Starting antiretroviral therapy early essential to battling not one, but two killers

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Medication against the nonhuman primate version of HIV given two weeks after infection helped keep tuberculosis in check.

SAN ANTONIO (February 15, 2022) – Two weeks makes a big difference in treating the animal version of HIV and latent tuberculosis, researchers from Texas Biomedical Research Institute, Southwest National Primate Research Center and colleagues report this month in the Journal of Clinical Investigation. The finding is another piece in the puzzle of the complex interaction between HIV and tuberculosis (TB), and can help advance development of therapies and a combined vaccine for the two diseases in humans.

“Most humans are able to control a low dose of TB infection by maintaining it in a dormant form called latent tuberculosis infection,” says Riti Sharan, PhD, a staff scientist at Texas Biomed and first paper author. “But if they get co-infected with HIV, then there is a high possibility that TB is reactivated and the patient ultimately dies of TB. Our objective is to improve existing interventions or identify new ones to prevent latent TB from being reactivated.”

To help study what happens in humans, researchers turn to nonhuman primates, which contract simian immunodeficiency virus (SIV), the monkey version of HIV, as well as tuberculosis. The researchers found that when animals with a latent TB infection start combined antiretroviral therapy (cART) against SIV two weeks after infection, the animals fare much better than if cART is started at four weeks post SIV infection.

“Originally, we did not think that two weeks would make this much of a difference, but to our surprise, it did,” Sharan says. “The findings were very dramatic and clear.”

Specifically, in the group that started cART at two weeks post infection, chronic immune activation was significantly reduced, as was SIV replication, and latent TB was not reactivated as much as in the group that started cART four weeks post infection. In fact, the lungs in the group that started treatment at four weeks looked more like they were not receiving any treatment at all.

Lung tissue of animals with TB
Lung tissue of animals with TB that started cART two weeks post SIV infection (left) versus at four weeks post SIV infection (right). There are far fewer green spots on the left, which indicate fewer macrophages are dying and latent TB is kept more under control, thanks to starting cART earlier. Red spots are also macrophages. Credit: Texas Biomed

Chronic, or ongoing, activation of an immune response, might sound like it should be a good thing to help fight illness. But it can also play a central role in exacerbating illness. When the immune cells are chronically activated, it leads to exhaustion and cell death, and this opens up a major gap in the body’s defense system, Sharan explains. That is when is appears latent tuberculosis can become reactivated.

“This paper adds to the growing body of evidence from our lab that shows chronic immune activation is key to driving reactivation of latent TB,” says Deepak Kaushal, PhD, a professor at Texas Biomed and senior paper author. “But it is the first to really look at the timing difference for administering ART in animal models, which is will be critical for future studies and helping develop treatments and vaccines.”

The researchers note that the difference of two weeks may not directly apply to humans, in part, because most people are unlikely to be diagnosed and begin treatment for HIV within two weeks of infection. The real value of the finding is identifying chronic immune activation as the main driver of latent TB reactivation following HIV infection, and now being able to study potential mechanisms for protection.

“Ultimately, we aim to use this information to design a therapy that would enable patients to prevent latent TB reactivation by limiting the HIV-driven chronic immune activation,” Sharan says.

The research was done in collaboration with the Emory University School of Medicine, Tulane National Primate Research Center and Washington University in St. Louis.

This investigation used resources supported by the Southwest National Primate Research Center grant P51 OD011133 from the National Institutes of Health Office of Research Infrastructure Programs.

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ABOUT TEXAS BIOMED

Texas Biomed is one of the world’s leading independent biomedical research institutions dedicated to eradicating infection and advancing health worldwide through innovative biomedical research. Texas Biomed partners with researchers and institutions around the world to develop vaccines and therapeutics against viral pathogens causing AIDS, hepatitis, hemorrhagic fever, tuberculosis and parasitic diseases responsible for malaria and schistosomiasis disease. The Institute has programs in host-pathogen interactions, disease intervention and prevention, and population health to understand the links between infectious diseases and other diseases such as aging, cardiovascular disease, diabetes and obesity. For more information on Texas Biomed, go to www.TxBiomed.org.

Initial COVID-19 infection on the single-cell level, revealed

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Sequencing more than 170,000 single cells from animal models have provided exceptionally detailed insight into the early immune response to SARS-CoV-2 in the lungs. The findings will help inform future treatment options for the current pandemic and future coronaviruses.  

Using fluorescent markers, Texas Biomed researchers and colleagues identified the cell populations active in the lung in the first few days of COVID-19 infection. Under the microscope, they observed immune cells called macrophages (the large multicolored circles) responding to SARS-CoV-2 infection, at three days following infection (center). These macrophages were not present in the lung before infection (left) and most were no longer detected two weeks after infection (right). Blue spots are nuclei of normal lung cells. Credit: Texas Biomed

SAN ANTONIO (February 7, 2022) – What is going on at the single-cell level in the first days of SARS-CoV-2 infection in the lungs?

Researchers at Texas Biomedical Research Institute and Southwest National Primate Research Center (SNPRC), in collaboration with Washington University in St. Louis, have clarified what immune cells are present in the lungs in the first days of SARS-CoV-2 infection, and what some of those cells are doing to fight off the virus. The findings, reported in Nature Communications this week, will help guide the development of future treatments for COVID-19.

“This is the most detailed analysis of early SARS-CoV-2 infection to date thanks to the latest single-cell sequencing technologies, and animal models developed at Texas Biomed and SNPRC,” says Deepak Kaushal, Ph.D., SNPRC Director and senior paper author.

The analysis has shed light on a key mystery throughout the COVID-19 pandemic: the role of a class of signaling proteins called Type I Interferons (IFN). During viral infections, interferon molecules act like sentries or alarm bells blaring “intruder alert!” to other cells, so they can boost their defense systems. However, some reports have shown a lower Type I Interferon response to SARS-CoV-2, allowing the virus to spread more readily. At the same time, runaway interferon “cytokine storms” have been a hallmark of severe COVID-19.

Scientists have been trying to figure out if interferon fights SARS-CoV-2 or is somehow dysregulated, especially early on in infection. Clarifying this is important for developing treatments that aim to limit harmful inflammation linked to excessive interferon activity, without blocking its protective mechanisms.

This new research shows interferon plays a key role in clearing the virus, by alerting other immune cells, called macrophages, to search and destroy the virus. Macrophages are akin to Pac-Man, gobbling up cells infected with the virus.

“Our analysis shows there is a massive population of macrophages in the lungs at day three after infection, amounting to 80 to 90 percent of all cells in the airways at that moment,” says Dhiraj K. Singh, Ph.D., a Staff Scientist at Texas Biomed and first paper author. “We can also tell by looking at the genes that are activated in those macrophages, that they are specifically responding to an interferon signal.”

The finding was possible thanks to the latest, highest-resolution genetic sequencing technology: single-cell RNA sequencing. The team sequenced the gene expression profiles of more than 170,000 individual cells. These profiles, which tell them what genes are turned up or down, indicate what the cell is and what it is doing at the time. Singh worked closely with Shabaana Khader, Ph.D., and Maxim Artyomov, Ph.D., and their teams at Washington University in St. Louis to analyze and interpret the massive amounts of raw, high-resolution data.

“RNA sequencing has been around for 10 years, but it averages out gene expression activity for an entire tissue,” Singh says. “In contrast, the latest single-cell RNA sequencing can tell you what genes are on and off in say, B cells versus T cells. It is so much more specific.”

single cell sequencing data
Using single-cell RNA sequencing, the researchers identified the different cell types present in the lungs before COVID-19 infection (left), in the first few days of infection (center), and towards the end of infection (right). Each color represents a different cell type. The red represents macrophages, which clearly increase at three days post infection. Credit: Texas Biomed

But the data could not have been collected in the first place without animal models. To get a snapshot of the lung environment before, during and after infection, scientists collect what amounts to a lung wash at key time points from rhesus macaques.

“Often, by the time people go to the clinic when they are sick, the virus is already well established,” Singh says. “Primates are the only model where we can actually look at those early acute responses.”

Kaushal underscored how at the start of the COVID-19 pandemic, the San Antonio community rallied behind Texas Biomed and SNPRC, donating more than $5 million in a week to support the institute’s efforts to develop animal models for COVID-19 research. The animal models have since been critical for testing vaccines and therapies, including the Pfizer-BioNTech vaccine and Regeneron’s monoclonal antibody cocktail.

“This new research is a continuation of the animal model that we generated, which would not have been possible without the generous contribution of the San Antonio community and ongoing support from the National Institutes of Health’s Office of Research Infrastructure Programs,” Kaushal says. “It shows once you’ve established a model, what is possible. You can really advance knowledge in the area.”

Singh has recently received a San Antonio Medical Foundation grant to see what happens when more interferon is added to the lungs, and compare that with other ongoing studies blocking interferon. If the studies ultimately confirm interferon’s positive role in marshalling macrophages early in infection, it could potentially lead to interferon-based therapies for COVID-19. These have been tried for other diseases, and so could move quickly to clinical trials.

“In my opinion, the potential applications don’t stop at COVID-19,” Kaushal says. “It’s quite likely that the next pandemic in the next 10 years or so will be caused by another coronavirus. So having all this knowledge is going to be very critical.”

This investigation used resources that were supported by the Southwest National Primate Research Center grant P51 OD011133 from the Office of Research Infrastructure Programs, National Institutes of Health.

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ABOUT TEXAS BIOMED

Texas Biomed is one of the world’s leading independent biomedical research institutions dedicated to eradicating infection and advancing health worldwide through innovative biomedical research. Texas Biomed partners with researchers and institutions around the world to develop vaccines and therapeutics against viral pathogens causing AIDS, hepatitis, hemorrhagic fever, tuberculosis and parasitic diseases responsible for malaria and schistosomiasis disease. The Institute has programs in host-pathogen interactions, disease intervention and prevention, and population health to understand the links between infectious diseases and other diseases such as aging, cardiovascular disease, diabetes and obesity. For more information on Texas Biomed, go to www.TxBiomed.org.

Texas Biomed breaks ground on new Animal Care Complex

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The complex will provide brand new indoor/outdoor housing for up to 800 nonhuman primates and advanced veterinary care capabilities.

Rendering of the new Animal Care Complex
An architectural rendering of the new Animal Care Complex at Texas Biomed and Southwest National Primate Research Center. Credit: Flad Architects

SAN ANTONIO (December 8, 2021) – Texas Biomedical Research Institute (Texas Biomed) and the Southwest National Primate Research Center (SNPRC) broke ground today on four new buildings that will enable them to continue providing exceptional care for nonhuman primates, play a central role in addressing the nation’s nonhuman primate shortage, and accelerate the Institute’s growth in infectious disease research.

Animal models are a critical resource in the development of diagnostics, therapies and vaccines for infectious diseases, such as COVID-19, HIV, Ebola and tuberculosis, as well as understanding related cancers, diabetes, neurodegeneration and more.

The Animal Care Complex will be built on Texas Biomed’s 200-acre campus, with construction estimated to get underway after the holidays and finish in early 2023. The complex consists of four structures: three large indoor/outdoor housing spaces that can support multiple primate species. The 18,000-square-foot animal care building will feature a top-of-the-line veterinary clinic, pathology labs and a central meeting space for animal care staff.

“First and foremost, this project is about providing the best possible care for our animals,” says Deepak Kaushal, PhD, Director of the SNPRC. “Our talented and compassionate team provide exceptional care to our 2,500 primates, and these new facilities will ensure they can continue to do that well into the future.”

Texas Biomed and SNPRC are committed to exceeding the highest standards of care for laboratory animals, and are fully accredited by the international agency AAALAC. The new care complex will support those efforts through modernized facilities and structures designed to withstand extreme weather events, which are projected to occur more frequently as the climate changes.

The care complex will also enable SNPRC to strategically expand its critical role supporting biomedical research. The ongoing national primate shortage was exacerbated during the COVID-19 pandemic, with not enough animals available for required pre-clinical tests of vaccines and treatments before moving into human clinical trials.

“Nonhuman primates are the unsung heroes of biomedical research and are essential to helping us eradicate infectious diseases here in San Antonio and around the world,” says Larry Schlesinger, MD, President and CEO of Texas Biomed. “This complex will enable us to strategically grow our colony and help ensure the nation is better prepared for future pandemics.”

This is the first major construction project as part of Texas Biomed’s 10-year Strategic Plan launched in 2019. A $4 million grant from the U.S. Economic Development Administration kick-started fundraising efforts for the more than $15 million project, and generous donor support and institutional funds are covering the remaining costs.

San Antonio City Councilwoman Melissa Havrda notes that the growth for Texas Biomed in the next 10 years will be a win-win for her district and the overall region.

“Texas Biomed is a critical piece of the city’s public health infrastructure and an important economic development partner in my district,” she says. “Studies show Texas Biomed will contribute $3 billion to our region’s economy once this decade of growth culminates. That impact will be phenomenal.”

Breaking ground on the new Animal Care Complex
Breaking ground on the new Animal Care Complex (from left to right): Cory Hallam, PhD, Texas Biomed VP, Business Development and Strategic Alliances; Walter Embrey, Texas Biomed Board of Trustees Member and Facilities Committee Chair; Deepak Kaushal, PhD, Director, Southwest National Primate Research Center; Akudo Anyanwu, MD, Texas Biomed VP, Development; Joanne Turner, PhD, Texas Biomed Executive VP, Research; Andy Anderson, DVM, Texas Biomed Board of Trustees Vice Chair; Bexar County Judge Nelson Wolff; Councilwoman Melissa Cabello Havrda, District 6, City of San Antonio; Andrew Hunt, President, Founder’s Council; Councilwoman Phyllis Viagran, District 3, City of San Antonio; State Representative Steve Allison, District 121, Texas House of Representatives; Matt Majors, MBA, Texas Biomed VP, Operations. Credit: Texas Biomed

Flad Architects is the architectural design firm working closely with the SNPRC team to ensure all facilities are maximized for functionality, safety and care, with a close eye to details to make life better for animals and their caretakers.

SNPRC is one of seven National Primate Research Centers and houses several species of nonhuman primates with unique features: the largest colony of baboons in the U.S., which has lived at Texas Biomed for eight generations; the largest group of geriatric marmosets in the U.S., which help study disease and aging; and rhesus macaques bred to be free of specific pathogens, which are integral to the study of HIV, TB, COVID-19 and other infectious diseases.

Alternative methods for studying diseases and treatments are still under development and there is no replacement for evaluating how an entire body will respond to a medicine or vaccine. Studies carefully move through a process and only proceed to primates if showing promise in cells and smaller animals. The fewest possible animals are used and humanely treated throughout.

“We all have great respect for these animals and the detailed insights they can provide to improve animal and human health,” Dr. Kaushal explains. “Our top priority is taking care of them and we are excited for this project to get underway.”

Significant medical advancements that have come from working with SNPRC primates include: the neonatal high frequency ventilator, hepatitis B vaccine, hepatitis C cure and Ebola virus treatment and vaccine. COVID-19 therapeutics and vaccines were shown to be safe and effective through studies at SNPRC before moving into human clinical trials.

Dr. Schlesinger adds, “Alongside our scientists, the animals at SNPRC are saving lives, and it is our honor and privilege to care for them as they provide so much for human health.”

The Southwest National Primate Research Center is also supported by the Office of Research Infrastructure Programs, National Institutes of Health through the grant P51 OD011133.

A version of this story appeared in the Summer 2022 edition of TxBiomed magazine. See more stories from TxBiomed here.

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About the Southwest National Primate Research Center at Texas Biomed

Texas Biomed is one of the world’s leading independent biomedical research institutions dedicated to advancing health worldwide through innovative biomedical research focused on protecting the global community from the threats of infectious diseases. The Institute is home to the Southwest National Primate Research Center (SNPRC) and provides broad services in primate research. SNPRC contributes to a national network of National Primate Research Centers (NPRCs) with specialized technologies, capabilities and primate resources, many of which are unique to the SNPRC. The Center also serves investigators around the globe with research and technical procedures for collaborative projects. For more information on Texas Biomed, go to www.TxBiomed.org or for more information on SNPRC, visit www.SNPRC.org.

Compound shows promise for minimizing erratic movements in Parkinson’s patients

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Erratic, involuntary movements often emerge as a side effect of the primary medication used to treat Parkinson’s disease. Now, Texas Biomed researchers and their collaborators have shown a compound can substantially reduce those movements in animal studies.

SAN ANTONIO (December 1, 2021) – A new study from Texas Biomedical Research Institute (Texas Biomed) and collaborators has identified a promising drug candidate to minimize uncontrolled, erratic muscle movements, called dyskinesia, associated with Parkinson’s disease.

The small molecule, called PD13R, reduced dyskinesia by more than 85% in the marmoset animal model of Parkinson’s disease. And, the animals got much better sleep taking this compound compared to another drug often prescribed for dyskinesia. The results were published in the journal Experimental Neurology.

Dyskinesia is a common side effect in patients with Parkinson’s disease. It is not a symptom of the disease itself, but typically emerges about five years into taking levodopa, the leading medication used to restore balance, reduce shaking and manage other motor control issues patients experience.

“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, PhD, an associate professor at Texas Biomed and lead paper author.

receptor and molecule
The small molecule PD13R (magenta) interacting with the dopamine D3 (grey) and D2 (purple) receptors cryo-EM structures, as predicted by RhodiumTM. Credit: SwRI

Designing drugs for Parkinson’s and its side effects is notoriously difficult. This is in part due to the progressive nature of the disease as neurons deteriorate, and because it involves the neurotransmitter dopamine. There are five types of dopamine receptors, all with different functions, yet very similar structures. Finding a compound that only interacts with the desired receptor is a major challenge.

To try to identify a compound that only binds to dopamine receptor #3 (D3), Daadi teamed up with Southwest Research Institute. SwRI’s drug discovery software RhodiumTM identified PD13R as a likely candidate and predicted how it would bind to D3. Daadi reached out to medicinal chemists at Temple University to synthesize the compound, who are currently working on this class of compounds for their antipsychotic properties.

Daadi and his team at Texas Biomed explored how well the compound targeted the D3 receptor compared to the other dopamine receptors in cell culture tests. They found it had a 1,486-times higher selectivity for D3 than for D2, which is the most similar in structure.

The team then administered PD13R to the marmoset animal model of Parkinson’s. Like human patients, the nonhuman primates developed dyskinesia after receiving levodopa. When treated with PD13R, dyskinesia dropped dramatically.

“We were very excited to see the robust antidyskinetic effect of the drug,” Daadi explains.

The animals wore activity monitors, and with PD13R, their activity was low at night, when they normally sleep. In contrast, when given a different drug currently on the market for dyskinesia, their nighttime activity was significantly high, suggesting that PD13R may be a good treatment option without this side effect.

Daadi and his team plan to continue with safety and efficacy studies required by the U.S. Food and Drug Administration (FDA) before human clinical trials can begin. “I am very hopeful we can move this into Phase 1 clinical trials within two years,” Daadi says.

members of Daadi's lab
Professor Marcel Daadi (third from left) and members of his lab. Credit: Texas Biomed

Funding Acknowledgements:

This investigation used resources that were supported by the Southwest National Primate Research Center grant P51 OD011133 from the Office of Research Infrastructure Programs, National Institutes of Health. This work was supported by the Worth Family Fund, The Perry and Ruby Stevens Charitable Foundation, The Robert J. Jr. and Helen C. Kleberg Foundation, The Marmion Family Fund, The William and Ella Owens Medical Research Foundation, the National Institute on Aging R56 AG059284.

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About the Southwest National Primate Research Center at Texas Biomed

Texas Biomed is one of the world’s leading independent biomedical research institutions dedicated to advancing health worldwide through innovative biomedical research focused on protecting the global community from the threats of infectious diseases. The Institute is home to the Southwest National Primate Research Center (SNPRC) and provides broad services in primate research. SNPRC contributes to a national network of National Primate Research Centers (NPRCs) with specialized technologies, capabilities and primate resources, many of which are unique to the SNPRC. The Center also serves investigators around the globe with research and technical procedures for collaborative projects. For more information on Texas Biomed, go to www.TxBiomed.org or for more information on SNPRC, visit www.SNPRC.org.

NIH establishes center to end HIV/AIDS in Texas

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Texas Biomed joins Baylor College of Medicine and UT Health-Houston to boost HIV research in Texas, create a regional hub for research from pre-clinical to public health

Deepak Kaushal
Professor Deepak Kaushal, Ph.D.
Director of the SNPRC

SAN ANTONIO (June 1, 2021) – A group of Texas scientific institutes are joining forces to grow and optimize HIV and AIDS research, thanks to a $5 million dollar grant from the National Institutes of Health (NIH). The five-year grant is helping to launch the new Texas Developmental Center for AIDS Research (Texas D-CFAR), which will foster research and health services in Texas and beyond, as well as mentor the next generation of HIV researchers.

Texas D-CFAR brings together three leading organizations working on HIV/AIDS in Texas: Baylor College of Medicine (Baylor) in Houston, University of Texas Health Science Center at Houston (UT Health-Houston), and Texas Biomedical Research Institute (Texas Biomed) in San Antonio.

“The new center helps us combine our unique strengths, identify and address research gaps and synergize our efforts to address the ongoing HIV epidemic,” said Texas Biomed Professor and Director of the Southwest National Primate Research Center (SNPRC) Deepak Kaushal, Ph.D. “The expertise in HIV/AIDS research and clinical practice among the three institutions is invaluable, and the unique resources of the SNPRC positions the Center to make great progress in the fight against AIDS.”

Kaushal will be one of three co-directors of the center, with Thomas Giordano, M.D., M.P.H., a Baylor Professor and Section Chief of Infectious Diseases at the helm. Specifically, Texas D-CFAR will serve as the state’s central hub for collaborations among scientists, clinicians, public health officials and the community for HIV/AIDS research. Activities will encompass basic and translational research as well as clinical trials and health services. Essential for success will be working closely with the local communities most affected by HIV in Houston and San Antonio through a community advisory board.

The ultimate aim is to reduce infections, find new ways to treat the disease, and improve health outcomes. More than 91,000 Texans are living with HIV as of 2018, according to the Centers for Disease Control and Prevention’s most recent data.

“If you look at HIV in the U.S., it has shifted over the decades from the Northeast and West Coast to the South and Southeast, and Texas is responsible for a large portion of the HIV epidemic,” Giordano said. “…There are fewer people becoming newly infected by HIV in many places in the U.S., but the decline in Texas has been slower. We are fortunate to get this grant to try to accelerate the efforts in Texas.”

The center, one of 17 CFARs, will also place a strong emphasis on training the next generation of HIV researchers, through research grants, equipment, lab space, training and mentoring.

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About Texas Biomed

Texas Biomed is one of the world’s leading independent biomedical research institutions dedicated to eradicating infection and advancing health worldwide through innovative biomedical research. Texas Biomed partners with researchers and institutions around the world to develop vaccines and therapeutics against viral pathogens causing AIDS, hepatitis, hemorrhagic fever, tuberculosis and parasitic diseases responsible for malaria and schistosomiasis disease. The Institute has programs in host-pathogen interactions, disease intervention and prevention, and population health to understand the links between infectious diseases and other diseases such as aging, cardiovascular disease, diabetes and obesity. For more information on Texas Biomed, go to www.TxBiomed.org.