Human immunodeficiency virus (HIV) attacks the body’s immune system, resulting in rashes, fevers, fatigue, swollen lymph nodes, and other symptoms. It affects over 37 million people globally. When left untreated, HIV infections can progress to acquired immunodeficiency syndrome (AIDS), leading to a damaged immune system, severe opportunistic infections, and death.

Most replicating HIV – and its monkey version, simian immunodeficiency virus (SIV) – is found in follicles of the lymphoid tissues. However, most cytotoxic T-lymphocytes, the cells clearing HIV from the body, cannot reach the follicles. This explains the need for lifelong use of antiretroviral therapy’s current standard treatment. However, only 57% of those living with HIV are undergoing antiretroviral therapy, which leaves the rest able to infect others with the virus. Therefore, there is an urgent need for new treatment options, especially for those who do not have lifelong access to healthcare.

A group of AIDS researchers working with immunology and animal care experts on rhesus monkeys at the Wisconsin National Primate Center investigated the possibility of a new therapy targeting virus-specific T-cells to the follicles. They did so by engineering therapeutic T-cells to enter and concentrate in the lymphoid follicles to reduce viral replication. Led by Pamela Skinner, professor of veterinary and biomedical sciences at the University of Minnesota, the team used T-cells to express a chimeric antigen receptor (CAR) targeting the SIV virus. They added a follicular homing receptor called CXCR5 so the CAR/CXCR5 T-lymphocytes could kill the infected cells in the lymphoid follicles. The homing receptor allowed the T-cells to migrate into the follicles, which previously limited the effectiveness of the body’s response to infection.

In six SIV-infected rhesus monkeys, the CAR/CXCR5 T-cells were able to migrate to the follicles within two days and directly interact with the virally infected cells. Fluorescent imaging allowed the researchers to discover these T-cells could replicate and increase within the follicles. Even though levels of the specialized T-cells declined within four weeks after administration, the treated primates were able to maintain lower concentrations of SIV in their blood and follicles than those not given the CAR/CXCR5 T-cell immunotherapy. The researchers and veterinarians also looked at possible side effects of this treatment and found none of the primates had a poor reaction to T-cell administration.

The study, published in Public Library of Science Pathogens, provided preliminary evidence for effective and safe treatment of engineered T-cells for HIV infection. Data from these researchers set the stage for future preclinical studies involving larger populations of non-human primates to confirm the effectiveness of this treatment, along with studies looking at combining this treatment with other therapies.

About 24,000 kidney transplants are performed in the US each year, yet more than 90,000 people are waiting for a transplant. Even when patients get a transplanted kidney, organ rejection is a common complication in the first year after a transplant, affecting 1 in 3 people.                                                        

Sometimes finding a perfect match for a kidney can turn into an endless search – with blood, tissue, and antibody compatibility needed between donor and recipient. A study recently published in the journal Transplantation shows researchers may be able to help increase the number of kidney transplants thanks to a new transplant procedure working between mismatched donors and recipients. 

Rhesus monkeys at the Wisconsin National Primate Research Center are playing a starring role in a study to improve the success of kidney transplants. Animal care experts and pathologists worked with transplant surgeon Luis Fernandez and other researchers to test the new procedure. Fernandez directed the University of Wisconsin Hospital and Clinics liver transplant program until last year and is now a transplant division chief at Loyola Medicine in Chicago. Also on the research team were preclinical and clinical experts from the University of Wisconsin–Madison School of Medicine and Public Health, Texas Southwest Medical Center, Pharming Technologies BV in Leiden, The Netherlands, and Leiden University Medical Center.

The researchers focused on complement activation, implicated in delayed graft function. They used a high-dose complement blockade therapy called C1INH (or rhC1INH in rhesus monkeys) to discover it worked well in preventing delayed graft function and antibody-mediated kidney rejection. Furthermore, the researchers used donor kidneys from deceased animals to make up for the lack of available deceased human kidney donors (approximately 20% of human donor kidneys are discarded due to the length of storage time or advanced donor age).

Of all the mismatched kidney transplant recipients, four out of five monkeys treated with a saline control developed delayed graft function complications, whereas only one in eight rhC1INH-treated recipients experienced difficulties. The other seven animals in the treatment group underwent successful transplants with fully functioning kidneys.

The study results support high-dose C1INH complement blockade therapy in mismatched transplant recipients as an effective strategy to reduce kidney injury and inflammation, prevent delayed graft function, delay antibody-mediated rejection development, and improve transplant outcomes.

The research team thanks the veterinary and SPI staff at the Wisconsin National Primate Research Center for their “extraordinary care for the animals during the observation period.”

Zika is spread mainly through the bite of an infected Aedes species mosquito. And while many people infected with the Zika virus will only have mild symptoms, contracting Zika during pregnancy can lead to severe brain defects.  

 The 2015-2016 Zika outbreak in Brazil and other countries in the Americas caused a surge in miscarriages and a constellation of congenital disabilities, prompting the World Health Organization to declare a public health emergency of international concern. 

 While there has never been a vaccine or medicine to prevent Zika, a recent collaboration between Trudeau Institute, Texas Biomedical Research Institute’s Southwest National Primate Research Center (SNPRC), and Walter Reed Army Institute of Research (WRAIR) demonstrated a vaccine candidate successfully prevented the virus from passing from mother to fetus during animal studies. 

 In-Jeong Kim, Ph.D., a viral immunologist at Trudeau Institute and the first paper author states, “Our proof-of-concept studies conducted at Trudeau and Texas Biomed show very promising results that the vaccine given before pregnancy will provide high levels of protection for mothers and babies.” 

 Testing pregnant women is highly restrictive due to ethical and safety reasons, which is why the Trudeau Institute and Texas Biomed team evaluated the vaccine in pregnant mice and marmosets. The results? More than 90% effectiveness in marmosets, making it a viable approach for countering the persistent threat of Zika in humans. 

Oxytocin, a brain chemical known for promoting social bonding and nurturing behavior, has been used in several studies to potentially treat disorders such as autism, but with inconsistent results. 

Yerkes National Primate Research Center Division Chief Larry Young and his research colleagues in Yerkes’ Division of Behavioral Neuroscience and Psychiatric Disorders as well as Emory’s Center for Translational Social Neuroscience found the dynamic response of neurons to oxytocin may vary depending on the past social experiences of the individual. 

The study was conducted in female prairie voles because they form lifelong bonds with their partners and focused on the nucleus accumbens because it plays an important role in the brain for pair bonding. Tissue from the nucleus accumbens was exposed to TGOT, a drug that mimics oxytocin signals. 

Robert Liu, PhD, professor of biology and director of Emory’s Neuroscience graduate program compared the electrical responses of neurons to oxytocin signals to an analog television, before and after the television is tuned to a station. “Before the animal forms a pair bond, oxytocin reduces the static noise: the neurons in the nucleus accumbens fire spontaneously less often,” said Liu. “But after an animal has been exposed to a partner, it increases the clarity of the signal from the station: the neurons gradually fire with greater strength – but only when electrically triggered.”

In an unexpected turn, researchers found that after bonding, oxytocin signals became coupled to endocannabinoids, molecules produced within the brain resembling the psychoactive substances found in cannabis. By blocking the endocannabinoids, the scientists could interfere with some aspects of the prairie voles pair interactions. 

Blocking endocannabinoid signals increased the likelihood the female vole would display a defensive upright posture, a sign of rejection, in the presence of their partner, but not toward a stranger. However, the pair-bonded animals still spent more time with their partner than a stranger. This reaction shows endocannabinoid signaling is modulating defensive interactions, rather than pair bonding. 

The study suggests the way oxytocin modulates brain circuits changes with prior experience, which may help explain inconsistent results from human studies involving oxytocin.

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease that destroys memory and other important mental functions. AD affects more than 44 million people worldwide and more than six million Americans. Given this prevalence, studying AD is a high priority, and researchers have been searching for better ways to learn more about the disease.

Now, researchers at the Wisconsin National Primate Research Center and other institutions at UW-Madison have shown rhesus monkeys can be a new, translational model for studying late-onset Alzheimer’s disease. “Age is a major risk factor for late-onset Alzheimer’s disease (AD) but seldom features in laboratory models of the disease,” the researchers write in the scientific publication Aging Cell.

The researchers studied brain tissues from transgenic mice, old monkeys with age-related amyloid plaques and post-mortem brain tissue from donors who were aged 72 to 96 and diagnosed with AD after death. This approach provides an alternative to the most common approaches to modeling AD, which tend to use young mice in which plaques and tangles are genetically imposed and seldom include age as part of the study design.

The new study design, however, shows the aged environment impacts inflammatory processes linked to neurodegeneration. In the monkeys and humans, where plaques develop as a function of age, each demonstrated differences from mice in the immediate vicinity of amyloid plaques, but were similar to each other.

In all three species, the authors discovered new structures enriched in mitochondria surround the plaques, and the presence of these plaques influences metabolism. In the monkeys and humans, said Dr. Ricki Colman of the WNPRC, “this mitochondrial dysfunction appears to be suggestive of Alzheimer’s disease.”

The published study concludes that, given the clear parallels between amyloid plaques in monkeys and humans, further studies in nonhuman primate models are warranted. Monkey models are more likely to translate to human disease than mouse studies and could help advance treatments for AD.

Parkinson’s disease is a slowly progressive chronic neurologic condition, causing a gradual loss of the nerve cells producing the neurotransmitter dopamine in the brain. While there are no standard diagnostic tests for Parkinson’s, the diagnosis is clinical and based on findings of a neurological exam and information provided by the patient. Tremors occur in about 70% of those living with Parkinson’s, typically appearing on one side of the body, in a hand or a foot, while relaxed or at rest.*

The primary and most potent medication used to treat Parkinson’s disease is Levodopa, which helps restore balance, reduce shaking, and manage other motor issues patients experience. Overall, this treatment is radically helpful for those suffering, but erratic involuntary movements often emerge as a side effect of this drug over time.

“Levodopa is amazing, it works like magic, but it has side effects. If we can eliminate these side effects, it could change the life of patients with Parkinson’s,” says Marcel Daadi, Ph.D., an associate professor at Texas Biomed and lead paper author.

Dyskinesia is a common side effect in patients with Parkinson’s disease. It is not a symptom of the disease itself. Still, it typically emerges about five years into taking Levodopa. And like human patients, primates develop Dyskinesia after receiving Levodopa.

A study commenced at Texas Biomedical Research Institute (Texas Biomed) to help make strides in the reduction of Dyskinesia in humans. During this time, Daadi and collaborators administered the compound PD13R (created by medicinal chemists at Temple University) to the marmoset animal model of Parkinson’s. When treated with PD13R, primates experienced relief from uncontrolled movements as their Dyskinesia dropped by more than 85%, a measurement made by with the help of wearable activity monitors.

*https://parkinsonrockies.org/live-well/diagnosis-and-symptoms/?gclid=Cj0KCQiA8vSOBhCkARIsAGdp6RTNBEB0jvY01T0sel6voKUxEkV3GrikEtZbWVghPiKl5jk1CToebVQaAvtIEALw_wcB

One of the few therapies currently available to treat patients with COVID-19 is REGEN-COV, a monoclonal antibody cocktail that combines two antibodies that can bind to and neutralize the SARS-CoV-2 virus. The Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute (Texas Biomed) worked with Regeneron Pharmaceuticals Inc., maker of REGEN-COV, to test the effectiveness of the medication before it moved to human clinical trials. The result: the Food and Drug Administration granted emergency use authorization for REGEN-COV as a treatment for mild to moderate COVID-19 patients as well as for patients at high-risk for severe COVID-19 after an exposure to the virus. 

SNPRC’s work began quite early during the pandemic. Texas Biomed has been a longtime collaborator with Regeneron, and the two organizations had just wrapped up work on a successful Ebola virus treatment as COVID-19 began to spread. 

That established relationship made it easy to team up on SARS-CoV-2, the virus that causes COVID-19, explained Professor Ricardo Carrion, Jr., Ph.D., who co-leads the Disease Intervention & Prevention Program and directs high containment contract research at Texas Biomed. “We had the experience and processes in place for evaluating therapeutics in animal models of emerging diseases and understood what we needed to do to be successful in a short timeframe,” Carrion, Jr. said.

Within three months, SNPRC and Texas Biomed researchers had evaluated or established several different animal models for SARS-CoV-2, including rhesus macaques, transgenic mice and golden Syrian hamsters. The researchers tested the antibody cocktail for Regeneron in rhesus macaques. The data from these advanced, pre-clinical studies helped the candidate COVID-19 therapy move forward to clinical trials in people.  

Carrion, Jr. was not surprised the initial results, published in the peer-reviewed scientific journal Science, showed the antibody cocktail was safe and effective. “They are a very professional company and very good at what they do,” he said. “Regeneron ensured that all the tests that could be done prior to moving to animals were done, so there was a high likelihood of this antibody cocktail succeeding.” 

As variants of SARS-CoV-2 emerged, SNPRC and Texas Biomed scientists continued to work with Regeneron to evaluate the lasting effectiveness of the cocktail, which was determined a resounding success. The study, published in the journal Cell, featured information from both human trials and hamster animal models of COVID-19. The animal models enabled researchers to gather precise insights in a highly controlled environment, which help explain what is observed in the human population.

Such teamwork drives scientific advancements and, in this case, has been critical to helping people who have COVID-19 overcome the virus.

California National Primate Research Center (NPRC) Director and neuroscientist John Morrison, PhD, is a leader in sharing science with the public. His latest public outreach effort is serving as the lead scientist behind the exhibit, “Life of a Neuron.” This comes after years of collaboration between Washington, D.C.’s technology-based art space ARTECHOUSE and the Society for Neuroscience, a professional organization that represents neuroscientists around the globe. The immersive experience marries cutting-edge science and art to illuminate the life experience of the brain’s 86 billion neurons.

Read more about the exhibit and Dr. Morrison’s involvement here, and listen to NPR’s coverage here. 

Endometriosis is a condition that occurs when patches of the endometrium, a layer of tissue lining the uterus, travel throughout the body and attach to other organs, like the ovaries or intestines. Unfortunately, 1 in 10 women experiences pain and even infertility due to this disorder. Current treatments include surgery to remove the mislocated tissue and drug treatment to suppress ovarian activity, which can lead to weight gain, mood changes and headaches. 

After decades of study, a team of researchers, including Wisconsin National Primate Research Center scientists, discovered a possible new therapy for endometriosis that zeroes in on a particular region of chromosome 7 as the responsible gene. 

A thorough study of the DNA of women in 32 families with deep-rooted histories of endometriosis helped researchers narrow in on this single gene variant – neuropeptide S receptor 1 (NPSR1) – which they found in many, but not all, of the women with more severe cases of endometriosis.  

To learn more about this complex disease, researchers simulated endometriosis in mice by injecting bits of bacteria or uterine lining into their abdomens while attempting to silence the culprit gene. The researchers saw positive results with the rodents experiencing less inflammation and abdominal pain.  

As a next step, researchers will study this same treatment in monkeys, which have been an animal model for endometriosis studies for several decades. Joseph Kemnitz, former director of the Wisconsin National Primate Research Center, explains, “We documented the similarities of endometriosis in our monkeys compared to affected women in collaboration with Stephen Kennedy at Oxford.” The teams recognized the Wisconsin monkeys offered an excellent opportunity to examine endometriosis and have continued building on early results that revealed a familial pattern, suggesting a genetic risk.

As genomic tools continue to advance and analysis costs decrease, the rate of testing treatments stands to increase. Such comprehensive scientific progress is excellent news for the pursuit of improved human health. 

Source: Science Translational Medicine on Aug. 25, 2021. 

Dengue spreads to humans through the bite of an infected mosquito generally living in tropical climates. Symptoms (lasting 2-7 days) commonly seen with dengue include fever, nausea, rash, aches, and pains.

While most people who contract the virus see minimal long-term effects, the Wisconsin National Primate Research Center is studying whether the severity of maternal and fetal Zika virus infection increases in pregnant women who previously had dengue fever.

This first-ever study relating dengue to Zika arose from a concern that a previous dengue infection may become the catalyst leading to more potentially dangerous immune system responses when contracting Zika, especially in pregnant women and their fetuses.

Rhesus macaques were used for the study because their placental development closely mimics humans. Using them as the control, researchers uncovered prior exposure has no measurable impact on Zika replication in maternal plasma. All animal pregnancies resulted in healthy births and infants (in contrast to a small percentage of human infants born to women infected with the disease).

Researchers believe further study to understand the risks of antibody-dependent enhancement to pregnant women worldwide is needed as vaccines against dengue and Zika are developed.

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.

Sources: https://www.cdc.gov/dengue/index.html