Tag Archives: Autoimmunity

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of …

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of the world’s population. RA happens when a person’s own antibodies attack joint tissue, causing painful swelling, stiffness, and redness. Some research has suggested that there is a link between RA and gum disease.

Image credit: Pixabay

Gum disease is estimated to affect up to 47 percent of adults, and in the disorder, oral microbes can move to the blood after the gums start to bleed. An increase in disease activity has been observed in RA patients who also have gum disease. Gum disease has been shown to be more common in RA patients who carry a certain type of antibodies, called anti-citrullinated protein antibodies (ACPAs), though ACPAs are often found in the blood of individuals with RA. The presence of ACPAs can often predate the diagnosis of RA by a few years.

A new study investigated the connections between these observations. In this work, the researchers collected blood samples from a small group of ten people with RA, five with and five without gum disease. These samples were collected every week for one year, and the investigators assessed the expression of both human and bacterial genes in those samples.

Certain types of inflammatory immune cells carried gene expression signatures that were associated with the autoimmune flares of arthritis patients who also had periodontal disease, as well as the presence of certain oral bacteria in the blood.

Many of these oral bacteria were chemically altered by deimination; they were citrullinated. Citrullination can change the structure and function of proteins. Although citrullination can be a part of the normal function of tissues, high levels of citrullination have been linked to inflammation.

Citrullination can also create targets for ACPAs; when the normal, unconverted forms of the oral bacteria were incubated with ACPAs, the antibodies did not react, but when the citrullinated oral bacteria were exposed to ACPAs, there was a reaction. ACPAs appear to be bound to oral microbes in RA patients.

The findings have been reported in Science Translational Medicine.

The study noted that the immune response to oral microbes could be influencing RA flares, that oral microbes can trigger a specific antibody reaction in patients with both RA and gum disease, and that RA flares cause varying immune signatures, which could reflect different flare triggers.

It could be that gum disease repeatedly causes the immune system to respond, and as the immune system keeps reacting and repeatedly increasing inflammation, RA may eventually begin to emerge. More work will be needed, however, to fully understand whether gum disease is playing a causative role in the development of RA.

Source: Science Translational Medicine

Carmen Leitch

Even though humans are complex organisms and bacteria are single cells, and each are made of completely different …

Even though humans are complex organisms and bacteria are single cells, and each are made of completely different cell types (eukaryotic and prokaryotic cells, respectively), there are some similar immune mechanisms at work in both of them. Scientists have now learned more about how a complex found in both human and bacterial cells, a group of enzymes called ubiquitin transferases, works to regulate immune pathways. The findings, which have been reported in Nature, may provide new insights into treatments for a wide range of human diseases, suggested the researchers.

Image credit: Pixabay

“This study demonstrates that we’re not all that different from bacteria,” said senior study author Aaron Whiteley, an assistant professor at the University of Colorado Boulder. “We can learn a lot about how the human body works by studying these bacterial processes.”

Some research has suggested that the immune system found in humans has its origins in bacterial cells. Bacteria have to fight their own infections from other microbes like bacteriophages, viruses that infect bacterial cells. The CRISPR gene editing tool is derived from a bacterial immune defense.

An enzyme called cGAS (cyclic GMP-AMP synthase) can be found in humans, and a simpler version of it is also carried by bacteria; cGAS works to activate an immune defense when viral pathogens are detected.

Researchers have now analyzed the structure of bacterial cGAS, and revealed other proteins that are involved in the response to a viral infection. This study has shown that in bacteria, cGAS is modified by a simplified form of ubiquitin transferase, a crucial enzyme also found in human cells.

Bacteria are far easier to manipulate genetically compared to human cells, so this opens up a world of new research opportunities, said co-first study author Hannah Ledvina, PhD, a postdoctoral researcher. “The ubiquitin transferases in bacteria are a missing link in our understanding of the evolutionary history of these proteins.”

In this research, the scientists have also revealed two critical parts of ubiquitin transferase: Cap2 and Cap3 (CD-NTase-associated protein 2 and 3) that activate and deactivate the cGAS response, respectively.

In humans cells, ubiquitin tags also work to mark cellular garbage, like dysfunctional or unnecessary proteins that have to be degraded and disposed. Problems with this system can lead to a buildup of cellular trash, which may lead to some disorders, such as neurodegeneration.

Thus, while more research is needed, the study authors are hopeful that this work will enable us to learn more about many diseases, including autoimmune disorders like arthritis or neurodegenerative diseases such as Parkinson’s disease

Parts of the bacterial ubiquitin transferase complex, like Cap3 – the off switch, could be harnessed to eliminate some pathologies related to human disease, suggested Whiteley.

Sources: University of Colorado at Boulder, Nature

Carmen Leitch

Genetic disorder that causes immunodeficiency and susceptibility to opportunistic infections discovered

An international consortium co-led by Vanderbilt University Medical Center immunogeneticist Rubén Martínez-Barricarte, PhD, has discovered a new genetic disorder that causes immunodeficiency and profound susceptibility to opportunistic infections including a life-threatening fungal pneumonia.

The discovery, reported Jan. 20 in the journal Science Immunology, will help identify people who carry this in-born error of immunity (IEI). “Our findings will provide the basis for genetic diagnosis and preventive treatment for these groups of patients,” Martínez-Barricarte said.

IEIs, also known as primary immunodeficiencies, are genetic defects characterized by increased susceptibility to infectious diseases, autoimmunity, anti-inflammatory disorders, allergy, and in some cases, cancer.

To date, 485 different IEIs have been identified. It is now thought that they occur in one of every 1,000 to 5,000 births, making them as prevalent as other genetic disorders, including cystic fibrosis and Duchene’s muscular dystrophy.

Despite recent medical advances, about half of patients with IEIs still lack a genetic diagnosis that could help them avoid debilitating illness and death. That’s why this research is so important.

The error in this case is a mutation in the gene for the protein IRF4, a transcription factor that is pivotal for the development and function of B and T white blood cells, as well as other immune cells.

As a postdoctoral fellow at The Rockefeller University, Martínez-Barricarte was part of an international research team that, in 2018, identified an IRF4 mutation associated with Whipple’s disease, a rare bacterial infection of the intestine that causes diarrhea, weight loss, and abdominal and joint pain.

Martínez-Barricarte is now an assistant professor of Medicine in the Division of Genetic Medicine, and of Pathology, Microbiology & Immunology in the Division of Molecular Pathogenesis.

In 2020, after moving his lab to VUMC, he began collaborating with Aidé Tamara Staines-Boone, MD, and her colleagues in Monterrey, Mexico. They were caring for a young boy who was suffering from severe and recurrent fungal, viral, mycobacterial, and other infections.

Martínez-Barricarte and his team sequenced the protein-encoding regions of the boy’s genome and discovered a de novo IRF4 mutation, which originated in the patient and was not inherited from his parents.

Upon consulting with IRF4 experts at the Imagine Institute for the study and treatment of genetic diseases in Paris, they were told that seven other groups were independently characterizing the same mutation. They now collaborate as the IRF4 International Consortium.

In the current study, the consortium identified seven patients from six unrelated families across four continents with profound combination immunodeficiency who experienced recurrent and serious infections, including pneumonia caused by the fungus Pneumocystis jirovecii. Each patient had the same mutation in the DNA-binding domain of IRF4.

Extensive phenotyping of patients’ blood cells revealed immune cell abnormalities associated with the disease, including impaired maturation of antibody-producing B cells, and reduced T-cell production of infection-fighting cytokines.

Two knock-in mouse models, in which the mutation was inserted into the mouse genome, exhibited a severe defect in antibody production consistent with the combined immune deficiency observed in the patients.

The researchers also discovered the mutation had a “multimorphic” effect detrimental to the activation and differentiation of immune cells.

While the mutant IRF4 binds to DNA with a higher affinity than the native form of the protein (in a hypermorphic way), its transcriptional activity in common, canonical genes is reduced (hypomorphic), and it binds to other DNA sites (in a neomorphic way), altering the protein’s normal gene expression profile.

This multimorphic activity is a new mechanism for human disease. “We anticipate that variants with multimorphic activity may be more widespread in health and disease,” the researchers concluded.

Co-authors from Martínez-Barricarte’s lab included graduate students Jareb Pérez Caraballo and Xin Zhen, and research assistant Linh Tran. His research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant #AI171466).

Journal reference:

IRF4 International Consortium (2023) A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency. Science Immunology. doi.org/10.1126/sciimmunol.ade7953.

Targeting T cell iron metabolism may offer a new approach for treating lupus

Targeting iron metabolism in immune system cells may offer a new approach for treating systemic lupus erythematosus (SLE) -; the most common form of the chronic autoimmune disease lupus.

A multidisciplinary team of investigators at Vanderbilt University Medical Center has discovered that blocking an iron uptake receptor reduces disease pathology and promotes the activity of anti-inflammatory regulatory T cells in a mouse model of SLE. The findings were published Jan. 13 in the journal Science Immunology.

Lupus, including SLE, occurs when the immune system attacks a person’s own healthy tissues, causing pain, inflammation and tissue damage. Lupus most commonly affects skin, joints, brain, lungs, kidneys and blood vessels. About 1.5 million Americans and 5 million people worldwide have a form of lupus, according to the Lupus Foundation of America.

Treatments for lupus aim to control symptoms, reduce immune system attack of tissues, and protect organs from damage. Only one targeted biologic agent has been approved for treating SLE, belimumab in 2011.

It has been a real challenge to come up with new therapies for lupus. The patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.”

Jeffrey Rathmell, PhD, Professor of Pathology, Microbiology and Immunology and Cornelius Vanderbilt Chair in Immunobiology

Rathmell’s group has had a long-standing interest in lupus as part of a broader effort to understand mechanisms of autoimmunity.

When postdoctoral fellow Kelsey Voss, PhD, began studying T cell metabolism in lupus, she noticed that iron appeared to be a “common denominator in many of the problems in T cells,” she said. She was also intrigued by the finding that T cells from patients with lupus have high iron levels, even though patients are often anemic.

“It was not clear why the T cells were high in iron, or what that meant,” said Voss, first author of the Science Immunology paper.

To explore T cell iron metabolism in lupus, Voss and Rathmell drew on the expertise of other investigators at VUMC:

  • Eric Skaar, PhD, and his team are experienced in the study of iron and other metals;

  • Amy Major, PhD, and her group provided a mouse model of SLE; and

  • Michelle Ormseth, MD, MSCI, and her team recruited patients with SLE to provide blood samples.

First, Voss used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells.

The researchers found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron.

“We see a lot of complications coming from that -; the mitochondria don’t function properly, and other signaling pathways are altered,” Voss said.

An antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity, and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10.

“It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells,” Voss said. “If you’re trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That’s exactly what targeting the transferrin receptor did.”

In T cells from patients with lupus, expression of the transferrin receptor correlated with disease severity, and blocking the receptor in vitro enhanced production of IL-10.

The researchers are interested in developing transferrin receptor antibodies that bind specifically to T cells, to avoid any potential off-target effects (the transferrin receptor mediates iron uptake in many cell types). They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity.

Skaar is the Ernest W. Goodpasture Professor of Pathology and director of the Vanderbilt Institute for Infection, Immunology, and Inflammation. Major, associate professor of Medicine, and Ormseth, assistant professor of Medicine, are faculty members in the Division of Rheumatology and Immunology. Rathmell is the director of the Vanderbilt Center for Immunobiology.

Other authors of the study include Allison Sewell, Evan Krystofiak, PhD, Katherine Gibson-Corley, DVM, PhD, Arissa Young, MD, Jacob Basham, MD, Ayaka Sugiura, PhD, Emily Arner, PhD, William Beavers, PhD, Dillon Kunkle, PhD, Megan Dickson, Gabriel Needle, and W. Kimryn Rathmell, MD, PhD.

The research was supported by the National Institutes of Health (grants DK105550, AI153167, DK101003, AI150701, CA253718) and the Lupus Research Alliance William Paul Distinguished Innovator Award to Jeffrey Rathmell.

Journal reference:

Voss, K., et al. (2023) Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus. Science Immunology. doi.org/10.1126/sciimmunol.abq0178.

New Collaborative Research Center investigates how Treg cells influence immunological and tissue-specific diseases

The German Research Foundation (DFG) has approved the establishment and funding of the Collaborative Research Center/Transregio (CRC/TRR) 355 “Heterogeneity and functional specialization of regulatory T cells in distinct microenvironments”. Under the leadership of the Mainz University Medical Center, the CRC investigates how so-called regulatory T (Treg) cells influence immunological and tissue-specific diseases. Based on these findings, tailored immunotherapies could be developed in the future with the help of Treg cells. Ludwig-Maximilians-Universität München and the Technical University of Munich are involved in the CRC as cooperation partners. For the four years of the first funding period, the CRC/TRR 355 will receive approximately EUR 13 million.

The Chief Executive Officer and Medical Director of the Mainz University Medical Center, Professor Norbert Pfeiffer, is pleased with the DFG’s decision: “The University Medicine Mainz is now involved in a total of eleven Collaborative Research Centers. We are the spokesperson for three of those CRCs. This makes us a university medical center with a particularly high number of participations in CRCs. This is an outstanding success and showcases our excellent research, which we also translate directly into patient care.”

The newly approved CRC/TRR 355 investigates the role of so-called regulatory T cells in immune-related and tissue-specific diseases. Regulatory T (Treg) cells play a major role in controlling the immune response. Absent or defective Treg cells can lead to autoimmunity. Excessive Treg cell activity, on the other hand, can impair important immune responses, such as those against pathogens. Treg cells are also integrated into the functional architecture of various tissues. Despite some similarities, Treg cells also exhibit significant differences depending on their function. The new CRC explores this heterogeneity of Treg cells. The goal: using Treg cells for the development of tailored immunotherapies as well as for tissue regeneration.

The spokesperson of the CRC/TRR 355 and head of the Institute of Molecular Medicine at the Mainz University Medical Center, Professor Ari Waisman, explains: “We are investigating the prerequisites and consequences of the heterogeneity and functional specialization of Treg cells in a variety of tissue- and disease-specific questions. In addition to the function of Treg cells in immune or autoimmune responses, we are also taking a close look at the central nervous system as well as various tissues and organs, such as the muscles, lungs, and intestines. The goal is to identify the relevant molecules and mechanisms for which a Treg cell-directed therapeutic approach might be appropriate. With these findings, we could exploit the full potential of Treg cells – not only for tailored immunotherapy, but also targeted for tissue-specific processes such as organ regeneration.”

The Mainz University Medical Center is cooperating in the CRC/TRR 355 with Ludwig-Maximilians-Universität Münchenand the Technical University of Munich. Of the 22 projects, 13 are located at the Mainz University Medical Center. In addition to the Institute of Molecular Medicine, the Institute of Immunology, the Department of Medical Microbiology and Hygiene, the Department of Neurology, the Department of Dermatology, the Center for Thrombosis and Hemostasis (CTH), and the Institute for Translational Immunology at the Mainz University Medical Center are also involved in this interdisciplinary research project.

That it is a very good day for biomedical research at the Mainz University Medical Center and at Johannes Gutenberg University Mainz emphasizes Professor Ulrich Förstermann, Scientific Director and Dean of the Mainz University Medical Center: “The CRC/TRR 355 strengthens once again the research focus on immunology at the Mainz University Medical Center. It is the third immunological CRC at the Mainz University Medical Center and covers another important aspect that can be of great significance for modern immunotherapy. I am convinced that our scientists will gain pioneering insights into the use of regulatory T cells in immunotherapy. At the same time, two other biomedical CRCs were approved or reapproved by the DFG, in each of which the Mainz University Medical Center is involved with several projects. The CRC 1551 ‘Polymer Concepts in Cellular Function’ was newly established by the DFG under the auspices of Johannes Gutenberg University Mainz. The CRC 1361 ‘Regulation of DNA Repair and Genome Stability’ enters the second funding period under the leadership of the Mainz-based Institute of Molecular Biology (IMB).”

Collaborative Research Centers enable the processing of innovative, challenging and long-term research projects in a network. They are thus intended to serve the formation of focal points and structures at the applicant universities. In the case of transregional Collaborative Research Centers, several universities are involved in the application process. The close cooperation between these universities is intended to create a complementary and synergistic research network. Collaborative Research Centers are funded by the DFG for a maximum of three funding periods of four years each.

Skin Bacteria May Trigger Lupus: Mouse Study

ABOVE: Staphylococcus aureus bacteria colony © iStock.com, ksass

In individuals with lupus, the immune system turns against the body. The disease mainly affects women who, sometimes in their teens and twenties, begin to suffer from fever, renal failure, hair loss, seizures, and joint pain. Seventy percent of lupus patients have systemic lupus erythematosus (SLE), which affects the whole body, including the organs and skin, and can be fatal if left untreated. 

Some people may be more susceptible to lupus based on their genetics, but what ultimately triggers the disease is unknown. New work published today (October 28) in Science Immunology offers one possible answer, finding that skin microbes can induce full-blown, systemic lupus in mice. 

“The paper is really beautiful. It’s very well done and very well controlled,” says Michelle Kahlenberg, a rheumatologist and researcher at the University of Michigan who was not involved in the work.

Gut microbes likely also play a role in disease progression, with some studies showing that antibiotics can alleviate SLE symptoms in mice.

See “Do Commensal Microbes Stoke the Fire of Autoimmunity?

Hitoshi Terui, a coauthor and dermatologist at Tohoku University School of Medicine, says that a lot of research has shown the relationship between gut microbes and autoimmune disease, but no study had linked skin microbes to autoimmune inflammation, though researchers already suspected that the epidermis—specifically keratinocytes, the skin cells that produce keratin—is involved in lupus.

Terui and his colleagues used a mouse model of Sjögren syndrome, a milder autoimmune disease that is also present in roughly 20 percent of human patients with SLE. The mice lack a functional version of a protein called IκBζ— known to help fight infection—but only in their skin. The mice develop autoantibodies similar to those of human Sjögren syndrome patients, as well as some autoantibodies associated with lupus, and have dermatitis, another symptom of SLE.

The researchers first observed that skin swabs from IκBζ knockout mice contained greater numbers of the bacterium Staphylococcus aureus than those from normal mice. qPCR revealed a possible reason for this: Compared to wildtype mice, the skin cells of IκBζ knockout mice produced less of the mRNA needed to make antimicrobial peptides (AMP), small molecules crucial for fighting infection. Mice treated with oral antibiotics against S. aureus showed less severe autoimmune symptoms. The antibiotics also brought down their autoantibody levels and ameliorated their dermatitis, hinting that S. aureus might be related to the disease.

The team then applied more S. aureus to the skin of knockout mice, and found that their levels of autoantibodies such as anti–double stranded DNA and anti-Smith antibodies (both of which are highly specific to lupus patients) increased relative to control mice. “That was the most exciting moment,” says Terui. The bacteria heightened inflammation and worsened autoimmune symptoms in knockout mice to a greater extent than in wildtype controls. The knockout mice also developed renal failure, a common complication of SLE. 

The study also connected two cytokines, IL-17 and IL-23, to the worsening autoimmune symptoms. Histological experiments revealed that knockout mice had higher levels of T cells than normal mice, and these cells produced IL-17. IL-17 wasn’t just found in the epidermis—researchers detected higher levels of the cytokine circulating throughout the bodies of knockout mice. Finally, the researchers found that administering antibodies blocking IL-17 and IL-23 alleviated SLE symptoms in knockout mice exposed to the bacteria, implicating the cytokines’ activity in SLE progression.

According to Terui, these findings weren’t entirely surprising. Scientists were already “very familiar with the IL-17/IL-23 pathway because that pathway is used for the treatment of . . . psoriasis,” another autoimmune disease, he says.

Further experiments in culture showed that keratinocytes are involved in inducing autoimmune inflammation. The keratinocytes of knockout mice undergo apoptosis in response to coculture with S. aureus, which causes neutrophils to produce histone-rich, weblike structures called neutrophil extracellular traps. These structures, which can capture and kill pathogens, also induce T cells to produce IL-17 by activating dendritic cells. 

See “CAR T Cells Treat Lupus in Mice

“They did a really beautiful job teasing out the mechanism in this paper, but I think how it translates to the role of Staph aureus and human lupus is still a question that needs to be investigated,” Kahlenberg cautions. “There have been several studies that have suggested important roles for IL-17 signaling in mouse models [of lupus]. But when we look into human data, especially in the skin, we don’t see as much role for IL-17.” 

The researchers also caution that dysfunctional IκBζ hasn’t been directly linked to lupus in humans and that more research is needed before these findings can be translated. They point out that patients with atopic dermatitis, a disease in which S. aureus is found in skin lesions, are at an increased risk of developing SLE. Still, Terui and study coauthor Kenshi Yamasaki, a dermatologist at Tohoku University in Japan, express hope that clinical trials of therapies using anti-IL-17 and anti-IL-23 antibodies can alleviate symptoms in SLE patients. “I believe this mechanism is working in humans too,” Yamasaki says. 

Natalia Mesa

Gut bacteria have been linked to an ever-increasing number of diseases. Research is now going beyond establishing a …

Gut bacteria have been linked to an ever-increasing number of diseases. Research is now going beyond establishing a link between a disorder and the community of gut microbes, and has begun to identify specific organisms that are responsible for certain conditions. Scientists have now shown that a strain of bacteria in the Subdoligranulum genus can lead to the production of autoantibodies, which appears to cause the development of rheumatoid arthritis. The findings have been reported in Science Translational Medicine.

Image cresit: Pixabay

Rheumatoid arthritis is an autoimmune disease in which the joints are erroneously attacked by the immune system, and the inflammation and damage that occurs in affected joints causes pain, the loss of mobility, and other serious problems. Disruption of mucosal immunity, in the gut, has been proposed to be one cause of rheumatoid arthritis.

In this work, the researchers obtained blood samples from people who are at risk of developing RA, and the autoantibodies were isolated from those samples.

The scientists found that the autoantibodies were causing a response in certain bacteria in the Lachnospiraceae/Ruminococcaceae families. Further work revealed that bacteria of the genus Subdoligranulum, a member of those families that was isolated from the feces of people ate risk for RA, could bind to the autoantibodies and cause the activation of CD4+ T cells. This was occurring in individuals with RA, but not in healthy people.

The Subdoligranulum bacteria was put in an animal model, and the animals began to develop the same RA risk markers found in the blood of people who are at risk for RA. Some of the animals also developed RA.

“Through studies in humans and animal models, we were able to identify these bacteria as being associated with the risk for developing RA. They trigger an RA-like disease in the animal models, and in humans, we can show that this bacterium seems to be triggering immune responses specific to RA,” said study leader Kristine Kuhn, MD, Ph.D., an associate professor at CU School of Medicine.

This microbe could be a good therapeutic target for RA treatment, noted Kuhn. Now, the scientists want to assess large populations of people who are at risk for RA to see if the Subdoligranulum microbes are also linked to other factors like genetics, mucosal immunity, and environmental conditions that can lead to RA. It may help scientists find prevention strategies or other ways to stop the microbes from causing disease, added Kuhn.

Sources: CU Anschutz Medical Campus, Science Translational Medicine

Carmen Leitch

Duke receives federal funding for HIV vaccine research

The Duke Human Vaccine Institute (DHVI) and the Department of Surgery at Duke University School of Medicine received a grant from the National Institute of Allergy and Infectious Diseases for HIV vaccine research that could total $25.9 million with full funding over five years.

The funding supports a multi-institutional effort called The Consortium for Innovative HIV/AIDS Vaccine and Cure Research that is built around two areas of scientific focus: identification of the components and the mechanisms of protection of preventive vaccines; and the use of the newly identified preventive vaccines along with other immune therapies in advancing potential treatments and/or cures.

The grant’s principal investigators are Guido Ferrari, M.D., a professor in the Department of Surgery and research professor in the Department of Genetics and Microbiology, and Wilton Williams, Ph.D., an associate professor in the departments of Surgery and Medicine, and assistant professor in the Department of Immunology at Duke University School of Medicine.

The researchers will lead work that builds upon ongoing HIV vaccine development research at DHVI and expands investigations of vaccine strategies, including innovative mRNA approaches that induce protective immune responses in non-human primate models.

This grant is synergistic with everything going on at Duke, notably the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) initiative to design an HIV vaccine. We are excited about the wonderful science that will be done in the context of this grant. It expands the capacity at Duke, UNC and others who are collaborating on this effort to move forward with both vaccines and potential cures.”

Barton Haynes, Director of the DHVI

Combining vaccine approaches with cure efforts is designed to stimulate innovative collaborations toward both. Studies in nonhuman primates will investigate how effective HIV/AIDS vaccines protect from initial infection and systemic infection.

Vaccines and other immune interventions will also be used as cure strategies with the goal of eliminating all the infection in the cells. While advances have been made in boosting cellular and antibody immunity, it remains unclear whether the boosted immune response can prevent reinfection after antiretroviral treatments are stopped. With the newly funded grant, the researchers hope to answer that and other questions.

“This grant enables us to do something current vaccine research is not funded to do – explore vaccines with a mission to cure,” Williams said. “Right now, it’s either prevention or cure, and we want to achieve a combination of those things.”

Ferrari said vaccine research has advanced far enough that researchers can now begin applying potential components of vaccines, as well as new technologies such as mRNA vaccine design, to explore ways of eradicating the HIV from infected cells.

“The beauty of mRNA is its ability to be adapted quickly and we can produce it in a timely manner to address new variants, which is important for HIV,” Ferrari said. “We will now focus on how we can capitalize on the current science to eradicate infection.”

“The science underpinning this program has broad applicability, spanning from the immediate goals of eliminating HIV disease, to a more generalizable harnessing of the immune system to prevent emerging infectious diseases, control cancer, and accelerate our understanding of autoimmunity and transplant biology,” said Allan D. Kirk, M.D., Ph.D., chair of the Department of Surgery.

“Our department sees the promise of basic investments like these for transformational approaches to care that do not traditionally fall within a surgical department,” Kirk said. “Drs. Williams and Ferrari are vital members of our translational science community.”

In addition to Williams and Ferrari, collaborators at Duke are Priyamvada Acharya, Mihai Azoitei, Derek Cain, Thomas Denny, Robert J. Edwards, Barton Haynes, David Montefiori, Justin Pollara, Keith Reeves, Wes Rountree, Kevin Saunders, Shaunna Shen, Rachel Spreng, Georgia Tomaras, Kevin Wiehe, Kelly Cuttle and Cynthia Nagle.

Study partners include Katharine Barr, Michael Betts, Beatrice Hahn, George Shaw, Drew Weissman at the University of Pennsylvania; Richard Dunham and David Margolis at the University of North Carolina at Chapel Hill; Sampa Santra at Harvard University; Andrew McMichael, Persephone Borrow and Geraldine Gillespie at Oxford University; Bette Korber and Kshitij Wagh at Los Alamos National Laboratory; and Mark Lewis at BIOQUAL.