treatment.

Thanks to stem cell research breakthroughs pioneered at the NPRCs – and advanced by many researchers and doctors who have joined the field since – we are finally unraveling the mysteries of cell biology from early development through aging as never before. Read more here.

One primary objective of tuberculosis (TB) research is to discover how to treat people with the latent (or inactive) form of the disease so they don’t develop symptomatic TB.

Now, a breakthrough study from the Yerkes National Primate Research Center (YNPRC) and Southwest National Primate Research Center (SNPRC) has revealed how a specific combination of antibiotics could help.

For the study, the scientists created a latent infection in a group of rhesus macaques. They then treated half of the animals with a once-weekly combination of two antibiotics—isoniazid and rifapentine—for three months. The other half was untreated.

Numerous factors—including HIV infection, diabetes, aging or other diseases—can cause latent bacteria to become symptomatic and infectious again. To test whether the antibiotics had cleared bacteria from their lungs, both treated and untreated animals were infected with SIV (Simian immunodeficiency virus), which mimics HIV in humans. 

Of the animals that had no treatment for latent TB, 70 percent developed active TB after SIV infection. However, none of the animals that had the three-month course of antibiotics developed active TB after SIV infection, which suggests the treatment cleared the bacteria and prevented reactivation.

Because the current treatments for latent TB are lengthy, and many patients don’t finish them, a shorter treatment cycle like the one demonstrated in this study could be highly beneficial.

“The antibiotic treatment we used for this study is a new, shorter regimen the CDC recommends for treating humans with latent tuberculosis, but we did not have direct evidence for whether it completely clears latent infection,” explained Jyothi Rengarajan, PhD, Associate Professor of Medicine at Emory University and the Yerkes National Primate Research Center. “Our experimental study in macaques showing almost complete sterilization of bacteria after treatment suggests this three-month regimen sterilizes humans as well.”

The researchers at the NPRCs are working daily to find new potential treatments and cures for this infectious disease. Take a look at some of our other recent studies to learn about the progress we’ve made toward a TB-free world.

According to the World Health Organization, malaria infection affects an estimated 200 million people and kills more than 400,000 people worldwide every year—most of them children. Plasmodium parasites cause the disease, and malaria spreads to people by the bite of infected Anopheles mosquitoes. While important information, the scientific community still has much to learn about malaria in order to limit its impact.

“We don’t know what is inside malaria infections,” explained Ian Cheeseman, PhD, Assistant Professor at Texas Biomedical Research Institute, which is home to the Southwest National Primate Research Center (SNPRC). “We don’t know how many different genetically distinct strains of parasites there are. We don’t know how related they are to each other. We don’t know how many mosquitoes they came from.”

To help answer these questions, Cheeseman and an international team of collaborators turned to a process called single cell genome sequencing. This technology allows for individual malaria parasite cells to be isolated and their genome amplified before being analyzed by a genome sequencer, which enables researchers to capture the genetic mutations present in a single cell. The process has been adopted by cancer researchers to understand how tumors evolve, but this study marked the first time the technology has been used to study malaria transmission.

The team examined single malaria-infected cells from patients in Malawi, a country heavily affected by the disease. Patients who donated malaria-infected blood samples used in this study reside in Chikhwawa, a region with a large mosquito population where people may be bitten by a malaria-infected mosquito every 48 hours.

The single cell sequencing approach applied in this study provides a new perspective on how often bites from an infected mosquito lead to a malaria infection. What researchers discovered went against conventional wisdom, as nearly all the infections they studied likely came from one mosquito bite each.

“We found that complex malaria infections are predominantly caused by a single mosquito bite transmitting many genetically diverse but related parasites into the bloodstream of a patient,” said Standwell Nkhoma, MSc, PhD, lead author on the study and a Malawian national.

Knowing this will enable scientists to design more effective interventions to block mosquitoes from spreading malaria and build better models to predict malaria transmission patterns and the spread of drug resistance. While a diagnosis of malaria is often treatable with drugs, the rise of antimalarial drug resistance is a major threat to malaria control across the world, as resistance to artemisinin and piperaquine, two common antimalarial drugs, continue to spread.

To learn more about how NPRC researchers are making progress toward controlling and eliminating infectious diseases worldwide, visit this link.