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.

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. 

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.

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

Fear struck many when HIV (human immunodeficiency virus) and AIDS (acquired immunodeficiency syndrome) began in the mid-to the late 1970s. No one knew the causes of this mysterious new virus, and there were no treatments, preventions, or cures available. Over the past few decades, scientific advances have enabled patients to receive life-extending treatments and medications. 

The majority of HIV researchers agree that the virus evolved from the closely related simian immunodeficiency virus (SIV), transferring from non-human primates to humans.

CytoDyn Inc., a late-stage biotechnology company developing a drug called leronlimab, released an exciting study in partnership with Oregon National Primate Research Center showing that the drug prevents non-human primates from being infected with simian human immunodeficiency virus (SHIV), a monkey-human chimeric form of HIV. 

“Our study findings indicate leronlimab could be a new weapon against the HIV epidemic,” said Jonah Sacha, Ph.D., an Oregon Health & Science University professor at OHSU’s Oregon National Primate Center and Vaccine & Gene Therapy Institute.

Five clinical trials demonstrate how leronlimab can significantly reduce or control HIV viral load in humans—and ultimately prevent human infection from the virus that causes AIDS. If approved for clinical use, leronlimab will join other AIDS PrEP drugs (“Pre-Exposure Prophylaxis”), medicines taken by individuals who are at risk for exposure to HIV to prevent infection. The drug also benefits other diseases (NASH, cancer, and COVID-19) without the side effects previously experienced from other treatments such as kidney and bone problems.

While the research and trials are still ongoing, early results are promising. To learn more about NPRC research into HIV, please click here.

Lyme disease, also known as Lyme borreliosis, is an infectious disease caused by Borrelia burgdorferi bacterium, which is spread by ticks. The most common sign of infection is a red rash that appears at the site of the tick bite. Other signals of Lyme include flu-like symptoms, joint pain and weakness in the limbs.

After a 69-year-old woman was diagnosed and repeatedly treated for Lyme disease for 15 years before her death, researchers at the Tulane National Primate Research Center who had previously discovered the persistence of B. burgorferi  despite antibiotic therapy found that the same bacterium was still intact upon autopsy. 

In addition to the typical symptoms of Lyme, she experienced continual neurological decline, including a severe movement disorder and personality changes. The woman eventually passed away after being diagnosed with Lewy body dementia— a disease that presents itself with similar declined motor functions of Parkinson’s Disease with the added element of significant memory issues.  

The Tulane research team found that her central nervous system (CNS) still harbored intact spirochetes despite aggressive antibiotic therapy for Lyme disease at different times throughout her illness. The findings may lead to a correlation between Lyme disease and Lewy body dementia.

“These findings underscore how persistent these spirochetes can be in spite of multiple rounds of antibiotics targeting them,” said Monica Embers, associate professor of microbiology and immunology at Tulane. “We will be interested in investigating the role that B. burgdorferi may play in severe neurological disease, as this is an area of research that has not yet been fully explored.”

To learn more about research being done by Tulane NPRC, please visit here.

HIV (human immunodeficiency virus) attacks the body’s immune system, and if left untreated, HIV can lead to AIDS (acquired immunodeficiency syndrome). HIV/AIDS currently impacts 38 million people worldwide. While there is no cure yet, proper medical care can control the disease and allow for a relatively long and healthy life. In particular, antiviral therapy (ART) is the current leading treatment for HIV/AIDS and can reduce the virus to undetectable levels. 

Yerkes National Primate Research Center researchers, in collaboration with Institut Pasteur, recently determined that when added to ART, a combination immunotherapy of Interleukin-21 (IL-21) and interferon alpha (IFNɑ) is effective in generating highly functional natural killer (NK) cells that can help control and reduce simian immunodeficiency virus (SIV), the primate equivalent to HIV, content in tissue.

“Our results indicate the ART plus combo-treated rhesus monkeys showed enhanced antiviral NK cell responses,” says Justin Harper, lab manager of Dr. Mirko  Paiardini’s research lab at Yerkes. “These robust NK cell responses helped clear cells harboring virus in lymph nodes, which is normally shielded from robust immune responses and serves as a critical tissue that supports viral persistence.”

These new findings open the door to additional treatment strategies to help support remission without using ART, a costly treatment option that requires strict, long-term adherence. Ultimately, the researchers are working to reduce the burden of HIV to individuals and the world. To learn more about NPRC research into HIV/AIDs, please visit here. 

Tuberculosis (TB) is a serious infectious disease that typically affects the lungs. Spread of TB typically occurs in the air via coughs or sneezes. Treatment often poses a challenge to immunologists, as it represents a chronic infection characterized by persistence of the pathogen despite development of antigen-specific immune responses.

Researchers at Emory University and the Yerkes National Primate Research Center have completed the first study to report on temporal dynamics of Mycobacterium tuberculosis (Mtb)-specific T cell responses in latent Mtb infection. With it, they discovered the T cell response emerged as early as three weeks post infection and continued throughout the six-month study. 

“Because TB is the leading infectious disease killer, claiming 1.5 million lives every year, we want to know why some people who are infected with Mtb progress to TB disease while others remain asymptomatic and do not,” says Jyothi Rengarajan, PhD, lead author and associate professor of medicine, Division of Infectious Diseases, Emory University School of Medicine and a researcher at the Emory Vaccine Center and Yerkes National Primate Research Center. 

Because TB is difficult to assess in humans, researchers worked with primates because they develop and respond to the disease much like humans do

Rengarajan states, “Monkeys develop and respond to latent TB infection similar to the way humans do, which makes them an excellent translational model for studying the immunological basis for asymptomatic TB and then applying the results to humans and animals.”

Findings proved the rapid response of T cells, and knowing where to activate them (lungs versus blood) will help researchers create better treatments and even a vaccine to prevent TB infections.

NPRC researchers are working 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.

Tuberculosis (TB) is a serious disease that mostly affects the lungs, but can also cause damage to the kidneys, spine or brain. TB spreads from person to person through small droplets transferred via coughing and sneezing. Symptoms of TB include severe coughing for over three weeks, chest pain and coughing up blood or mucus.

Even after years of research, tuberculosis still remains one of the world’s deadliest diseases— especially in low-income countries. While TB related deaths have decreased by 30% globally, 1.4 million people died from it in 2019. Fortunately, researchers at the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute are getting closer to pinpointing a new way to treat and control TB.

“Single-cell RNAseq is a novel approach that has developed in the past three or four years. It’s an approach that allows us to look at the immune response more granularly, in higher resolution. We were able to identify an immune response to Mtb infection in single lung cells as the infection progressed to disease, in some cases, or was controlled in others,” stated Deepak Kaushal, Ph.D., director of SNPRC.

The study highlights that plasmacytoid dendritic cells, which sense infections in the body, overproduce Type I interferons—a response correlated with disease instead of control. This discovery gives scientists the information needed to alter vaccines.

Dr. Kaushal explains, “When we have a more precise understanding of how an infection develops, that knowledge can lead us to identify new drugs or therapies to treat disease and improve vaccines.”

Overall, the research being done by SNPRC may lead to finding a way to control and prevent TB. Learn more about our TB-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.