Author: The Wistar Institute

Progress Toward a Cure: A Conversation with Leading Wistar HIV Research Scientist on World AIDS Day

Written by The Wistar Institute on December 21, 2021. Posted in Featured News.

On the eve of World AIDS Day, we chat with trailblazing scientist Dr. Luis Montaner, Herbert Kean, M.D., Family Professor, and leader of the HIV Research Program at Wistar. On Dec. 1, tune in to hear him in person as part of the NIH World AIDS Day 2021 Virtual Event.

Q: Tell me about the National Institute of Health’s (NIH) World AIDS Day virtual event. Is this the first time you’ve taken part?

A: Yes, it is, and it coincides with the release of the national HIV/AIDS strategy. We are discussing the research priorities moving into the future. I’m part of a panel to discuss recommendations, and community engagement.

Q: Have you taken stock of your most meaningful accomplishments over the last year? Have you reflected on the Wistar HIV Program you’re building, the type of researchers you’re recruiting, and what this means?

A: The last year has been transformational because we were able to successfully renew our Delaney grant with a larger coalition of investigators and a larger budget than the first award. Community engagement has also developed to a much greater extent than what we had before. We also were able to recruit additional investigators into the HIV program with Drs. Amelia Escolano and Dan Claiborne. Wistar efforts also developed the infrastructure for bringing humanized mouse models of disease into our HIV Program, identified novel predictors of HIV control, and completed recruitment of a human trial testing a novel strategy of immunotherapy against HIV in spite of COVID-19. Last year was critical to creating a great foundation for the impact Wistar will have on the search for an HIV cure in the coming years.

Q: What does World AIDS Day mean to you?

A: World AIDS day is really a reminder that we still have a lot of unfinished business to address. Although therapy has made living with HIV a chronic disease, there is still global disparity in access to therapy.

In addition, the need to generate a cure remains. On one hand, World AIDS Day is a reminder that we still have added efforts to move forward to provide answers as to how best to reach a cure, but at the same time, it’s sort of a time to reflect and recognize our progress in moving cure-directed efforts forward.

Q: Tell me about this year’s theme Ending the HIV Epidemic: Equitable Access, Everyone’s Voice. How do you ensure community representation in the recruitment of your clinical trials? How do you equally include minorities in clinical trial representation?

A: Community engagement across all NIH efforts is a priority and is reflected in the focus of the NIH virtual discussion happening on 12/1.

We at Wistar have recognized that it’s an important feature of our efforts from the beginning. Community outreach in Philadelphia has been effective in bringing voices from all people living with HIV into the Wistar research fold. It is reflected in the Jonathan Lax lectures we’ve held for over 25 years, the Legacy Awards earlier this year in which we acknowledged our partners, and the development of a cure research-directed Community Advisory Board (CAB), which now directly convenes around our research. Bringing together Philadelphia FIGHT with our Community Advisory Board, we now have created a Community Engagement Group that we call the CEG. The perspective from community groups is different than the perspective of individual persons living with HIV (members of the CAB). But together, each bring a lot more voices into the research effort.

Q: Tell me a few of the successes you’ve had in the course of your career thus far and why they are important?

A: I think the biggest success is the development of coalition of researchers singularly focused towards a cure. Bringing together and growing a group that nurtures new investigators and advances seasoned investigators towards a common goal, is a great story.

Q: In latest news, a second person has been cured naturally by their own immune system. What does it mean for the HIV cure research that you’re doing, and future?

A: I think this case gives us all hope as it shows that our immune systems can overcome an established infection. We still have the open question as to how it happened – but the fact it did means we can reach towards that goal for all.

Q: You work closely with community partners to continue advancing research towards an HIV cure. Is there any person or people who taught you what community outreach means and how to do it? What did you learn from them? How did they teach you? What do you think you taught them?

A: A lot of times we get so invested in the research effort that we have to stand back to see it from the community perspective, from individuals living with HIV, and all affected populations. Persons living with HIV come from all walks of life including those with disparities in access to health care, economic challenges, class challenges that may include a whole series of life experiences including domestic violence, or other types of unique circumstances that has shaped how HIV affected their lives. The recent creation of a CAB bringing community input into our cure-directed efforts has taught me the power of individual experience when deciding how best to communicate with and/or work with community partners to advance research towards a cure.

Congratulations to Kylie Konrath the 2021 Monica H.M. Shander Memorial Fellowship Awardee

Written by The Wistar Institute on December 20, 2021. Posted in Featured News.

This prestigious award was established in 1981 in memory of former Wistar predoctoral trainee Monica H.M. Shander and is given annually to a predoctoral trainee who displays excellence in scholastics as well as aptitude and diligence in the laboratory.

Q: What does your work consist of in the Kulp lab?

A: A lot of my work is understanding the structures of proteins. In the Kulp lab, we are focusing on viral glycoproteins and understanding how their structure can be modified.

We want to understand how the immune system recognizes a pathogen so we can tailor or change the immune response that’s elicited by vaccination to direct antibody responses to the most important sites for immunity. So, a lot of my day is spent looking at the binding sites of antibodies and at interactions between different proteins to understand how modifications might change those interactions.

Q: When and why did you join the Kulp lab?

A: I rotated into the Kulp lab during the first year of my Ph.D. I really fell in love with the critical thinking aspect of this research and the interesting ways that we create vaccines that alter what the immune system is recognizing in order to induce a more potent response.

It’s fascinating to look at these modifications and think about how you can trick the immune system. And it’s a very creative, but rational process to creating vaccines. I was interested in doing vaccine work before I came to Penn and was working at the National Institutes of Health before that. Those prior experiences sparked my interest in the preclinical development side of vaccines.

Q: What was your undergrad degree in?

A: My undergraduate degree is in biochemistry.

Q: What brought you to science?

A: I started having health problems when I was a teenager, but I was also very interested in the intellectual side of asking questions and finding answers. I wanted to be able to create answers and help clinically translate research into future drugs or therapies.

Q: What does this award mean to you?

A: An important part of the graduate level training is improving how you communicate your research. This is a great opportunity to share science with other people and I’m hoping to use the money from this award to go to a scientific conference and be able to learn and bring back what I learned to further our research. I also just want to be able to share and have interesting conversations with other scientists.

Fox Chase Cancer Center, The Wistar Institute Announce Opening of Phase 1 Clinical Trial of Anticancer Drug Candidate

Written by The Wistar Institute on December 2, 2021. Posted in Press Releases.

PHILADELPHIA — (Dec. 2, 2021) — Fox Chase Cancer Center has opened an investigator-initiated, phase 1 clinical trial to evaluate the safety and efficacy of gamitrinib in patients with advanced cancer. Gamitrinib is a first-in-class, mitochondrial-targeted inhibitor of the molecular chaperone heat shock protein-90 (HSP90) that works by inhibiting tumor cell metabolism and survival.

Gamitrinib was developed at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease, and vaccine development, and the two Philadelphia institutions are collaborating to bring this potential new therapy to patients.

The study is a single center, open-label, phase 1 clinical trial of weekly intravenous gamitrinib administration. It is designed to enroll 18 to 36 patients. The primary goal of the study is to determine safety and tolerability. It will be complemented by analyses to determine how gamitrinib is metabolized in humans, assess biochemical evidence of target engagement, and gauge early efficacy signals.

Anthony J. Olszanski, MD, RPh, director of the Phase 1 Development Therapeutics Program and vice chair of clinical research at Fox Chase, is the principal investigator on the gamitrinib trial. “We are excited to share the news that the gamitrinib trial is now open for accrual. We hope to make progress in this very first step toward a promising new treatment for patients with advanced cancer, where there remains a high unmet need for new, effective therapies,” said Olszanski.

“Gamitrinib has had a long and storied journey,” said Dario C. Altieri, MD, Wistar president and CEO, director of The Wistar Institute Cancer Center, and the Robert & Penny Fox Distinguished Professor. His laboratory designed and developed the new drug candidate for clinical use.

“It is a humbling moment to see what started as a research tool advance through preclinical development and now reach our patients. From the start, and continuing to this milestone, this project has embodied our nation’s investment in research solely and continuously supported by competitively awarded public funds,” Altieri said.

“This new trial is important on many levels,” said Jonathan Chernoff, MD, PhD, Cancer Center Director at Fox Chase, which is part of the Temple University Health System. “Delivering anticancer agents inside mitochondria has not previously been brought to the clinic in oncology. It is a highly collaborative, longstanding endeavor across cancer centers here in Philadelphia and delivers considerable innovation for a first-in-human, investigator-initiated clinical trial.”

Known as the powerhouses of the cell for their ability to produce large quantities of cellular energy, mitochondria have been recognized as important tumor drivers, sustaining many critical disease traits. This involves a pool of the HSP90 chaperone that selectively accumulates in the mitochondria of tumor cells and helps in the folding and stability of critical mitochondrial proteins exploited in cancer.

Although conventional HSP90 inhibitors previously tested as cancer drugs failed to accumulate in mitochondria, gamitrinib was designed by the Altieri laboratory to selectively localize to mitochondria, inhibit the function of HSP90, and induce the collapse of mitochondrial metabolism and tumor cell survival.

Funding for the phase 1 clinical trial to evaluate the safety of gamitrinib is being provided by the National Institutes of Health’s National Cancer Institute, the U.S. Army Medical Research and Development Command’s Congressionally Directed Medical Research Program, and Gateway for Cancer Research, a nonprofit organization dedicated to funding meaningful breakthrough treatments and cures for patients worldwide.

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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.

About Fox Chase Cancer Center
The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center, that no one shall be excluded from or denied the benefits of or participation in the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

Wistar Scientists Identify Genes Critical to Protecting Ovarian Cancer from the Immune System

Written by The Wistar Institute on November 30, 2021. Posted in Press Releases.

PHILADELPHIA — (Nov. 30, 2021) — Immunotherapies have shown striking clinical benefit in the treatment of many cancers, especially when used in combination with chemotherapy. However, some cancers respond poorly to immunotherapy, and ovarian cancer is among the most resistant. Now a new study by scientists at The Wistar Institute, a biomedical research leader in cancer, immunology, infectious disease, and vaccine development, identifies two genes that play a critical role in protecting ovarian cancer from the immune system.

The findings, published in Cancer Immunology Research, a journal of the American Association for Cancer Research, could be a step forward in developing new treatments aimed at making ovarian cancer, and other types of cancer, more vulnerable to immunotherapy.

“Ovarian cancer has a relatively poor response to immunotherapy compared to other types of cancer, like melanoma and non-small cell lung cancer,” says Rugang Zhang, Ph.D., deputy director of the Cancer Center, Christopher M. Davis Endowed Professor and program leader in the Immunology, Microenvironment & Metastasis Program, at The Wistar Institute. “However, we still want to take advantage of immunotherapy, so in order to do that, we have to identify a new strategy.”

For the study, the researchers used CRISPR screening, a tool that allows scientists to scan through a large group of genes and determine which ones perform a specific function. In a screen of genes taken from mouse ovarian cancer cells, they identified genes encoding a complex called SETDB1-TRIM28 as playing a critical role in suppressing the immune system.

They then went on to review genetic data from human ovarian cancer patients and found that these genes were negatively correlated with immune profiles. That suggests patients who had more of these genes tended to respond poorly to immunotherapy.

Notably, the complex identified in the study is over-expressed in many types of cancers, especially ovarian cancer, where it’s prevalent in as many as 25% of patients. The findings could lead to the development of new treatments that target the complex and boost the effectiveness of immunotherapies against resistant cancers, including ovarian cancer.

First author Jianhuang Lin, Ph.D., a postdoctoral fellow in the Zhang Laboratory, noted that drugs already exist that broadly target the type of enzyme that interacts with the immune-suppressing complex. These drugs could be modified to specifically target SETDB1-TRIM28.

“There are a number of histone methyltransferase inhibitors in development, however none are currently being advanced against this particular target,” he said. “Because our discovery is brand new, it holds promise for creating new combination immunotherapies for ovarian cancer.”

In addition to ovarian cancer, new treatments could benefit patients with other cancers in which these genes are over-expressed.

Next, the Zhang lab is moving on to exploring how to best target this newly discovered complex to boost anti-tumor immunity.

Co-authors: Dajiang Guo, Heng Liu, Wei Zhou, Chen Wang, Andrew Kossenkov, and Rugang Zhang from The Wistar Institute; Iris Müller and Kristian Helin from Memorial Sloan Kettering Cancer Center; Ronny Drapkin from the University of Pennsylvania; and Benjamin G. Bitler from the University of Colorado.

Work supported by: National Institutes of Health grants R01CA202919, R01CA239128, and P50CA229881; Department of Defense grants OC180109 and OC190181; The Honorable Tina Brozman Foundation for Ovarian Cancer Research and The Tina Brozman Ovarian Cancer Research Consortium 2.0; and Ovarian Cancer Research Alliance [Collaborative Research Development Grant #596552 and the Ann and Sol Schreiber Mentored Investigator Award #649658].

Publication information: SETDB1-TRIM28 complex suppresses antitumor immunity, Cancer Immunology Research, 2021. Online publication.

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Wistar Study Identifies Two Genes That Protect Ovarian Cancer from the Immune System

Written by The Wistar Institute on November 30, 2021. Posted in Featured News.

Discovery could make immunotherapy more effective for ovarian and other cancers.

Immunotherapy has shown significant benefits in treating many cancers, especially when combined with chemotherapy. But many cancers are resistant to immunotherapy. Ovarian cancer in particular tends to respond poorly to this kind of treatment.

Now a new study by scientists at The Wistar Institute helps explain why.

The new research identifies two genes that help protect cancer cells from the immune system. While these genes are found in many types of cancer, they are especially prevalent in ovarian cancer, where they are over-expressed in as many as 25% of patients.

“Ovarian cancer has a relatively poor response to immunotherapy compared to other types of cancer,” says Rugang Zhang, Ph.D., deputy director of the Cancer Center, Christopher M. Davis Endowed Professor and program leader in the Immunology, Microenvironment & Metastasis Program, at The Wistar Institute. “So we need a new strategy.”

The discovery could lead to the development of new treatments to make ovarian cancer, and other cancers, more vulnerable to immunotherapy.

For the study, researchers scanned genes taken from mouse ovarian cancer cells, looking for genes that suppressed the immune system. They identified a complex of genes called SETDB1-TRIM28 as playing a key role in immune suppression.

They compared this to genetic data from human cancer patients and found that patients who had more expression of these genes tended to respond poorly to immunotherapy.

The findings could lead to the development of new treatments that target these genes and boost the effectiveness of immunotherapies against resistant cancers, including ovarian cancer.

The Wistar Institute Receives $4 Million in Funding From the Commonwealth of Pennsylvania to Advance COVID-19 Research, Address COVID-19 Risk on Vulnerable Populations, and Assess Pandemic Preparedness

Written by The Wistar Institute on November 23, 2021. Posted in Press Releases.

PHILADELPHIA — (Nov. 23, 2021) — The Commonwealth of Pennsylvania has granted The Wistar Institute $4 million to fund COVID-19 research focused on understanding the impact of COVID-19 on certain at-risk populations and supporting the commonwealth’s preparation and emergency response planning for future pandemics. Wistar is a biomedical research leader in cancer, immunology, infectious disease, and vaccine development. The award is a bipartisan investment helmed by Governor Tom Wolf, the legislative leadership of Donna Oberlander, Kerry Benninghoff and Stan Saylor of the Pennsylvania House of Representatives and Department of Human Services (DHS).

“For nearly two years, Pennsylvania, the nation, and the world have collectively endured a global pandemic the likes of which most have not lived through. While advances in vaccines and therapeutics have allowed us to make great strides in our fight against COVID-19 and our ability to keep people safe, we have a responsibility to learn all we can from this time so we are more prepared for potential public health risks that may come,” said Governor Wolf. “This project will allow us to look more closely at the impacts of this pandemic on those among us who are more vulnerable to the greatest risks of the pandemic, and I am grateful for this partnership that will bolster Pennsylvania’s ability to embed lessons of the last two years in future planning and preparation.”

“We are proud to leverage an all-Pennsylvania-based public-private partnership to tackle one of the most severe health crises ever seen, with the goal of bringing critical and timely solutions to all citizens of Pennsylvania and beyond. The Wistar Institute and its scientists are enormously grateful to our state lawmakers for their essential role in this bipartisan initiative,” said Dario Altieri, M.D., Wistar president and CEO, director of The Wistar Institute Cancer Center and the Robert and Penny Fox Distinguished Professor. “The funding we’ve received is a tremendous catalyst to the important work being done in response to COVID-19, and it will help position the commonwealth and our Philadelphia region at the forefront of the world fight against coronavirus, as well as other emerging threats.”

The Wistar Institute was issued a $4 million grant to study the impact of COVID-19 on vulnerable populations like older Pennsylvanians, people with an opioid use disorder, and people who are HIV positive. Clinical trials designed to measure the impact of COVID-19 on identified populations will be supported through Philadelphia FIGHT, Prevention Point Philadelphia and the University of Pennsylvania in conjunction with Wistar. Dr. Luis Montaner, VP of Scientific Operations, Herbert Kean, M.D., Family Endowed Chair Professor and leader of the HIV Research Program at The Wistar Institute Vaccine & Immunotherapy Center, will lead the community outreach effort and enroll a clinical trial with the three subgroups and 100 people per category.

Information collected through the clinical trials will help policymakers better understand the impact of COVID-19 on these vulnerable populations as well as how they have been challenged and how they have endured since March 2020 given their disproportionate vulnerability and the general public health risk. The goal of this study is to provide insights and recommendations that can inform the commonwealth’s ongoing response to the pandemic and shape planning efforts to better prepare state and local response and protections for high-risk Pennsylvanians in future public health emergencies.

“The COVID-19 pandemic has affected all of us in different ways, but we know that its impacts have been felt most acutely by older Pennsylvanians and others whose co-occurring conditions or socioeconomic circumstances created greater risk. We must use this experience to better understand what we can do to protect vulnerable Pennsylvanians and not further exacerbate pre-existing health disparities,” said DHS Acting Secretary Meg Snead. “The Wistar Institute’s research will help us better understand the exact impact on the health and lives of people affected by COVID-19 so we can continue to support all Pennsylvanians on a path to good health and overall well-being. This research will be a valuable resource to inform policy and programs designed to assist and uplift vulnerable Pennsylvanians moving forward, and I look forward to the collaboration that will come.”

Pennsylvania’s investment, which is granted through DHS, will also support Wistar’s COVID-19 research that is early-stage and translational to develop programs that create second generation therapeutics and vaccines against COVID-19; focus on pandemic preparedness for the next outbreak we may face and how to easily develop and deploy needed medicines for future pandemics; and recruit faculty who are top experts in the field of infectious diseases.

Wistar scientists are collaborating in early-stage and translational COVID-19 research programs to provide promising solutions to pressing issues of creating new and better therapeutics and vaccines against COVID-19 and support the state’s emergency response to future emerging pathogens.

“Our members became aware of Wistar’s groundbreaking advancements when the House Majority Policy Committee traveled to the Institute and firsthand observed the learning and technologies being developed in early 2019,” said Rep. Donna Oberlander (R-Clarion/Armstrong/Forest) serving 63rd Legislative District. “The Philadelphia-based Wistar Institute has been actively engaged in COVID-19 research since the pandemic was first recognized and has made pioneering efforts to develop next generation COVID-19 vaccines. This investment will help all Pennsylvanians, but will also get our economy back on track. I’m happy that these efforts will continue with this investment.”

Work on this project is expected to be complete by June 30, 2022.

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

Written by The Wistar Institute on November 18, 2021. Posted in Featured News.

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 Champion Run for Research 2021

Written by The Wistar Institute on November 15, 2021. Posted in Featured News.

Our annual run has turned out to be special in more ways than one this year. We were able to rally together for the first time since the pandemic and feel the spirited comradery among our fellow colleagues that has been greatly missed. In addition, this year we not only exceeded our fundraising goal but received an Institute match bringing our total funds raised to over $10,000!

On behalf of Wistar, we would like to thank all of our dedicated trainees and staff who supported this cause that directly benefits the training, education and development of our future scientific leaders.

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

Written by The Wistar Institute on November 11, 2021. Posted in Press Releases.

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.

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Wistar Legacy Awards: Saluting Leaders in the Earliest Days of the AIDS Pandemic and Recognizing Their Lasting Legacy 25 Years Later

Written by The Wistar Institute on November 2, 2021. Posted in Featured News.

The Wistar Legacy Awards and 25th Jonathan Lax Lecture was a poignant night celebrating the people and organizations that 25 years ago came together from backgrounds in community activism, philanthropy, faith, government, law, and science to fight against the inequality, inaction and death that the AIDS pandemic brought to Philadelphia.

The virtual event, hosted by Dr. Luis Montaner, Herbert Kean, M.D., Family Professor; director, HIV-1 Immunopathogenesis Laboratory and leader, HIV Research Program, featured trailblazers that fought to bring top quality services and care to people with HIV/AIDS, prevent infection from those at-risk, and move HIV cure research forward.

They included philanthropist Ken Nimblett, who remembered a time in the 80s and 90s when he and others worked “tirelessly against what HIV brought into this world”. Alongside mother-in-law Martha Stengel Miller and husband Rusty Miller, Ken continued the pledge his family made to invest in cutting-edge HIV science towards a cure. He said Martha and Rusty would be so proud to see the scientific accomplishments today that are global in reach.

Philadelphia Foundation president & CEO Pedro Ramos spoke about how philanthropy, coupled with community advocacy, was critical to move the scientific needle forward and attaining larger federal funding, laying the groundwork for the major research programs we have today.

Bishop Ernest McNear spoke on behalf of Philadelphia FIGHT’s Board of Trustees about a truly fruitful partnership and shared vision that continues onward today.

Then Philadelphia FIGHT chief executive director Jane Shull was lauded for her leadership saving countless lives and creating the many programs that Philadelphia FIGHT oversees to care for those with HIV/AIDS and their families.

Activist David Fair spoke to Shull’s community organizing days and his own focused on improving quality of life and preventing infection amongst those at risk. “Jane empowered people and not just to get them on Medicare, but she created a system of care for the at risk—they had an advocate.” He honored Shull as a hero of the city.

Ronda Goldfein, Esq., echoed Fair’s words saying, “Those of us that work in HIV know the high quality and range of services can be traced to one person…Jane Shull. And that she lived by a simple moral code: every life is precious.”

Past Mayor of Philadelphia Reverend Dr. Wilson Goode called Shull a Renaissance woman and a “smart, creative, innovative, and bold person committed to solving problems others walked away from.” Adding, “She created a local model with national and international implications.” She began the FIGHT organization with $25K and today it runs on a $54M budget.

Jane Shull thanked her friends saying, “Each life is precious, and each death diminishes us all.”

Through Philadelphia FIGHT, the organization she helped build, she wanted to be closer to science and for women, black, LatinX people to get closer to access for clinical trials.

“The epidemic was not only in gay white men, but it also included many people in Philadelphia who were not really visible outside of their communities—where they were dying in great numbers,” said Shull.

She went on to say, “Ordinary people can take control of their lives and communities and decisions should be made by people for their communities.”

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, would follow in a pre-taped appearance and give his 25th Jonathan Lax Lecture. He hit home just how far HIV cure research has pushed the envelope in the last 20 years and how research continues to get closer to the eradication of HIV.

At the very end Dr. Pablo Tebas, professor of Medicine, Hospital of the University of Pennsylvania, joined Montaner to answer questions from the views about COVID-19 and HIV.

While everyone acknowledged the immense amount of work accomplished against HIV/AIDS these last 25 years of partnership with Wistar, there is still much to be done. But the fire burns bright in each and every one of the these game-changing leaders. Until the next 25.