In findings that have implications for potential new HIV therapies, researchers from Texas Biomedical Research Institute (Texas Biomed) used genetic sequencing techniques on the nonhuman primate version of the virus to identify that lymph nodes in the abdomen are the leading source of rebound infection after the first week of stopping antiretroviral treatment.

The study regarding simian immunodeficiency virus (SIV) was reported in the journal Science Translational Medicine. SIV is very closely related to HIV and is commonly used as a proxy to study HIV in animal models.

“Lymphoid tissues are known to be large reservoirs of latent HIV,” says Texas Biomed Professor Binhua “Julie” Ling, MD, PhD, and senior paper author. “However, there has been no definitive proof that they are the source of initial viral rebound – it has been a hypothesis. Now, we have evidence that SIV, and therefore potentially HIV, is hiding in specific types of lymph nodes and spleen tissues and is some of the first to reemerge in blood when treatment is stopped.”

Antiretroviral therapy (ART) does an excellent job at suppressing HIV to undetectable levels in the blood. However, small amounts of latent virus hide throughout the body, including in the brain, lung, gut, spleen, lymph nodes and other organs. When treatment is stopped, it opens the door for the virus to rebound.

“If we can identify the starting point of the virus rebound, we can work on developing treatments that target those tissues and stop the virus from spreading in the first place,” Dr. Ling says.

Dr. Ling and her team used several advanced genetic tools and sequencing techniques to track the virus. They teamed up with Brandon Keele, PhD, at the AIDS and Cancer Virus Program at Fredrick National Laboratory, who generated barcoded viruses. More than 9,000 individual viruses in the stock have unique genetic barcodes, “like when you go to Walmart and each item has its unique barcode to scan,” Dr. Ling explains.

Those barcoded viruses were given to seven nonhuman primates. After infection was established, the primates began receiving antiretroviral therapy. After four to six months on ART, the animals had either very small amounts or no detectable virus circulating in blood, much like people living with HIV who are on ART. When treatment was stopped after more than a year of ART, researchers were able to assess the very earliest stages of viral rebound.

Thanks to the barcoded viruses, they could identify in which tissues the virus had replicated the fastest and spread the furthest just seven days after treatment was stopped. They matched the barcodes most prevalent in blood plasma to the barcodes detected in specific tissues. Notably, the standard test did not detect any virus in blood at the seven-day mark – the amounts present were too low to be detected – but more sensitive deep sequencing did.  

The researchers found three leading contributors: mesenteric lymph nodes, which are found in the tissue connecting the intestines to the abdominal wall; the spleen, which is a part of the lymphatic system that filters blood; and inguinal lymph nodes, which are located in the groin.

Through additional analyses, the researchers found CD4 T cells, a type of immune cell, in the mesenteric lymph nodes and spleen had higher amounts of intact virus and replication activity, which corresponded with higher rates of barcoded viruses from those regions in blood plasma. This was further confirmed using a novel technology by Qingsheng Li, PhD, at University of Nebraska-Lincoln.

Interestingly, some animals showed no evidence of viral rebound, indicating they had better control of the virus in the first week after treatment was stopped than others. Through single cell sequencing and transcriptomic analyses, the team identified a few genes of interest that contribute to dysregulation of normal cell function and could play a role in the differences between animals who experienced very rapid rebound and the animals who continued to suppress viral activity. The researchers are interested in learning more about these genes and how they might affect human immune responses.

The researchers acknowledge that the study size of seven animals is small, and that tissue sample size was also limited. Nonetheless, the results point to key organs to explore specific, targeted therapies.

“There are more than 800 lymph nodes throughout the body,” says Dr. Ling. “Knowing which types of lymph nodes to target can lead to more tailored therapies or treatments and hopefully prevent HIV from spreading and prolong HIV remission.”

Paper:

Antonio Solis-Leal et al., Lymphoid tissues contribute to plasma viral clonotypes early after antiretroviral therapy interruption in SIV-infected rhesus macaques. Sci. Transl. Med.15,eadi9867(2023). DOI:10.1126/scitranslmed.adi9867

Nine Texas Biomed scientists have received more than $628,000 in philanthropic funding to study a range of infectious diseases – including Ebola virus, Chikungunya virus and tuberculosis – and develop new tools and solutions to combat them.

The Douglass Foundation, the Cowles family and the Texas Biomedical Forum provide support for scientists across the career spectrum: a graduate student pursing a PhD, postdoctoral researchers, staff scientists and faculty. This funding is especially critical to enable researchers to gather preliminary data that can then help with larger grant applications.

“The ongoing support from the Douglass Foundation, the Cowles family and the Texas Biomedical Forum provides our investigators invaluable resources to pursue scientific questions that will help us find solutions to address devastating infectious diseases and improve global health,” says Joanne Turner, PhD, Texas Biomed’s Executive Vice President for Research.

Here is the full list of awards:

2024 Texas Biomed Graduate Fellowship, supported by the Douglass Foundation

Armando Mendez (PI: Dr. Ebrahimi) holds a masters in epidemiology and is pursuing a PhD at UTSA, with plans to become a data scientist/bioinformatician. This fellowship enables him to train in Texas Biomed Professor Diako Ebrahimi’s lab, where he will develop his bioinformatic skills. Specifically, he will sequence nonhuman primates to further understand the molecular differences in immune genes among these models. Subsequently, he will develop a user-friendly bioinformatic tool to facilitate the analysis and visualization of these data. The ultimate goal is to leverage these insights to shape future research endeavors focused on refining models that more accurately replicate human biology.

2024 Cowles Postdoctoral Fellowship, supported by the Cowles family

Jenna Hulke (PI: Dr. Anderson) will study schistosomiasis, a parasitic disease that affects about 170 million people a year. Specifically, she will breed a Schistosome species that primarily infects humans with a Schistosome species that primarily infects cattle – both from East Africa – to determine the genetic characteristics of the hybrid offspring. While several natural populations of these parasites in West Africa show evidence of past interbreeding, there is currently no evidence of this happening in East Africa. The project aims to understand why this is and identify genes responsible for enabling the parasites to infect specific hosts, which could potentially be used as drug targets to help prevent human infection.

Ajai D’Silva, PhD, (PI: Dr. S. Kulkarni) will study Pemphigus disease, a life-threatening autoimmune disease that causes blisters on the skin. Specifically, he will analyze two genes FCAR and LENG8-AS1 to understand the functional role they play in this disease. He will investigate two mutations linked to the disease as well as long noncoding RNAs – which are RNA that do not code for proteins directly, but influence gene expression of protein-coding RNAs – to discern how they impact disease progression and outcomes.

Niloofar Haghjoo, PhD, (PI: Dr. Ebrahimi) will study a versatile family of editing enzymes known as APOBEC3. These enzymes can have both beneficial and deleterious effects, such as fighting invading viruses and introducing mutations that can lead to tumor development and evolution. Dr. Haghjoo will use advanced computational and evolutionary biology techniques to create a comprehensive map of amino acid interactions within these enzymes to understand which specific interactions are responsible for different functional features of these multifunctional proteins. These insights can help with the future development of new antivirals and cancer interventions, as well as advancing novel gene editing technologies.

2024 Forum Staff Scientist Award, supported by the Texas Biomed Forum

Anna Allué Guardia, PhD, will work on a new type of vaccine for tuberculosis (TB), a disease that is one of the leading killers worldwide. The current TB vaccine helps protect children, but has varied efficacy in adults. Dr. Allué Guardia will work on developing codon-deoptimized, or weakened versions, of the bacteria that could be potentially used in live-attenuated vaccines.

Israel Guerrero-Arguero, PhD, will study Chikungunya virus (CHIKV), a mosquito-borne pathogen that causes rash, high fever, neurological symptoms and incapacitating joint pain that can persist for years. Specifically, Dr. Guerrero-Arguero will generate a version of CHIKV that expresses a cherry red fluorescent protein, which will enable him and others to visually track and observe the virus in cells and in new humanized mouse models. He is particularly interested in learning more about how the virus evades the immune system and affects the brain, as well as about other host-pathogen interactions that could guide development of drugs or therapies aimed at mitigating CHIKV’s effects.

2024 Forum Faculty Award, supported by the Texas Biomed Forum

Olena Shtanko, PhD, will study the interplay between Ebola virus infection and mitochondria, the energy-producing organelle of cells. Specifically, she will investigate if Ebola virus replicates inside mitochondria and how the virus alters mitochondria function. These insights could help with future development of interventions against the virus.

Smita Kulkarni, PhD, in collaboration with Dr. Shtanko,will study the role of long, noncoding RNAs in Ebola virus infection. Long, noncoding RNAs (lncRNAs) are large RNAs that do not directly translate into proteins but regulate expression of protein-coding genes. The Kulkarni and Shtanko labs have observed changes in lncRNA expression in cells infected with Ebola virus and has dubbed these changes “Ebola virus induced long, noncoding RNAs,” or EVILs, for short. In this project, they will use advanced gene editing techniques, including CRISPR/Cas9, to analyze how EVILs impact Ebola replication and host immune response.  

Luis Martinez-Sobrido, PhD, will work on developing a live attenuated vaccine for a group of deadly arenaviruses that cause hemorrhagic fever in humans, such as Lassa virus. Specifically, he will work on developing a vaccine approach that incorporates a genetic sequence in the virus that will target the virus for degradation and, therefore, will result in attenuation when delivered as a vaccine to humans. Importantly, this approach could also be used for the development of live attenuated vaccines for other hemorrhagic fever causing viruses. 

SAN ANTONIO (Dec. 7, 2023) — A Marburg virus vaccine tested at Texas Biomedical Research Institute (Texas Biomed) is progressing in clinical trials, moving a step closer towards becoming the world’s first vaccine against the deadly virus.

The Sabin Vaccine Institute recently announced it launched Phase 2 clinical trials of its Marburg virus vaccine, which will initially enroll 125 healthy volunteers in Uganda and Kenya. Early tests demonstrating the vaccine’s efficacy, safety and optimal dosage were completed at Texas Biomed and elsewhere in animal models, which are essential before any vaccine or therapy can be administered in humans.  

“We have been partnering with Sabin since 2019 and are very excited to see their Marburg vaccine candidate move into Phase 2 clinical trials,” says Ricardo Carrion, Jr., PhD, the Director of Maximum Containment Contract Research at Texas Biomed. “An effective vaccine is critical to protect people from this deadly virus, especially as we see the frequency of outbreaks increasing in more places.”

Marburg virus is a part of the same filovirus family as Ebola virus and causes severe hemorrhagic fever. It is extremely deadly with up to a 90% fatality rate. Two outbreaks occurred earlier this year: an outbreak in Equatorial Guinea killed 12 out of 17 confirmed cases, with another 23 probable deaths, according to the World Health Organization. Tanzania also saw its first-ever Marburg outbreak, which killed six out of eight confirmed cases. First documented in 1967, Marburg has cropped up more than a dozen times over the past 56 years. There is no approved vaccine or treatment.

Texas Biomed’s scientists led the development of the well-characterized nonhuman primate model for Marburg, conducting the foundational studies needed to accurately evaluate vaccines and therapies against the virus in macaques. The work was completed in collaboration with the Biomedical Advanced Research and Development Authority (BARDA), the federal agency that oversees the development of biodefense countermeasures.

Texas Biomed has a well-established biosafety level 4 (BSL-4) laboratory, which is the highest level of biocontainment and is required to work on deadly airborne pathogens that have no vaccines or cures such as Marburg virus.

“We applaud our partners at Sabin on this significant milestone and are proud that our specialized expertise in biocontainment, filoviruses and animal model development has helped advance Sabin’s vaccine candidate forward,” says Cory Hallam, PhD, Executive Vice President for Applied Science and Innovation at Texas Biomed.

The Phase 2 clinical trial will build on promising results from preclinical studies and a smaller Phase 1 clinical trial. Texas Biomed continues to partner with Sabin to gather more detailed information that can only be gained through tightly controlled animal studies, including how soon protection is induced after being vaccinated.

“In an outbreak situation, the virus is spreading rapidly, so it is important to know how soon after receiving the vaccine a person would expect to be protected,” says Dr. Carrion.

Texas Biomed has conducted similar work on Sabin’s closely-related Sudan ebolavirus vaccine, which was delivered to Uganda last year as part of a World Health Organization-coordinated outbreak response.

Vaccine researchers from across San Antonio and South Texas will gather to exchange their latest findings at the 11^th annual Vaccine Development Center of San Antonio (VDCoSA) Conference this week.

The conference, taking place Nov. 9 at UTSA, features headline speakers from across industry, healthcare and academia:

• Ashlesh Murthy, MD, PhD, Director of Bacterial Vaccines and Technology at Pfizer
• Stephanie Watowich, PhD, Professor of Immunology at MD Anderson Cancer Center
• Guangming Zhong, PhD, Professor of Genetic and Environmental Risk at UT Health San Antonio

VDCoSA is a collaboration between four of San Antonio’s leading research organizations: The University of Texas San Antonio (UTSA), The University of Texas Health Science Center at San Antonio (UT Health), Southwest Research Institute (SwRI) and Texas Biomedical Research Institute (TX Biomed).

The VDCoSA conference aims to foster synergy, exchange and innovation throughout San Antonio and beyond to accelerate the development of vaccines against a range of diseases, from influenza to tuberculosis to COVID-19. This year’s topics will also include the emerging field of vaccine technologies to fight cancer. While originally focused on San Antonio, the conference has grown to include key collaborators from throughout South Texas, including from Galveston and Houston.

“Each year, the conference continues to grow and we are excited to foster those meaningful conversations and exchanges,” says Tracey Baas, PhD, the Manager of the Vaccine Development Center of San Antonio and Texas Biomed’s Innovations Manager.

The conference provides opportunities for scientists at all levels, including students, early career researchers and faculty, to share their work in posters and talks with their peers. Dr. Baas stressed a key aim of VDCoSA is to support the next generation of scientists working on vaccines.

“This conference gives them an opportunity to present, which is very important for their development moving on the next phase of their careers,” says Dr. Baas.

Story highlights the national research primate shortage and balances concerns around animals in biomedical research with the global need to develop vaccines and cures that help both animals and people.

Texas Biomed is featured in a Texas Monthly story that details how our infectious disease research enabled the fastest development of a vaccine in history, which helped slow a raging pandemic and save countless lives. The magazine piece highlights the strategic growth of the Institute, its vision for the future and the role of its Southwest National Primate Research Center (SNPRC).

Reporter Will Bostwick wrote: for each animal used in COVID research…, “countless more human lives were saved. Infectious disease experts worldwide agree that there will be other pandemics, and Texas Biomed intends to help develop the next cures.”

The story goes on to lay out a fundamental crux of biomedical research: to develop cures and vaccines, nonhuman primates are a required and important part of the process. Not only because the Food and Drug Administration requires that most treatments be tested in animals before being given to humans, but also because the technologies that one day aim to replace animals in research are not advanced enough to adequately replicate a complete biological system.

In the article, Texas Biomed’s President/CEO Larry Schlesinger and SNPRC Director Corinna Ross share how deeply committed Texas Biomed and SNPRC are providing the absolute best care to its animals. Dr. Schlesinger spoke about the Institute’s work to address the current national shortage of research primates by expanding animal housing and research space.

Here are a few excerpts from the story:

Read the full article here.