December 18, 2020

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.

December 15, 2020

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. This is why the NPRCs support establishing a strategic reserve of NHPs to be used in times of national health crises. 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.

November 30, 2020

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.

November 24, 2020

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.

October 20, 2020

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.

September 28, 2020

The seven National Primate Research Centers (NPRCs) are participating in SciFest All Access 2020. This is the virtual answer to the postponed USA Science & Engineering Festival, which is recognized as the nation’s top science and engineering festival for K-12 students, college students, educators and families. Happening now through Oct. 3, registered participants can visit the NPRCs in the “Exhibit Portal, Health & Medicine Zone II.”

The NPRC booth includes links to NPRC.org, our collective website, as well as individual web pages for the seven centers. All pages are filled with educational resources and links to help you learn more about our research, the scientific advancements we’re making and the care we provide our research animals. Direct access links to these seven pages are provided below.

NPRC representatives will be “on site” at SciFest All Access answering questions registered participants submit via the “Ask a Question” link in the booth. We’re also answering questions participants email us at nprcoutreach@gmail.com.

You can learn even more about the NPRCs’ research to improve human and animal health by visiting NPRC.org and following us on Twitter at @NPRCnews.

We look forward to joining thousands of students, educators and families at this year’s SciFest All Access!

SciFest All Access NPRC Web Pages

California NPRC

Oregon NPRC

Southwest NPRC

Tulane NPRC

Washington NPRC

Wisconsin NPRC

Yerkes NPRC

August 24, 2020

Note: The NPRCs will update this blog with our latest COVID-19 news.

Since beginning COVID-19 research in early 2020, NPRC researchers have made encouraging progress in efforts to better understand, diagnose, prevent and treat this novel disease. We’re committed to conducting and enabling research to end this global pandemic and to providing information so the public has ready access to our scientific results.

Our most recent COVID-19 news includes: 

  • February 9, 2021: Tulane NPRC unravels what makes people COVID-19 super-spreaders
  • February 4, 2021: Yerkes NPRC researchers developed a COVID-19 vaccine that is safe and effective in animals models, easily adaptable to address variants and may be equally effective with a single dose. Hear directly from the lead researcher here (beginning at 23:03) and watch the latest update here.
  • February 3, 2021: Tulane NPRC leads national research partnership to speed up COVID-19 vaccines and drug discoveries

Below is even more information about our extensive and collaborative COVID-19 research:

Diagnostics:

Prevention:

Treatments:

Additional NPRC COVID-19 News:

Bookmark this page so you can easily return here for the latest NPRC COVID-19 research information. We’ve also compiled a list of resources here and provided links to previous NPRC COVID-19 news and national media stories here.

July 30, 2020

Could HIV vaccines be reducing their own effectiveness by stimulating too much help? According to scientists at Yerkes National Primate Research Center (YNPRC), this could be the case.

In a recent paper that considered information from four studies on macaques immunized against SIV (HIV’s relative) or the hybrid SHIV virus, the researchers concluded a certain type of immune system cell known for helping may actually represent a weak spot in the body’s defenses.

HIV targets and replicates inside helper T cells, which aid in the body’s antiviral immune response. The problem comes when vaccination generates too many of a particular type of helper immune cell, Th1 cells.

We can think of Th1 cells as the well-intentioned first responders to a zombie attack. These cells travel to mucosal tissues, such as the rectum, cervix and vagina, where HIV/SIV first enters the body in the majority of infections. Th1 cells combat the virus initially, but then they get taken over.

What’s needed instead are Tfh cells, which remain in the lymph nodes and aid the immune system in creating antibodies. 

“We’re not saying Th1 cells are bad,” noted Rama Rao Amara, PhD, YNPRC and Emory Vaccine Center researcher, and co-director of Emory’s Consortium for Innovative AIDS Research in Nonhuman Primates. “But if you have too many, they take away from effective vaccine protection.”

“It’s a matter of stimulating just the right amount of immune help for a strong immune response, but not so much that it increases susceptibility to the virus,” added Eric Hunter, PhD, co-author and co-director with Amara of the AIDS research consortium, and an Emory Vaccine Center researcher. 

This could possibly be achieved using adjuvants, which are vaccine components that enhance the immune response. Amara noted the need for the effects of adjuvants to be explored in future research, and he further stated scientists studying candidate HIV vaccines in humans should examine whether these vaccines create too many Th1 target cells. This information could help immunologists design vaccines that provide more reliable protection against HIV.

Researchers across the NPRC network continue to explore new treatments for HIV/AIDS every day. You can keep up with the latest breakthroughs here.

July 21, 2020

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.

 

June 24, 2020

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.

 

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