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Tag: Abdel-Mohsen

Dr. Mohamed Abdel-Mohsen

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

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (June 29, 2021) — New biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are critical for the development of new therapeutic strategies that can achieve infection control without ART, a condition defined as functional cure. These biomarkers can also provide critical clues into the biological mechanisms that control HIV replication after stopping therapy, and can help design novel strategies to cure HIV. Scientists at The Wistar Institute have identified metabolic and glycomic signatures in the blood of a rare population of HIV-infected individuals who can naturally sustain viral suppression after ART cessation, known as post-treatment controllers. These findings were published in Nature Communications and may provide new, non-invasive biomarkers to predict both the likelihood and duration of HIV remission after treatment interruption.

Cure-directed clinical trials are designed to test new therapeutic interventions to eradicate HIV infection. These trials require study participants to undergo analytical treatment interruption (ATI) to allow researchers to evaluate their strategies in the absence of the confounding effect of ART. HIV remains undetectable during ART, yet in the vast majority of cases viral loads go up within a few days or weeks after stopping ART and need to be carefully monitored. Currently, there are no simple, non-invasive methods available to monitor viral rebound after ATI. Therefore, biomarkers are urgently needed to improve the safety of ATI by predicting how long a patient can be off ART, and will be critical to understanding the mechanisms of post-ART viral control.

“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. “This condition is extremely rare and provides very important insights into what a functional HIV cure looks like. Analyzing the blood of these individuals, we 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 recapitulate this promising phenotype in the millions of HIV-infected individuals worldwide.”

The study was conducted using blood samples available from two cohorts of patients who participated in previous clinical trials: a group of 24 HIV-infected individuals who underwent an open-ended ATI without concurrent immunoregulatory agents (the Philadelphia cohort) and one group of 74 individuals from six AIDS Clinical Trial Group (ACTG) clinical studies that evaluated different vaccines and immunotherapies. Importantly, this cohort included all 27 participants from these studies that were identified as post-treatment controllers and 47 non-controllers from the same studies.

Researchers analyzed blood samples collected shortly before ATI for the presence and quantity of certain small molecules produced as a result of cellular metabolism, called metabolites, and proteins that have sugar molecules attached to them, called glycoproteins. Metabolites and glycoproteins are secreted or leaked from various tissues and enter the circulation, therefore their abundance and chemical characteristics can reflect the overall status of multiple organs, making them excellent candidates for biomarker discovery.

The team first performed metabolomic analyses on the Philadelphia cohort samples and identified a select set of metabolites linked to inflammation whose pre-ATI levels are associated with time to viral rebound. These observations were confirmed in virus reactivation assays in vitro.

They then extended the metabolomic analysis to the larger cohort, also including glycomic studies to measure the levels of sugar-bound proteins. Since this cohort includes post-treatment controllers and non-controllers, Abdel Mohsen and colleagues were able to confirm their observations by comparing the two groups.

Using machine learning algorithms, they then combined the identified biomarkers to create two models for prediction of the likelihood and timing of viral rebound, with 95% and 74% accuracy, respectively.

“A growing body of research applies metabolomics and glycomics methods for the unbiased discovery of biomarkers associated with clinical conditions,” said Leila Giron, Ph.D., postdoctoral fellow in the Abdel-Mohsen lab and first author on the study. “We are among the first to apply this strategy in the context of ATI to analyze two carefully selected and well characterized groups of individuals, including a rare population of post-treatment controllers.”

Overall, this study identified potential biomarkers associated with control of HIV after ART and has the potential to contribute significantly to both HIV cure research and discovery of novel biological mechanisms underlying viral control in people living with HIV.

Co-authors: Qin Liu, Xiangfan Yin, Emmanouil Papasavvas, Mohammad Damra, Aaron R. Goldman, Hsin-Yao Tang, and Luis J. Montaner from The Wistar Institute; Clovis S. Palmer (co-first author) from The Burnet Institute, Melbourne, Australia and Monash University, Melbourne, Australia; Radwa Sharaf, Behzad Etemad and Jonathan Z. Li from Brigham and Women’s Hospital, Harvard Medical School; Rowena Johnston from amfAR, The Foundation for AIDS Research; Karam Mounzer and Jay R. Kostman from Philadelphia FIGHT; Pablo Tebas from University of Pennsylvania; Alan Landay from Rush University; and Jeffrey M. Jacobson from Case Western Reserve University School of Medicine.

Work supported by: amfAR, The Foundation for AIDS Research; National Health Institutes (NIH) grants R21 AI143385, R01 DK123733, R01 AG062383, R01NS117458, R21 AI129636, R21NS106970, R01AI48398, BEAT-HIV Martin Delaney Collaboratory to cure HIV-1 infection (1UM1Al126620), UM1 AI068634, UM1 AI068636, UM1 AI106701, and Penn Center for AIDS Research (P30 AI 045008); W.W. Smith Charitable Trust; the Herbert Kean, M.D., Family Professorship; and the Robert I. Jacobs Fund of the Philadelphia Foundation. Support for The Wistar Institute core facilities was provided by Cancer Center Support Grant P30 CA010815. This work was also supported by NIH instrument award S10 OD023586.

Publication information: Non-Invasive Plasma Glycomic and Metabolic Biomarkers of Post-treatment Control of HIV, Nature Communications, 2021. Online publication.

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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.org.

In Severe COVID-19, What Happens in the Gut Doesn’t Stay in the Gut

Written by The Wistar Institute on . Posted in Featured News.

Shortly after the pandemic began, when doctors and scientists knew little to nothing about the novel coronavirus that has been sweeping across the globe for almost a year now, one thing became clear quickly: people who get severely ill or die of COVID-19 experience generalized inflammation and extensive damage to their lungs and often to other vital organs, sometimes leading to multi-organ failure.

Fast forward a few months. The amount of knowledge has grown exponentially and scientists are now unraveling the factors that determine whether SARS-CoV-2 infection will be mild, or even asymptomatic, or cause severe illness and possibly become fatal.

The Wistar lab of Dr. Mohamed Abdel-Mohsen is one of the first to investigate the link between SARS-CoV-2 infection, inflammation and gut integrity, based on previous knowledge from other respiratory conditions.

Dr. Abdel-Mohsen and team are dissecting the so-called “gut-lung” axis, whereby a disruption of the normal crosstalk between gut microbiota and the lungs contributes to the severity of respiratory diseases.

We tend to think of the lungs and the gut as two unrelated, distant organs. It takes some effort to understand their interaction and the influence microorganisms that colonize the intestine can have on the lungs.

Let’s break it down. Conditions that damage the intestinal wall and cause it to become abnormally permeable allow gut-resident microbes and their products to translocate into the blood stream and reach the lungs. This has a pro-inflammatory effect on the whole body — and the lungs in particular. Other lung-associated diseases, including asthma and acute respiratory distress syndrome, are known to disrupt gut integrity and cause a similar translocation of inflammatory molecules.

Now, Wistar scientists are testing this hypothesis, as it might be the case in COVID-19 as well. A  vicious cycle may become established whereby SARS-CoV-2 infection in the lungs causes a generalized inflammation that results in breakdown of the gut barrier, which causes microbial translocation that in turns hastens inflammation and lung injury.

The fact that SARS-CoV-2 can also infect intestinal cells and directly damage the gut structure and barrier strengthens the scientists’ case.

To test this hypothesis, the Abdel-Mohsen lab is studying blood samples from COVID-19 patients with varying degrees of disease severity and from age-matched healthy individuals and comparing the levels of several biologically active molecules to detect any meaningful shifts.

One type of microbial products that escape from the gut into the blood stream are special enzymes that microbes use to break down the intestinal mucus layer as a source of nutrients. While these enzymes are not harmful in the gut, once in the blood they can alter the sugar molecules present on circulating proteins and antibodies, resulting in enhanced inflammation. These enzymes are among the molecules Dr. Abdel-Mohsen and team are focusing on in their studies.

By shedding light on the link between gut barrier breakdown and COVID-19 pathogenesis, this research might help identify biomarkers for risk of severe disease and pave the way towards new strategies to prevent or reduce the severity of COVID-19.

Dr. Abdel-Mohsen thinks the information acquired through work will be useful to understand some of the health issues experienced by COVID-19 ‘long haulers’. COVID-19 symptoms can persist for months after infection has been cleared and may cause long-term health complications. The team’s preliminary data suggest that the disrupted gut barrier and gut dysfunction observed during severe COVID-19 may persist after recovery from acute disease and play a role in prolonged symptoms.

This research is made possible by urgent funding provided by the National Institutes of Health in response to the COVID-19 crisis.

National Institutes of Health Funding Powers Wistar Science in 2020

Written by The Wistar Institute on . Posted in Featured News.

Approaching the end of the year, Wistar takes stock of its federal funding performance.

During the 2020 fiscal year of the National Institutes of Health (NIH) — the U.S. government agency that supports biomedical research, it funded Wistar research by granting more than $43M in existing and newly awarded grants.

“Our ability to attract and maintain federal funding is vital for the success of our enterprise and speaks volumes to the quality of the science being pursued at Wistar,” said Dario C. Altieri, M.D., president and CEO, director of the Institute’s Cancer Center and the Robert & Penny Fox Distinguished Professor. “NIH grants fuel some of our largest and most ambitious research projects and our collaborative efforts and support our Cancer Center, a powerhouse of discoveries and advanced technologies in the region.”

The NIH is made up of 27 Institutes and Centers, each with a specific research focus on particular diseases or body systems, working together to support the nation’s research efforts. The vast majority of Wistar’s active grants are administered by the National Cancer Institute (NCI), reflecting Wistar’s vast commitment to cancer research. The second largest pool of grants comes from the National Institute of Allergy and Infectious Diseases, which supports basic and applied research on infectious, immunologic and allergic diseases, powering Wistar investigations into HIV, Epstein-Barr Virus, antimicrobial resistant bacteria, and tuberculosis.

Highlights from newly awarded grants include:

  • Two large grants over four and five years, respectively, to Mohamed Abdel-Mohsen, Ph.D., assistant professor in The Wistar Institute Vaccine & Immunotherapy Center, for his glycoimmunology research in HIV. Glycoimmunology is an emerging field focused on the role of sugar molecules present at the surface of our cells, also referred to as glycans or carbohydrates, in mediating immune responses.

    The new funding will support Abdel-Mohsen’s work investigating the role of altered host sugar repertoire, or glycome, in gut and brain inflammation and cognitive disorders in HIV. This research aims to discover new mechanisms that could be targeted to prevent or treat chronic inflammation that persists in individuals living with HIV despite antiretroviral therapy.

    Applying a similar research paradigm, Abdel-Mohsen obtained additional funding to expand his research to COVID-19. He seeks to understand the integrity of the intestinal barrier in inflammation and COVID-19 pathogenesis. SARS-CoV-2 infection alters the structure of the gut wall making it more permeable to intestinal microbes that can then enter and circulate in the blood. This may lead to a loss of anti-inflammatory circulating carbohydrate molecules in the body, which results in inflammation and worse disease outcomes. This research will lay the groundwork for developing novel biomarkers for disease risk and therapeutic interventions for the COVID-19-induced cytokine storm to prevent severe outcomes and death.
  • A five-year grant to Qing Chen, M.D., Ph.D., assistant professor in The Wistar Institute Cancer Center, for her studies on brain metastasis, which causes an increasingly heavy clinical burden due to its rising incidence and the limited efficacy of existing therapies. Chen is investigating the interaction between cancer cells and the surrounding brain cells to identify key mechanisms that could be targeted to disrupt this interaction and the cancer’s ability to grow in the brain, and eventually provide more effective therapies for cancer patients.
  • A five-year grant awarded to Maureen Murphy, Ph.D., Ira Brind Professor and program leader in The Wistar Institute Cancer Center, to further her studies on the p53 protein, a master regulator of numerous functions in the cell and frequently mutated in cancer. In particular, the Murphy lab is interested in the effects of specific genetic variants of p53 on the tumor-promoting ability of the mutant p53 protein. Murphy and her team investigate how these genetic variants affect the cancer risk in different populations, and this research has important implications for informing personalized medicine approaches.
  • A five-year grant to Rugang Zhang, Ph.D., professor and deputy director of The Wistar Institute Cancer Center, that enables the Zhang lab to study the mechanisms that allow a small number of “dormant” tumor cells to persist in the body after therapy. These cells can awaken from dormancy and start proliferating to give rise to metastases even years after the onset of the primary tumor. Elucidating the underlying mechanisms of tumor dormancy is crucial to achieve cancer eradication.
  • Two NIH Pathway to Independence Awards bestowed to staff scientists Thibaut Barnoud and Sergey Karakashev, both working in Wistar Institute Cancer Center labs. This prestigious and highly sought-after award supports outstanding postdoctoral researchers in their transition from mentored training to and independent faculty position and boosts the awardees’ competitiveness in the job market

The information on dollar amounts disclosed in this blog is publicly available and has been obtained through the NIH Research Portfolio Online Reporting Tools (RePORT).

The BEAT-HIV Martin Delaney Collaboratory Issues Recommendations on Measuring Persistent HIV Reservoirs in Cure-directed Clinical Trials

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Sept. 7, 2020) — Spearheaded by scientists at The Wistar Institute, top worldwide HIV researchers from the BEAT-HIV Martin Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (BEAT-HIV Collaboratory) compiled the first comprehensive set of recommendations on how to best measure the size of persistent HIV reservoirs during cure-directed clinical studies. This perspective article was published today in Nature Medicine.

Cure-directed studies seek to control or eradicate HIV beyond current antiretroviral therapy (ART) which can only suppress but not eliminate HIV. Long-term viral persistence on ART continues to cause immune activation, chronic inflammation and progressive damage to multiple organs. Multiple cure-directed studies are underway worldwide but no consensus statement was available to prioritize and interpret the many strategies available today to measure persistent HIV on ART.

“Bringing together many of the original investigators who developed current assays used to measure HIV, the BEAT-HIV Collaboratory has now issued recommendations for priority in HIV measures as a guide for cure-directed studies,” said Luis J. Montaner, D.V.M., D.Phil., the Herbert Kean, M.D., Family Professor and director of the HIV-1 Immunopathogenesis Laboratory at Wistar’s Vaccine & Immunotherapy Center, co-leader of the Delaney Collaboratory and corresponding author on the article. “A major obstacle to eradication is the virus hiding in some compartments of the immune system where it’s difficult to target and measure. The BEAT-HIV guidelines now provide specific information on the strengths and limitations of each assay available today.”

The ability to accurately measure the size of these HIV reservoirs is critical when evaluating potential therapeutic strategies to cure HIV. It is also necessary for monitoring viral levels and guide ART interruption.

“We systematically reviewed the state of the science in the field and provided a collective and comprehensive view on which viral measurements to prioritize in clinical trials,” said Mohamed Abdel-Mohsen, Ph.D., assistant professor in Wistar’s Vaccine & Immunotherapy Center and one of the authors of the paper. “I think this is a crucial step to take the best advantage of the most valuable resource available to researchers in their quest to find a cure for HIV, the blood and tissue samples from people living with HIV who generously participate in the HIV cure-focused clinical trials all over the world.”

In current HIV cure-directed studies in ART-suppressed people living with HIV, viral levels are monitored in peripheral blood cells obtained either by phlebotomy or leukapheresis (a laboratory procedure to separate white blood cells from whole blood) and biopsies from gut-associated lymphoid tissue or lymph nodes, though most trials only use peripheral blood because it is easier to collect.

In this work, the BEAT-HIV consortium compiled priority lists of the available assays and technologies to apply for each specimen type and collection method with the aim of aiding standardization of cure-directed trials.

Co-authors: Douglas Richman and David M Smith from VA San Diego Healthcare System and University of California, San Diego; Robert F. Siliciano and Janet D. Siliciano from Johns Hopkins University; Michel C. Nussenzweig, Christian Gaebler and Marina Caskey from The Rockefeller University; Bonnie Howell and Daria Hazuda from Merck & Co; Javier Martinez-Picado from IrsiCaixa AIDS Research Institute, Badalona, Spain, University of Vic – Central University of Catalonia, Spain and Catalan Institution for Research and Advanced Studies (ICREA), Spain; Nicolas Chomont from Université de Montréal, Canada; Katharine J Bar, Frederic Bushman, Michael R. Betts, Beatrice H. Hahn, Ian Frank, James L Riley, and Pablo Tebas from University of Pennsylvania; Xu G. Yu and Mathias Lichterfeld from Ragon Institute of MGH, MIT and Harvard and Brigham and Women’s Hospital; Jose Alcami and Maria J. Buzon from Instituto de Salud Carlos III, Madrid and Infectious Diseases Unit, IBIDAPS, Hospital Clinic, University of Barcelona, Spain; Adam M. Spivak and Vicente Planelles from University of Utah; Ya-Chi Ho from Yale School of Medicine; Mirko Paiardini from Yerkes National Primate Research Center and Emory University; Qingsheng Li from School of Biological Sciences and Nebraska Center for Virology, University of Nebraska-Lincoln; Jacob D. Estes from Vaccine and Gene Therapy Institute and Oregon National Primate Research Center (ONPRC), Oregon Health and Science University; Thomas J Hope from Northwestern University; Jay Kostman and Karam Mounzer from Jonathan Lax Center, Philadelphia FIGHT; and Lawrence Fox from Division of AIDS, NIAID, NIH. All authors contributed to the writing and editing of the manuscript.

Wistar authors were supported by: National Health Institutes (NIH)-funded BEAT-HIV Martin Delaney Collaboratory to cure HIV-1 infection 1UM1Al126620; NIH grants R01 AI065279, U01 AI065279, R01 DA048728, R01 DA049666, R01 DK123733, R01 AG062383, R01NS117458, R21 AI143385, R21 AI129636, and R21 NS106970; Herbert Kean, M.D., Family Endowed Chair Professorship; the Robert I. Jacobs Fund of the Philadelphia Foundation; amfAR, The Foundation for AIDS Research impact grant 109840-65-RGRL; W.W. Smith Charitable Trust grant A1901; Wistar Cancer Center Support Grant P30 CA010815-49S2; and the Penn Center for AIDS Research P30 AI 045008.

Publication information: Recommendations for Measuring HIV Reservoir Size in Cure-directed Clinical Trials, Nature Medicine, 2020. Online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease 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’s Business Development team is dedicated to accelerating the translation of Wistar discoveries into innovative medicines and healthcare solutions through licensing, start-ups and creative collaborations. wistar.org.

Wistar Science Highlights: New Discoveries on HIV Latency and How Cancer Cells Talk With Their Neighboring Normal Cells

Written by The Wistar Institute on . Posted in Featured News.

Antiretroviral therapy (ART) has dramatically increased the health and life expectancy of HIV-infected individuals, suppressing virus replication in the host immune cells and stopping disease progression; however, low yet persistent amounts of virus remain in the blood and tissues despite therapy. Virus persistency limits immune recovery and is associated with chronic levels of inflammation so that treated HIV-infected individuals have higher risk of developing a number of diseases.

This persistent infection stems from the ability of HIV to hide in a rare population of CD4 T cells. Finding new markers to identify the virus reservoir is of paramount importance to achieve HIV eradication.

The lab of Mohamed Abdel-Mohsen, Ph.D., assistant professor in the Vaccine & Immunotherapy Center, may have discovered a new way of identifying and targeting hidden HIV reservoirs during ART.

The sugar molecules present on the surface of immune cells play a critical role in regulating their functions and fate. Researchers explored the role of the sugar component on the surface of host cells and described a “glycomic — or sugar — signature” that can impact HIV persistence.

Published in Cell Reports, the findings may have translational implications for improving the long-term care of HIV positive people.

The crosstalk between cancer cells and their neighboring normal cells is important to promote cancer progression.

The lab of Dario C. Altieri, M.D., Wistar president and CEO, director of the Institute’s Cancer Center and the Robert & Penny Fox Distinguished Professor, studied how this exchange happens to gain more clues on how tumors “hijack” their microenvironment and promote disease progression and recurrence.

Researchers cultured breast cancer cells in low-oxygen to mimic a condition known as hypoxia, which is a hallmark of the microenvironment surrounding most solid tumors. In this setting, they discovered that cancer cells package oncogenic messages into tiny particles called extracellular vesicles and send them to neighboring normal epithelial cells. This results in reprogramming of the shape and position of their mitochondria — the cell’s powerhouse — to ultimately alter tissue structure.

These findings, published in the journal Developmental Cell, suggest novel therapeutic targets to disrupt the pro-tumorigenic changes caused by cancer cells to the microenvironment.