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 7, 2020

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.

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 10, 2020

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.

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.

October 14, 2020

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.

September 15, 2020

When fighting cancer, patients need every advantage possible, and new research results have shown a potential breakthrough that could help protect the health of those undergoing chemotherapy.

Scientists at the Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin–Madison (UW) have developed a more efficient way to grow white blood cells, which serve as front-line defenders against bacterial infections but are often depleted during cancer treatment. Chemotherapy can leave cancer patients with a very low number of a specific type of white blood cell called neutrophils. This can result in febrile neutropenia, a dangerous condition marked by fever and heightened risk of infection.

This condition is usually treated with a transfusion of the white blood cells from a donor. But collecting enough neutrophils for transfusion is difficult, according to Igor Slukvin, MD, PhD, professor of pathology and laboratory medicine at the UW School of Medicine and Public Health, and the transfusions don’t always show the intended benefit in controlled trials.

“The complicated logistics of granulocyte collection, the need for pre-treating donors with G-CSF (a treatment that stimulates bone marrow to produce granulocytes) or steroids, difficulties in collecting a sufficient number of good quality granulocytes and the limited storage time of around 24 hours all hamper the utility of granulocyte transfusion for correcting neutropenia and may contribute to the inconclusive results observed in clinical trials,” he said.

Now, Sluvkin and a team of researchers have developed a method to generate neutrophils for weeks on end using stem cells. This solution replaces the standard, expensive, relatively inefficient and time-intensive process for neutrophil production.

Using modified messenger RNA, the technique sparks the production of a specific protein that guides the stem cells through a developmental process to become a sheet of hemogenic endothelium (found in blood vessels), which then begins producing neutrophils. These white blood cells can eventually be collected and administered to patients without some of the risk caused by other blood products often carried along in transfusions.

This technique produces neutrophils in as soon as 14 days, compared to as much as a month in previous studies, and can generate up to 17 million neutrophils from one million human induced pluripotent stem cells.

Notably, the scientists learned the neutrophils generated using this method are functionally similar to peripheral blood neutrophils and can phagocytize (surround and swallow) and kill bacteria.

These neutrophils also create opportunities to study other diseases, since white blood cells produced from stem cells carrying genetic disorders that weaken or otherwise affect the neutrophils will still retain those problems. The new production method could give researchers a ready source of malfunctioning cells and enable observation in the earliest stages of development.

The NPRCs are conducting stem cell studies at our locations across the nation. See more ways we’re applying this research to help solve a variety of health issues.

August 26, 2020

Protecting against three diseases at once may seem improbable, but a recent study has produced a vaccine which may do just that.

In a joint collaborative effort involving Tulane National Primate Research Center (TNPRC), the National Institutes of Health and the U.S. Army, researchers have developed the first vaccine that provides complete protection against three types of equine encephalitic viruses in nonhuman primates.

There are no existing vaccines or treatments against Western, Eastern and Venezuelan equine encephalitis, all of which are spread by mosquitoes. During summer months when mosquitos increase, horse populations are particularly susceptible to fatal infection. Transmission from horses to humans can occur via mosquitoes and can cause serious illness and death in vulnerable populations like the elderly and children.

Using nonhuman primate and mouse models of aerosol infection, the study showed that the trivalent virus-like particle (VLP) vaccine induced an immune response and provided complete protection from all three viruses. The response was strong enough to effectively block the neurological effects of infection, which is normally present with any of the three viruses.

Chad Roy, PhD, director of Infectious Disease Aerobiology and Biodefense Research Programs at Tulane, said one reason this finding is significant is because of its possible influence on the field of bioweaponry. These encephalitic viruses are possible bioterrorism agents because of their potential to be aerosolized, underlining the need for a vaccine in the event of an attack.

“These findings are an important milestone in the development of a vaccine that could be employed in the event that these viruses are ever used in a deliberate release,” noted Roy.

Of course, the vaccine could also be used to prevent or slow the natural spread of equine encephalitic viruses.

“This is a significant step, not only in protecting human populations from possible threats of bioterrorism, but also protecting both animals and humans from natural vector-borne disease transmission,” said Vicki Traina-Dorge, PhD, associate professor of microbiology and immunology at Tulane.

As the global climate warms and human and animal populations increase, mosquito-borne infectious diseases have greater potential to spread. These vaccines could be highly useful in protecting global populations from both natural and man-made outbreaks.

August 12, 2020

As scientists continue to make progress in the fight against human immunodeficiency virus (HIV), a recent discovery suggests that certain other microbes may play a role in how the body responds to vaccination.

According to researchers at the California National Primate Research Center (CNPRC) at the University of California, Davis (UC Davis), microbes living in the rectum could alter the effectiveness of experimental HIV vaccines.

Evidence from human and animal studies with other vaccines suggests supplements containing the bacteria Lactobacillus can boost antibody production, while treatment with antibiotics can hamper beneficial immune responses, according to Smita Iyer, assistant professor at the UC Davis Center for Immunology and Infectious Diseases and School of Veterinary Medicine. 

Iyer and her team specifically sought to learn if microbes living in the rectum and vagina—sites of HIV transmission—interacted with an experimental HIV vaccine similar to the HVTN 111 vaccine currently in early stage clinical trials in humans. According to Iyer, a vaccine that produces antibodies at the mucosal membranes where infection takes place is thought to be crucial.

The team studied rectal and vaginal microbes from rhesus macaques before and after they were vaccinated. While vaginal microbes did not show much difference before and after vaccination, rectal microbes did, with certain bacteria decreasing after vaccination. 

Furthermore, the amounts of the common gut bacteria Lactobacillus and Clostridia in the rectum correlated positively with the immune response. Animals with high levels of either Lactobacillus or Clostridia made more antibodies to certain HIV proteins, the researchers found. Prevotella bacteria showed the opposite pattern: High levels of Prevotella were correlated with weaker immune responses.

It’s not clear what the mechanism could be for some bacteria to boost local immune responses in a specific site in the body, Iyer said. However, targeting these bacteria could help scientists get the best possible performance out of vaccines that do not induce a particularly strong immune response, as is the case with HIV vaccines.

The NPRCs are actively conducting HIV/AIDS research across the country. Discover more ways our scientists are making progress against this disease in the ongoing pursuit of a cure.

August 4, 2020

Tuberculosis (TB) kills 1.6 million people every year and is one of the top 10 causes of death globally. And while it’s been kept under control in most places, more than 95 percent of cases and deaths are in developing countries, according to the World Health Organization (WHO).

Traditionally, it’s been difficult to prevent and treat TB in such regions, which is why Southwest National Primate Research Center (SNPRC) researcher Professor Jordi Torrelles, PhD, is focused on making a change. He developed a TB test that has been adapted for the challenging conditions typically encountered when diagnosing TB in developing countries.

“The way it’s done now, it takes 42 to 60 days before you get results from a TB test,” Torrelles said. “That’s before the patient is informed of results. When you factor that in, it’s more like 65 to 80 days from when the patient gives a sputum sample to when they learn whether they have TB.”

Torrelles traveled to Mozambique, Swaziland and South Africa in early 2019 to establish research collaborations for testing this cheaper, faster, easier way to diagnose TB. The current widely-used, commercially available TB test costs 608 USD. Torrelles’ improved version has a projected cost of just 9 USD.

What’s more, the current test does not indicate if a person is infected with drug-resistant strains of TB. Patients with these strains are even more difficult to treat, as they do not respond to the most commonly used TB drugs, requiring expensive, lengthy treatment. Torrelles and team started with what’s known as an “agar” test—which shows if the patient is infected with TB and whether the bacteria type or strain is resistant to three commonly used drugs for treatment—and developed a special color plate that can test for resistance to 11 drugs. They created two versions: one diagnostic, the other a treatment-tracking version to check if the patient is responding to the treatment.

In the past, results have usually been returned in 21 days for TB strains that can be treated with drugs, and up to 80 days for drug-resistant strains. If the SNPRC team’s new test plates are kept refrigerated, results can be seen as soon as three to 14 days, Torrelles said. And while many health care facilities in developing countries don’t have access to refrigeration, the improved diagnostic test doesn’t require it. Even if kept at room temperature, results can be interpreted between three and 19 days.

TB research is a top priority for scientists across the National Primate Research Centers (NPRC) network. Check out more ways we’re working to eliminate the disease for good.

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