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Wistar Scientists Identify Pro-aging ‘Sugar Signature’ in the Blood of People Living with HIV

The Abdel-Mohsen lab findings shed light on how sugar molecules in the blood of people living with HIV may accelerate biological aging

PHILADELPHIA — (April 10, 2024) — The Wistar Institute’s associate professor Mohamed Abdel-Mohsen, Ph.D., along with his team and collaborators, has identified sugar abnormalities in the blood that may promote biological aging and inflammation in people living with HIV (PLWH). The findings, taken from a large data study comprising more than 1200 participants, are detailed in the new paper, “Immunoglobulin G N-glycan Markers of Accelerated Biological Aging During Chronic HIV Infection,” published in the journal Nature Communications.

Despite advances in HIV treatment, notably the success of antiretroviral therapy (ART) in suppressing the virus to undetectable levels, HIV remains incurable, with the virus persisting in a dormant state within the body. This chronic presence is linked to long-term health issues, including persistent inflammation and a higher prevalence of aging-related diseases such as cancer and neurocognitive disorders. These conditions tend to occur more frequently and at an earlier age in PLWH compared to the general population.

Abdel-Mohsen seeks to understand how chronic viral infection causes this accelerated biological aging, which refers to the body aging faster than one’s chronological years would typically indicate. By understanding the molecular mechanisms behind accelerated biological aging in people living with chronic viral infections, scientists can begin to formulate strategies to mitigate the negative effects.

While many factors in the body can contribute to accelerated biological aging, researchers focused on a novel factor: abnormalities of the human glycome — the totality of the various sugar structures circulating throughout the body. Previous studies have established a connection between aging and shifts in the glycan composition of immunoglobulins (IgGs), which are critical for immune regulation. As people age, their IgGs lose anti-inflammatory properties and gain pro-inflammatory characteristics.

Abdel-Mohsen’s research investigates whether living with a chronic viral infection, such as HIV infection, exacerbates these changes, leading to premature aging and related diseases. By comparing glycan profiles in more than 1200 individuals, both with and without HIV, the team discovered that PLWH exhibit elevated levels of inflammatory and pro-aging IgG glycan signatures. In a remarkable step forward, the team developed a machine-learning model that uses these glycan signatures to estimate the biological age of PLWH and assess the rate of aging acceleration. This glycan signature also has the potential to predict the onset of comorbid conditions in PLWH, such as cancer, years in advance.

To confirm that these glycan-associated disruptions were causal rather than merely correlative, the research team engineered HIV-specific antibodies designed to exhibit the same kind of aberrant IgG glycan modifications observed in PLWH. Testing these glycoengineered antibodies in vitro confirmed that the modified antibodies were less effective at mounting an immune response than their unmodified counterparts, suggesting that these sugar abnormalities might directly contribute to the worse clinical outcomes observed. Importantly, when they designed these antibodies to have glycans similar to those found in biologically younger individuals, these antibodies demonstrated a remarkable ability to enhance the immune system’s ability to fight virus-infected cells.

“Utilizing glycan signatures to predict early onset of diseases in people living with HIV marks a pivotal shift towards proactive healthcare,” said Abdel-Mohsen. “This could significantly alter clinical outcomes, allowing for timely interventions and personalized treatment plans. The impact on treatment and management in the HIV community could be revolutionary. Beyond biomarkers, antibodies glycoengineered to mimic biologically younger glycans offer a new therapeutic avenue. This method could enhance immune responses, paving the way for innovative treatments.”

Co-authors: Leila B Giron, Qin Liu, Opeyemi S Adeniji, Xiangfan Yin, Toshitha Kannan, Jianyi Ding, David Y. Lu, Joao L. L. C. Azevedo, Andrew Kossenkov, and Mohamed Abdel-Mohsen of The Wistar Institute; David Y. Lu of Cornell University; Susan Langan, Jinbing Zhang, Sabina Haberlen, Stephen Gange, Wendy S. Post, and Todd T. Brown of Johns Hopkins University; Shuk Hang Li and Ian Frank of the University of Pennsylvania Perelman School of Medicine; Sergei Shalygin and Parastoo Azadi of University of Georgia; David B Hanna of Albert Einstein College of Medicine; Igho Ofotokun of Emory University School of Medicine; Jason Lazar of SUNY Downstate Health Sciences University; Margaret A. Fischl of University of Miami; Bernard Macatangay and Charles Rinaldo of University of Pittsburgh; Adaora A. Adimora of University of North Carolina, Chapel Hill; Beth D. Jamieson of University of California, Los Angeles; Daniel Merenstein of Georgetown University Medical Center; Nadia R. Roan of Gladstone Institutes and University of California, San Francisco; Phyllis C. Tien of University ofCalifornia, San Francisco; Olaf Kutsch of University of Alabama at Birmingham; Steven M. Wolinsky of Northwestern University; Mallory D. Witt of Lundquist Institute of Biomedical Research at Harbor-UCLA Medical Center; and Alan Landay of Rush University.

Work supported by: This work is mainly supported by the NIH R01AG062383 and the NCI supplement to the Wistar Institute Cancer Center (P30 CA010815) to M.A-M. M.A-M is also funded by the NIH grants, R01AI165079, R01NS117458, R01DK123733, Penn Center for AIDS Research (P30 AI 045008), and the NIH-funded BEAT-HIV Martin Delaney Collaboratory to cure HIV-1 infection (1UM1Al126620). Mass spectrometry-based glycomic analyses was partially supported by NIH R24GM137782 and GlycoMIP, a National Science Foundation Materials Innovation Platform funded through Cooperative Agreement DMR-1933525. We would like to thank Drs. Michel Nussenzweig, Costin Tomescu, and Luis J. Montaner for providing the wild-type 10-1074 for the glycoengineering experiments and Dr. Daniel Kulp for providing HIV-1 Env trimer, BG505. Data in this manuscript were collected by the MACS/WIHS Combined Cohort Study (MWCCS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). MWCCS (Principal Investigators): Atlanta CRS (Ighovwerha Ofotokun, Anandi Sheth, and Gina Wingood), U01-HL146241; Baltimore CRS (Todd Brown and Joseph Margolick), U01-HL146201; Bronx CRS (Kathryn Anastos, David Hanna, and Anjali Sharma), U01-HL146204; Brooklyn CRS (Deborah Gustafson and Tracey Wilson), U01-HL146202; Data Analysis and Coordination Center (Gypsyamber D’Souza, Stephen Gange and Elizabeth Topper), U01-HL146193; Chicago-Cook County CRS (Mardge Cohen and Audrey French), U01-HL146245; Chicago-Northwestern CRS (Steven Wolinsky, Frank Palella, and Valentina Stosor), U01-HL146240; Northern California CRS (Bradley Aouizerat, Jennifer Price, and Phyllis Tien), U01-HL146242; Los Angeles CRS (Roger Detels and Matthew Mimiaga), U01-HL146333; Metropolitan Washington CRS (Seble Kassaye and Daniel Merenstein), U01-HL146205; Miami CRS (Maria Alcaide, Margaret Fischl, and Deborah Jones), U01-HL146203; Pittsburgh CRS (Jeremy Martinson and Charles Rinaldo), U01-HL146208; UAB-MS CRS (Mirjam-Colette Kempf, Jodie Dionne-Odom, Deborah Konkle-Parker, and James B. Brock), U01-HL146192; UNC CRS (Adaora Adimora and Michelle Floris- Moore), U01-HL146194. The MWCCS is funded primarily by the National Heart, Lung, and Blood Institute (NHLBI), with additional co-funding from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD), National Institute On Aging (NIA), National Institute Of Dental & Craniofacial Research (NIDCR), National Institute Of Allergy And Infectious Diseases (NIAID), National Institute Of Neurological Disorders And Stroke (NINDS), National Institute Of Mental Health (NIMH), National Institute On Drug Abuse (NIDA), National Institute Of Nursing Research (NINR), National Cancer Institute (NCI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute on Minority Health and Health Disparities (NIMHD), and in coordination and alignment with the research priorities of the National Institutes of Health, Office of AIDS Research (OAR). MWCCS data collection is also supported by UL1-TR000004 (UCSF CTSA), UL1-TR003098 (JHU ICTR), UL1TR001881 (UCLA CTSI), P30-AI-050409 (Atlanta CFAR), P30-AI-073961 (Miami CFAR), P30 AI-050410 (UNC CFAR), P30-AI-027767 (UAB CFAR), P30-MH-116867 (Miami CHARM), UL1 TR001409 (DC CTSA), KL2-TR001432 (DC CTSA), and TL1-TR001431 (DC CTSA). The MACS CVD2 study is funded by National Heart Lung and Blood Institute (NHLBI), R01 HL095129-01 (Wendy Post). The authors gratefully acknowledge the contributions of study participants and dedication of the staff at MWCCS sites.

Publication information: “Immunoglobulin G N-glycan 1 Markers of Accelerated Biological Aging During Chronic HIV Infection,” from Nature Communications.

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The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers.

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Wistar Scientists Discover Link Between Leaky Gut and Accelerated Biological Aging

Dr. Mohamed Abdel-Mohsen and collaborators discovered a connection between gut damage and premature biological aging in people living with chronic viral infection

PHILADELPHIA—(Feb. 21, 2024)—The Wistar Institute’s associate professor Mohamed Abdel-Mohsen, Ph.D., has demonstrated, with his lab and collaborators, a connection between viral damage to the gut and premature biological aging. The group found that this pro-aging connection can contribute to both gut permeability and premature systemic & intestinal tissue aging in people living with chronic HIV infection, and their discovery is detailed in the newly published paper titled, “Distinct Intestinal Microbial Signatures Linked to Accelerated Systemic and Intestinal Biological Aging,” published in the journal Microbiome.

When people’s bodies age faster than their chronological years — a condition known as accelerated biological aging — they become more vulnerable to serious health issues usually seen in older adults, including cancers, heart diseases, brain disorders, severe infections, and reduced vaccine effectiveness. Dr. Abdel-Mohsen investigates what drives this rapid aging and how to create ways to slow down biological aging and improve health.

A prime suspect in this aging puzzle is the gut microbiome and its potential leakage into the bloodstream. The Abdel-Mohsen lab investigates how gut leakage can impact the immune system and lead to chronic inflammation, which may accelerate aging.

To delve into this question, Dr. Abdel-Mohsen and colleagues analyzed samples from people living with chronic HIV infection. Living with chronic HIV infection is known to potentially accelerate or accentuate biological age, which makes it an excellent model to investigate mechanisms of accelerated biological age in people living with chronic conditions.

In particular, the investigative team analyzed colon, ileum, stool, and blood samples from people living with chronic HIV infection and well-matched controls. Their analysis revealed a significant connection between disrupted gut microbiomes, increased intestinal permeability (leaky gut), and faster biological aging.

Notably, they observed a connection between accelerated biological aging and the microbiomes of both the colon and ileum, but not the fecal microbiome. This suggests that the location of the microbiome significantly impacts its effects and highlights the importance of sampling intestinal tissues to accurately understand the connection between the microbiome and age.

Biological age can be measured through several advanced methods like telomere length analysis and “epigenetic clocks,” such as the Hannum and Horvath clocks, which evaluate age based on DNA methylation patterns. DNA methylation, which involves methyl groups attaching to nucleotides in DNA, varies with age, and these epigenetic clocks use certain variations in methylation to estimate biological age.

The team’s application of several advanced methods to measure biological age to blood and intestinal tissue samples is the first analysis of its kind in people living with HIV, and their examination of the link between the microbiome and intestinal biological age in this population is a novel exploration of chronic HIV’s aging effects in the microbiome.

The work of Dr. Abdel-Mohsen and his team highlights specific bacteria and their by-products as potential accelerators of aging. These findings open new avenues for developing strategies to mitigate these bacteria and their byproducts, which could potentially enhance the duration of good health in the lives of people living with chronic conditions like chronic infections.

“More investigation is needed to fully understand the underlying causes and potential impacts of our findings,” said Dr. Abdel-Mohsen. “Moreover, there’s a crucial need to create strategies to prevent intestinal dysbiosis and gut leakiness and to determine how these strategies could affect an individual’s biological age. Our work is just the beginning of an exciting journey into enhancing health and longevity.”

Co-authors: Shalini Singh, Leila B. Giron, Aaron R. Goldman, Joao L. L. C. Azevedo, Toshitha Kannan, and Mohamed Abdel-Mohsen of The Wistar Institute; Maliha W. Shaikh, Phillip A. Engen, Zlata R. Bogin, and Simona A. Bambi of Rush Center for Integrated Microbiome and Chronobiology Research; Shivanjali Shankaran, Alan L. Landay, and Ali Keshavarzian of Rush Center for Integrated Microbiome and Chronobiology Research and Department of Medicine, Rush University; Lorena Orgaz, Nuria de Pedro, and Patricia González of Life Length; Martin Giera, Aswin Verhoeven, and Elena Sánchez-López of Leiden University Medical Center; Ivona Pandrea of University of Pittsburgh; Ceylan E. Tanes and Kyle Bittinger of Children’s Hospital of Philadelphia; and Michael J. Corely of Weill Cornell Medicine.

Work supported by: National Institutes of Health grants R01DK123733, R01AA029859, R24AA026801, R01AG062383, R01AG062383-04S1, and R01NS117458; the Penn Center for AIDS Research (P30AI045008); and the NIH-funded BEAT-HIV Martin Delaney Collaboratory to cure HIV-1 infection (1UM1Al126620). The Wistar Proteomics and Metabolomics Shared Resource is supported in part by NIH Cancer Center Support Grant CA010815. The Thermo Q-Exactive HF-X mass spectrometer was purchased with NIH grant S10OD023586. This research was also supported in part by philanthropic funding from Mr. and Mrs. Larry Field, Mr. and Mrs. Glass, Mrs. Marcia and Mr. Silas Keehn, the Sklar Family, the Johnson Family, and Mr. Harlan Berk.

Publication information: “Distinct Intestinal Microbial Signatures Linked to Accelerated Systemic and Intestinal Biological Aging,” from Microbiome


The Wistar Institute, the first independent, nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a culture of biomedical collaboration and innovation. Wistar scientists are focused on solving some of the world’s most challenging and important problems in the fields of cancer, infectious disease, and immunology. Wistar has been producing groundbreaking advances in world health for more than a century, consistent with its legacy of leadership in biomedical research and a track record of life-saving contributions in immunology and cell biology.

Balancing Act: It’s a Fine Line Between Inflammation and Immunity When Viruses are Involved

Dr. Mohamed Abdel-Mohsen’s Pioneering Research on Siglecs Spotlights Their Role Helping the Immune System Recognize Viral Infections, and as Promising Future Therapy

Dr. Mohamed Abdel-Mohsen and his virology lab at The Wistar Institute review their work with a new class of immune checkpoints called Siglecs to discover the delicate balance between inflammation and immunity. Their findings could drive novel approaches for reducing damaging inflammation due to viral infections during HIV and possibly SARS-CoV-2, as well.

Twenty-five years ago, it was believed that the sequencing of the full human genome would solve all problems and cure all diseases. Today, scientists are discovering that human biology is much more complicated. To better understand cancer and antiviral activity, the field of glycobiology and the human-specific checkpoints known as Siglecs hold the key for richer, more diverse information and the promise of tailored medicines. 

Every immune cell in the human body has many sugar-binding proteins, and some, called negative checkpoint inhibitors, can suppress the immune function of cells. While immunity is important for health, when the immune system reacts too aggressively, it can harm the body — both by triggering excessive inflammation, and by blocking other critical immune functions, both which can make diseases more severe.

In a recently published, in-depth review in the Lancet journal EBioMedicine, Wistar virologist and glycobiologist Mohamed Abdel-Mohsen, Ph.D., looks at how inhibiting and activating immunological switches by manipulating these negative checkpoint inhibitors may both control inflammation and boost immunity during viral infections. 

The quest to learn more about finding the delicate balance between inflammation and immunity in viruses stems from the Abdel-Mohsen lab’s earlier work with both HIV and SARS-CoV-2. Some of the lab’s previous research looked at the relationship between molecules called glycans and siglecs, and how they help diseases evade the immune system. Glycans are a type of sugar molecule that coats cells in the body. In diseased cells, these glycans change to match special receptors, called siglecs, found on the surface of disease-fighting immune cells such as “natural killer” cells. By binding their glycans to these siglec receptors, researchers showed, the infected cells are able to blind the immune cells and avoid detection.

Previous research by Abdel-Mohsen’s lab has shown how interactions between siglecs and glycans play an important role in regulating the immune system when the body is fighting cancer. In their new paper, the researchers looked at the role this process plays in viruses. 

Viruses use several techniques to help them evade immune surveillance, including employing these negative checkpoint inhibitors to change the glycans, or sugars, on the surface of infected cells. Based on their previous discoveries, Abdel-Mohsen’s lab is now working on new treatments that will manipulate these interactions, supercharging the immune system’s ability to target and destroy infected cells.

They recently discovered a new approach that selectively targets and disables these interactions on the surface of HIV-infected cells, effectively making HIV “killable” for the first time. They’re also studying how these glyco-immune checkpoint interactions may help SARS-CoV-2, the virus that causes COVID-19, evade natural killer immune surveillance — and how those interactions could be targeted.

Siglecs are proteins that bind to glycans (sugars) and regulate the signals of immune cells, as well as the body’s inflammatory responses. By learning how to flip the switch to turn ‘on’ the checkpoints that boost immunity, and turn ‘off’ those that reduce inflammation, Wistar scientists hope to better understand and find new approaches for treating cancer, HIV, and potentially even “long COVID.”

The lab is now exploring siglecs to study the tug-of-war that occurs between viruses and the immune systems, with a goal of better understanding how immunological equilibrium is regulated during viral infections. The challenge, Abdel-Mohsen says, is to find ways of precisely managing this immunological equilibrium in a way that enhances the immune response without triggering excessive inflammation or inhibiting other critical immune functions. 

“If we really want to learn the most about human life, we must look at the glycan,” Abdel-Mohsen says. “Understanding glycobiology will help us as a scientific community to better understand the differences between humans and other organisms—as well as the differences that exists between humans. Investments in this next-level, bold science will allow us to achieve advances in precision medicine by developing specific medicines for specific diseases.” 

Wistar Institute HIV Researchers Win Grant to Explore Genetically Engineered Natural Killer Cells as HIV Therapy

PHILADELPHIA — (Jan. 19, 2023) — amfAR, The Foundation for AIDS Research, has awarded Luis J. Montaner, D.V.M., D.Phil., in collaboration with Mohamed Abdel-Mohsen, Ph.D., a Target Grant for $397,663 over two years. Montaner, who leads The Wistar Institute’s HIV Research Program, is studying the ability of a type of immune cell known as natural killer (NK) cells to kill HIV-infected cells.

“This grant to Dr. Montaner is the latest of several awards we have made to outstanding scientists at The Wistar Institute,” said Dr. Rowena Johnston, amfAR’s Vice President and Director of Research. “Dr. Montaner’s well-designed research project has significant potential for moving the HIV cure research field forward. We wish him and his team much success and look forward to receiving updates on their progress.”

Immunotherapy using gene-modified NK cells has been shown to be effective in treating some forms of cancer. Montaner and his team are studying whether the same effectiveness can be found in treating HIV. Montaner’s research relies on optimizing NK cells to effectively find and kill HIV-infected cells by modifying them outside the body to better bind to antibodies once infused as cell therapy.

The approach will also include use of a strategy by the Abdel-Mohsen laboratory to alter antibodies to have greater potency in increasing NK cell killing. These strategies will be combined and tested in mouse models with functional human immune cells able to support HIV infection. They will determine efficacy and whether, upon halting antiretroviral therapy, HIV can continue to be controlled.

“The Montaner lab tests immunotherapy approaches that harness several arms of the immune response to win over HIV, including immunotherapy using NK cells,” said Montaner, vice president of Scientific Operations and principal investigator of the BEAT-HIV Delaney Collaboratory to Cure HIV. “This new amfAR grant will allow us to initiate new work that will expand our ongoing studies so we can continue to achieve significant milestones in our research to test HIV cure strategies.”

Wistar is a member of the Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (BEAT-HIV Collaboratory), a consortium of more than 100 top HIV researchers working to test combinations of several innovative immunotherapies under new preclinical research and clinical trials, and one of the largest HIV-cure collaborations in the world. The Montaner lab and other groups in the BEAT-HIV Collaboratory were awarded a five-year award from the NIH last year.


ABOUT THE WISTAR INSTITUTE: The Wistar Institute, the first independent nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a highly enabled culture of biomedical collaboration and innovation, to solve some of the world’s most challenging and important problems in the field of cancer, immunology, and infectious diseases, and produce groundbreaking advances in world health. Consistent with a pioneering legacy of leadership in not-for-profit biomedical research and a track record of life-saving contributions in immunology and cell biology, Wistar scientists pursue novel and courageous research paths to life science discovery, and to accelerate the impact of early-stage discoveries by shortening the path from bench to bedside.

Looking Inside the Gut for Answers to Long-COVID

This Q&A offers a behind the science peek into some of the long-term effects of COVID on the body influenced by the gut microbiome.

In a paper published in JCI Insight, Mohamed Abdel-Mohsen, Ph.D., associate professor in The Wistar Institute Vaccine & Immunotherapy Center, and collaborators from across the country and world, found that changes to the human microbiome can contribute to certain symptoms of long-COVID. Abdel-Mohsen has been dissecting the “gut-lung” axis for years, and these new findings build upon past research on this system and further identifies a specific phenomenon – the translocation of fungal microbes from the gut and/or the lung to the blood – that could possess clinical relevance in the development of treatments for persistent, long term effects of SARS-CoV-2 on the body.

We had a conversation with Abdel-Mohsen to learn more about the latest knowledge surrounding “leaky gut” and long COVID.

Q: What is the gut microbiome and why is it important in combatting disease?

A: In our gut and other surfaces like our lungs and mouth, there are many microbes that are very important for maintaining human health. In the last decade, it has become very clear that these microbes play a very important role in regulating health and disease. The gut microbiome is a combination of microbes such as bacteria and fungus that occupy a host’s gut. There is a rising number of papers linking the microbiome with diseases such as Alzheimer’s and Parkinson’s. There is a lot of interest in understanding this microbiome, what microbes do, and how to take advantage of this knowledge to design novel strategies to fight different diseases. For example, in addressing cancer, cancer immunotherapy has been associated with changes in composition of the gut microbiome. Another example is that it has now become clear that the microbes in the gut can impact the brain through the gut-brain axis. The microbiome has also been associated with cardiovascular diseases through the gut-heart axis. And the gut microbiome could be involved in a biological cycle with the lung, which itself has a microbiome, through what’s called the gut-lung axis.

Q: What makes long COVID an interesting and particularly complex topic to study?

A: Some people do not completely recover from COVID-19. Between 10 to 30 percent of COVID-19 patients experience either persistent, recurrent, or even new symptoms. If they have these symptoms at least three months after acute COVID-19 infection, it can be called long-COVID or post-acute sequelae of SARS-CoV-2 (PASC). A person’s quality of life is significantly compromised by this syndrome, and some of the symptoms continue for more than a year. This is why we and many others are interested in understanding what might be causing these persistent, recurrent, or new symptoms three to four months after infection.

However, there is no good definition of the phenomena yet. It’s not clear what should be considered long COVID and what is not. There is nothing that the physician can measure to diagnose long COVID. People cannot go and take a test for long COVID, so physicians and researchers rely on self-reporting symptoms from patients, making it very difficult to study because scientists need a very clear system and a very good database. Furthermore, because long COVID is diverse, there are a lot of potential mechanisms that might be contributing to it either in the same individual or within a group of individuals, which makes it complex. One of these potential mechanisms is microbial translocation – some disruption in the gut and/or the lung that leads microbes to translocate which causes inflammation.

Q: What is microbial translocation?

A: Microbial translocation is when microbes translocate through the epithelial barrier of an organ like the gut or lung and go from where they should be to where they should not be – such as the blood. With infection or injury in the lung, like from SARS-CoV-2, comes inflammation in the body and the release of molecules by the host called cytokines.

Cytokines can injure the gut by disrupting the gut’s barrier, allowing microbes such as fungus or bacteria and their byproducts to translocate from the gut to the blood. When the immune system in the blood sees these microbes that should not be there, it reacts by increasing inflammation. This can worsen the original lung disease, which leads to more inflammation and so on, leading to a vicious cycle. This could cause immune exhaustion where this phenomenon of higher inflammation and lower immune function can lead to many diseases.

Q: Can you briefly summarize the findings of your recent research paper?

A: In this scientific collaboration, blood samples were studied from two independent cohorts of long COVID patients from San Francisco and Chicago. We looked at markers of gut barrier permeability and microbial translocation. We found that individuals with long COVID have higher level of markers of gut barrier permeability and fungal translocation compared to individuals who are fully recovered. This level of fungal translocation is correlated with more inflammation and a higher number of symptoms where this individual suffers from lower quality of life.

Specifically, to measure fungus in the blood, we measured β-glucan – a polysaccharide sugar molecule that is on the surface of the fungi. In patients with long COVID, we found levels of β-glucan higher than the normal level in people who are fully recovered or who never got COVID-19. That was interesting for us because the polysaccharide β-glucan can directly cause inflammation. We also did mechanistic experiments and showed that the amount of β-glucan in the plasma of people suffering from long COVID is enough to directly cause inflammation.

Q: How translatable are these findings to understanding the disease and toward the development of COVID therapeutics?

A: Inflammation by fungal translocation may be targeted by drugs. You can block the signaling pathway activated when a fungal polysaccharide binds to the cell, which prompts it to produce inflammation. There are many steps of the signaling pathway in the cell that can be inhibited.

In this paper, we use one small molecule inhibitor to inhibit this inflammation signaling pathway and saw the pathway could be inhibited successfully. In summary, we identified one of the potential mechanisms of long COVID which might contribute to inflammation directly and this mechanism can be targeted with a small molecule inhibitor.

There are many different potential drugs that may be further developed for inhibition. These are potential therapeutic applications that could be tested as soon as preclinical animal models of long COVID are available.

Q: What are some related questions or future directions you would like to see your own lab or other scientists take the findings of this paper in?

A: One of the most common symptoms of long COVID is neurological impact. We are interested in exploring the potential link between the gut-lung and gut-brain axis.

Also, how much does the gut versus the lung contribute to fungal translocation? How can we use antagonists as therapeutic options in a preclinical animal model to treat long COVID as a step to move it to the clinic?

Additionally, we need to understand whether the gut resilience to common stimuli is compromised after acute SARS-CoV-2 infection and whether this contributes to this microbial translocation we observed. I think there are a lot of studies we need to do on the upstream mechanism of this disruption.

Finally, we don’t believe that long COVID is solely caused by microbial translocation. This is probably one out of several mechanisms that contribute to symptoms. It is likely that long COVID is multifactorial in nature and involves multiple processes to some degree, either in the same individuals or in different groups of individuals. For example, how is fungal translocation related to the B cell dysfunction, related to SARS-CoV-2 antibodies, or related to the persistent virus? We eventually need to connect all these mechanisms together to see the full picture.

Q: What would you like readers to take away from this research?

A: The gut microbiome is being recognized as a very important contributor to overall health and conversely in association with many diseases. Persistent and recurrent symptoms have also been reported for SARS-CoV-1, MERS, polio, and many other infections. Understanding mechanisms that contribute to this post-acute infection sequela will be a very important factor moving forward for SARS-CoV2 but also for a plethora of existing and emerging infections. For long-COVID, this is an opportunity for us to understand the disease and how gut microbial translocation is likely a major contributor of these symptoms.

This research was supported by The Campbell Foundation, Commonwealth of Pennsylvania COVID-19 funding, and NIH Cancer Center Support Grant.

Wistar Science Synergy Through Fostering International Collaborations

Inaugural graduate students from Leiden University Medical Center speak to their Wistar experience.

The Wistar-Schoemaker International Postdoctoral Fellowship is a special exchange of postdoctoral fellows between our two institutes. We sat down with Katarina Madunić and Tamas Pongracz to hear more about this important science interchange and what is next in their research careers

What is your scientific expertise and how is it connected to Wistar?

Katarina Madunić: My mentor Dr. Manfred Wuhrer got to know Dr. Mohamed Abdel-Mohsen during a collaborative seminar that we organized together with Wistar and LUMC to exchange current research results. We learned very early on that we have mutual interests and might benefit from each other’s expertise. Dr. Abdel-Mohsen’s work is focused on various aspects of HIV biology and glycoimmunology. My Ph.D. was in cancer research where I studied glycosylation of colorectal cancer – specifically a largely unexplored type of glycosylation called mucin type O-glycosylation.

In my research at Leiden University Medical Center (LUMC), I discovered that sugar molecules attached to proteins (glycans) are specifically expressed by tumors, yet never appear in normal tissue of the patient. This makes glycans promising targets for antibody-based immunotherapy. At LUMC, our focus is on structural glycomics where we explore which glycans are expressed in different tissues and cells in different diseases. This is complementary to Dr. Abdel-Mohsen’s lab, which has more of a focus on the role of different glycans in the immune system, and in diseases like HIV.

In HIV infection, there is an interplay between gut tissue, its glycosylation, and microbiota. Translocation of the microbiota during HIV infection causes long term inflammation leading to health complications. The key question this work is trying to answer is whether glycosylation of the gut cells is linked to the diversity of the microbiota and their translocation during HIV infection. At Wistar, I am exposed to different techniques such as lectin array and mass spectrometry to analyze gut glycosylation. My expertise is in mass spectrometry, so when I observed the data, I brought a different perspective to its interpretation.

Tamas Pongracz: Our antibodies – crucial in the fight against the SARS-CoV-2 virus – are coated with sugars in a process called glycosylation. Part of my Ph.D. research focused on antibody glycosylation signatures in COVID-19 infection. Using mass spectrometry, I identified these antibody-linked sugars and found specific coating patterns that are associated with disease severity at hospitalization. Based on these patterns, we could predict how a patient’s disease would progress. The study took place within the framework of a multi-disciplinary collaboration at LUMC, turning the pandemic into a scientifically fruitful period. This is a complementary time to be at Wistar and observing the research taking place Mohamed Abdel Mohsen’s lab. Interestingly, sugars can modify their inflammatory potential depending on how antibodies are coated —Mohamed’s lab specializes in this topic. During my time, I got to see how specific sugars affect antibody function

We are so grateful to be here and supported through this Fellowship that brings researchers from Leiden to Wistar to nurture new scientific collaborations. While we are here, the visit also has a diplomatic flavor because we are the first visitors from Leiden. We are pioneering the collaboration between the two labs.

What are some next steps for you both – scientifically and professionally?

KM: I accepted a postdoctoral fellowship in Copenhagen, Denmark on the team of Dr. Adnan Halim. There, my work will be more focused on understanding what specific function glycans have on a particular protein. My long-term plan is to come back to the Netherlands after the postdoctoral fellowship. Colon glycosylation and it’s interplay with the gut microbiota in the context of different inflammatory diseases as well as cancer is a subject that sparks my interest the most, and I would like to continue working on this subject in the future.

TP: Once we are back at Leiden, both of us will spread the news about how great Wistar is and that international collaboration is key for both institutes. I feel very much attached to glycobiology. In the future, I would like to be part of an interdisciplinary team studying the mechanistic aspects of glycosylation, a field currently gaining more and more attention.

Anything to add about your experience?

KM: Dr. Abdel-Mohsen and members of his lab welcomed us very warmly here. Samson, Ferlina, and Shalini gave us a thorough understanding of the assays they utilize. They also organized a lab night out where we went bowling and got to know each other better.

TP: Leadership has welcomed us so warmly. We dined with Anne Schoemaker—her late husband Hubert is who this Fellowship has been named after, and we heard how supportive and brilliant he was as a scientist and how human he was. That was touching, and we are very privileged to be supported by this Program. I think that this has been a great kickstart of the collaboration. We already have ideas on what to explore when we return home and it’s going to be fruitful for everyone.

The Wistar Institute Is Pleased to Announce the Promotion of Dr. Rahul Shinde to Assistant Professor, and the Promotions of Drs. Mohamed Abdel-Mohsen and Alessandro Gardini to Associate Professor

Wistar is honored these talented and accomplished scientists commit each day in their lab to bringing new and creative insights to cancer, immunology, and infectious disease research. Their original research makes them leaders in their fields and goes beyond scholarly achievement, to their belief in collaboration, and the creation of scientific symposia, and educational programs that expand their respective scientific fields. All promotions were effective as of January 1, 2022.

Congratulations to Dr. Rahul Shinde—Promoted to Assistant Professor

Dr. Shinde joined Wistar in June of 2019 as our first Caspar Wistar Fellow and was programmatically appointed with the Immunology Microenvironment and Metastasis Program. In his relatively short time at the Institute, Shinde established a productive laboratory, initiated numerous collaborations both in and out of Wistar, received independent NIH funding, and developed an innovative research program on the impact of the immune microenvironment in pancreatic cancer, one of the deadliest malignancies in humans. His promotion is a tangible recognition of this track record of academic excellence and a testament to the Caspar Wistar Fellow program as an innovative and successful mechanism to help foster the transition to research independence of meritorious early career investigators.

Congratulations to Dr. Mohamed Abdel-Mohsen—Promoted to Associate Professor

Dr. Abdel-Mohsen was recruited to Wistar in 2017 as a member of Vaccine and Immunotherapy Center. As a junior faculty at the Institute, Abdel-Mohsen quickly established himself as an undisputed research leader in multiple fields of investigation, with innovative and groundbreaking contributions in various aspects of HIV biology and therapy, mechanisms of immune recognition and glycomics. In his short time at Wistar, he was recognized with an impressive number of scholarly achievements, including publications in top-tier scientific literature, large extramural funding and speaking engagements at national and international venues.

Dr. Abdel-Mohsen’s energy, collaborative spirit, and engaging personality, all about the science, have made him a go-to person at our Institute, and a premiere colleague and collaborator in the broader Wistar-Penn campus.

Congratulations to Dr. Alessandro Gardini—Promoted to Associate Professor

Dr. Gardini joined the Institute in 2015, establishing a successful, internationally recognized and highly collaborative scientific program. He is a vital contributor of the Gene Expression and Regulation Program in our Cancer Center and has made seminal contributions to our understanding of novel transcriptional networks exploited in tumor development and progression. In addition to his scientific and scholarly achievements, published in top journals, Dr. Gardini has been a great ambassador of Wistar, launching an exciting Ph.D. exchange program with the University of Bologna, establishing productive research collaborations with our colleagues at the Helen F. Graham Cancer Center at Christiana Care Health and organizing a number of scientific and educational venues, including the GER Mini Symposium in 2017.

Wistar Scientists Discover Sugar Molecule on HIV-infected Cell That Plays a Role in Evading Immune System

All cells have an outer layer of sugar molecules – like the candy coating on an M&M. Now a new study by Wistar scientists shows how these sugars play a key role in helping HIV cells evade the immune system. The study also shows how this mechanism can be disabled.

The findings, published in PLOS Pathogens, could lead to new treatments that don’t just suppress HIV-infected cells, but kill them. That would be a key step toward finally curing HIV.

Wistar’s Mohamed Abdel-Mohsen, Ph.D., assistant professor in the Vaccine & Immunotherapy Center, and his team looked at a type of sugar found on the surface of HIV cells called sialic acid. These sugars can trigger inhibitors on disease-fighting “killer” immune cells, shutting them down before they attack.

“We thought, ‘is it possible that these HIV-infected cells are covering themselves with these sugars to evade immune surveillance?” said Abdel-Mohsen.

The researchers used an enzyme that removed the sialic acid. This caused the immune cells to attack and destroy the HIV.

“The killer cells become a super killer for the HIV-infected cells,” he said.

Current treatments can reduce HIV to undetectable levels, but they can’t eradicate it entirely. The disease typically returns quickly when treatment stops.

Recent HIV research has focused on a “shock and kill” approach. This involves “shocking” the virus out of latency so it can be detected, then somehow destroying it.

“They have the shock, but they don’t have the kill,” Abdel-Mohsen said. “Our method actually increases the susceptibility of HIV-infected cells to killing, which is one of the top unmet needs in the HIV field.”

Wistar Scientists Discover Sugar Molecule on HIV-infected Cell Plays Role in Evading Immune System — They Exploit as Weakness to Make More Effective “Natural Killers” Against HIV

PHILADELPHIA — (Nov. 11, 2021) — A new study by researchers at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease, and vaccine development, shows how key features on the surface of HIV-infected cells help the disease evade detection by the immune system. It also shows how these features can be disabled. The findings, published in PLOS Pathogens, are a first step toward a new class of treatment aimed at not just suppressing virus replication, but killing cells harboring persistent virus that prevent us from curing HIV infection.

“We identified a glyco-immune checkpoint interaction as a novel mechanism that allows HIV-infected cells to evade immune surveillance,” said Mohamed Abdel-Mohsen, Ph.D., assistant professor in the Vaccine & Immunotherapy Center at The Wistar Institute and coauthor on the paper. “And we developed a novel approach that selectively targets these interactions on the surface of these infected cells.”

A cure or long-term remission remains the holy grail of HIV research. Current treatments can reduce HIV to undetectable levels, but they can’t eradicate it entirely. The disease typically returns quickly when treatment stops. And even when controlled, HIV increases risk for other health problems, including neurological disorders, cardiovascular disease, and cancer.

For the new study, researchers looked at a type of sugar molecule called sialic acid on the surface of HIV-infected cells. These sugars bind with special receptors called siglecs on the surface of disease-fighting “natural killer” immune cells. When activated, these receptors act as inhibitors, restraining the killer cells and causing them to stop killing. “We thought, ‘is it possible that these HIV-infected cells are using this interaction — covering themselves with these sugars to evade the natural killer immune surveillance?’” said Abdel-Mohsen.

The Abdel-Mohsen lab found that was indeed the case and these infected cells can take advantage of this inhibitory connection to evade immune surveillance. Researchers then investigated whether they could manipulate this connection to make the killer cells more effective at killing HIV-infected cells. First, they looked at whether disabling the inhibitors from the killer cells would unleash their full killing power. However, this can cause the immune cells to attack indiscriminately, destroying both healthy and unhealthy cells. The researchers then turned their attention to the HIV cells. They used an enzyme called sialidase to remove the sialic acid sugars that were activating the immune inhibitors. However, this again affected all cells, causing the killer cells to attack indiscriminately. Finally, they developed a sialidase conjugate linked to HIV antibodies. This antibody-sialidase conjugate only targeted sialic acid on HIV cells. With the sialic acid removed from these cells, the killer immune cells attacked and killed the HIV-infected cells, leaving healthy cells alone.

“The killer cells become a super killer for the HIV-infected cells and they now attack them in a selective manner,” said Abdel-Mohsen. “The discovery could be a missing link in the “shock and kill” approach to HIV treatment that has been a focus of research for the past several years,” he added. This two-step process involves first “shocking” the HIV out of latency so it can be detected, and then stimulating the immune system to “kill” the virus once and for all. However, while effective methods have been discovered to reverse latency, scientists haven’t yet found a way to make HIV-infected cells more killable once reactivated. “We may have the shock, but we don’t have yet the kill,” Abdel-Mohsen said. “Our method actually increases the susceptibility of HIV-infected cells to killing, which is one of the top unmet needs in the HIV field.”

First author Samson Adeniji, Ph.D., a postdoctoral fellow at Wistar, noted that the team’s approach could be tested in combination with broadly neutralizing antibody therapies currently being studied in clinical trials. “By combining approaches, we could turn these immune cells from a cop into a kind of Robocop,” he said.

The researchers also noted that, in addition to HIV, the approach could have a clinical application in treating other infectious diseases that may evade the immune system, including hepatitis and COVID. Next, the team is moving forward with animal studies to test their findings in vivo. They’re also investigating other sugar molecules on HIV that may play a similar role as sialic acid. “HIV-infected cells are likely evading immune surveillance through many potential glyco-immune checkpoints,” Abdel-Mohsen said. “We are investigating other mechanisms and how to break them.”

Co-authors: Opeyemi S. Adeniji, Ziyang Xu, Michelle Ho, Costin Tomescu, Qin Liu, Kar Muthumani, David B. Weiner, and Mohamed Abdel-Mohsen from The Wistar Institute; Leticia Kuri-Cervantes, Ziyang Xu, Michael R. Betts from University of Pennsylvania; Chenfei-Yu, Han Xiao from Rice University; Glen M. Chew, Cecilia Shikuma from University of Hawaii; Ashley F. George, Nadia R. Roan from Gladstone Institutes and University of California San Francisco; Lishomwa C. Ndhlovu from Weill Cornell Medicine.

Work supported by: National Health Institutes (NIH) grants R01 AI165079 to M.A-M and H.X; R21AI143385, P30 AI 045008, and UM1AI164570 to M.A-M; and R35 GM133706 and R21 CA255894 to H.X; The Robert I. Jacobs Fund of the Philadelphia Foundation; U.S. Department of Defense W81XWH-21-1-0789; Cancer Prevention & Research Institute of Texas (CPRIT) grant RR170014; and The Robert Welch Foundation C-1970.

Publication information: Siglec-9 Defines and Restrains a Natural Killer Subpopulation Highly Cytotoxic to HIV-infected Cells, PLOS Pathogens, 2021. Online publication.


The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible.

Wistar Scientists Discover Blood-based Biomarkers to Predict HIV Remission After Stopping Antiretroviral Therapy

Antiretroviral therapy (ART) is highly effective at controlling HIV infection, keeping the amount of virus in the blood so low as to be undetectable. This condition is called viral suppression.

Yet most people experience viral rebound and disease progression if they stop treatment, so scientists are looking to find a functional cure that allows infection control without ART.

Cure-directed clinical trials designed to test new therapeutic interventions require study participants to discontinue ART to allow researchers to evaluate new strategies. This is called analytical treatment interruption (ATI).

Currently, there are no simple, non-invasive methods available to monitor viral rebound after ATI. Therefore, new biomarkers are urgently needed to improve the safety of treatment interruption by predicting how long a patient can be off ART.

Scientists at The Wistar Institute have studied a rare population of HIV-infected individuals who can naturally restrain infection and sustain viral suppression after stopping ART, known as post-treatment controllers.

“We analyzed one of the largest sets of samples ever studied from post-treatment controllers, who don’t experience viral rebound after ART interruption,” said Mohamed Abdel-Mohsen, Ph.D., assistant professor in The Wistar Institute Vaccine & Immunotherapy Center, who led the study, published in Nature Communications. “This condition is extremely rare and provides very important insights into what a functional HIV cure looks like.”

Analyzing the blood of these individuals, scientists identified promising biomarker signatures that may fast-track future HIV cure trials and treatments.

“These biomarkers also provide us with insights on how post-treatment controllers restrain infection and how we can design novel HIV curative strategies to repeat this promising phenotype in the millions of HIV-infected individuals worldwide.”

For more information on this study, read our press release.