Tag: Montaner

This year, The Wistar Institute hosted the Annual Jonathan Lax Memorial Award Lecture virtually, bringing together HIV scientists and activists on a global stage. Celebrating 26 years of continuous HIV research collaboration, the event was streamed on June 28, 2022, and saw attendees from North and South America, Europe, Africa, and Asia. The event opened with a music video by Moses “Supercharger” Nsubuga, HIV Outreach and HIV Cure Research Advocate and musician from Uganda and the Stigmaless Band performing their song “Optimistic”. It set a positive and engaging tone, reminding everyone that researchers and activists are working toward a common goal of HIV cures that prevent, control, and treat the virus.

The keynote speaker delivering the Lax Lecture was Mike McCune, M.D., Ph.D., head of the HIV Frontiers Initiative of the Bill & Melinda Gates Foundation, who emphasized the scientific progress toward curative interventions for HIV for all parts of the world. He highlighted efforts toward the development of gene therapies and “single shot” vaccine candidates and looking forward to clinical trials.

McCune expanded on his view of the ideal HIV cure. It would be available in an outpatient clinic; it would be given in one shot—like a vaccine—and durable for three years, yet a lifetime would be ideal; it must prevent or control infection but doesn’t require complete eradication; and it would be affordable for underdeveloped nations/low-income nations at $1000-2000 per administration. Also, McCune mentioned creating an affordable home testing kit, similar to COVID-19 test kits, for people to monitor if the disease is under control.

McCune shared, “We need to have a long-term vision and we need to have steps along the way that show we’re moving towards it.”

The event also hosted a panel centered around the question “What does an HIV cure mean to you?”. The global community discussion included Moses “Supercharger” from Uganda; Philister Adhiambo, Community Liaison Officer and HIV Cure Advocate from Kenya; and Michael Louella, Community Engagement Project Manager of the defeatHIV collaborative in the U.S. They all agreed that research can move forward if it prioritizes the community. Their strong perpectives came from the realities they see every day in their communities: participation in cure-directed studies, of being female with HIV/AIDS, living with HIV/AIDS in low- and middle-income countries outside the U.S., remaining on antiretrovirals for decades not knowing the toll it takes on their bodies, and stigmatized people that lost opportunities because they were HIV positive.

“26 years ago, we set out to make a difference in HIV/AIDS treatment strategies through the most cutting-edge research, done shoulder-to-shoulder with clinicians, advocates, and people living with HIV/AIDS in Philadelphia,” said Luis J. Montaner, D.V.M., D.Phil., Herbert Kean, M.D., Family Professor, leader of the HIV Research Program at The Wistar Institute, and co-principal investigator of the BEAT-HIV Delaney Collaboratory. “Our program has now grown beyond the region and country to gain a network across the globe. Our mission hasn’t changed, but we have grown into a global center to report the most groundbreaking HIV cure research together with community input.”

McCune stated, “Now is the time to move forward. Solving these challenges is not going to happen overnight, but it’s starting now.”

Dr. Luis Montaner is a transformative leader in HIV research. Throughout his tenure at Wistar, his discoveries to find an HIV cure have elevated both the prestige and scientific prowess of the Institute while most importantly, helped inform the treatments for people around the globe suffering from HIV.

Montaner has spent the last 26 years at The Wistar Institute researching HIV infection and how to boost the immune system to fight the disease. With the goal of advancing treatment strategies toward HIV eradication, his research combines virology and immunology to study the mechanisms of HIV virus infection. Montaner is also involved in overseeing patient enrollment into innovative clinical trials through advocacy partners such as Philadelphia FIGHT, and this summer, he and his partners were awarded a $29.15 million Martin Delaney Collaboratories for HIV Cure Research award to the BEAT-HIV Martin Delaney Collaboratory to advance combination immunotherapy research towards a cure for HIV. This funding extends a grant originally awarded in 2016 based on research progress to date.

Dr. Luis Montaner joined Wistar in 1995 as an assistant professor and was promoted to professor in 2007. He holds many positions at Wistar including vice president, Scientific Operations; Hebert Kean, M.D., Family Professor; associate director for Shared Resources, The Wistar Institute Cancer Center; and director, HIV-1 Immunopathogenesis Laboratory and leader, HIV Research Program. Since his arrival, Luis has been a proponent of the power of scientific collaboration. He believes that by joining intellectual and resource strengths with partners, he can advance research faster and achieve better outcomes. As illustrated in the map, the Montaner lab collaborative studies extend from Philadelphia across the United States and Puerto Rico to Mexico, Europe, South America, Southern Africa, and Asia.

His work relies on laboratory models of viral infection, such as animal models, together with clinical cohort studies, to provide a clinic-to-bench research program. This approach informs new strategies to combat HIV that may also change how we think about prevention and treatment of other infectious diseases and cancer.

“Research moves faster and with greater impact when you bring together several experts with different knowledge and areas of discovery,” said Dr. Montaner. “Just like an orchestra conductor can draw different sounds to support the execution of a symphony, the ability to draw from basic researchers, animal model experts, clinicians, industry experts, international advisors, and community members under a common shared effort helps us accelerate progress towards an HIV cure.”

Nothing exemplifies the power of collaboration more than the incredible progress the HIV research field has enabled over the last forty years in diagnosing, treating, and preventing HIV. Even recently, from 2010 to 2017, the rate of HIV-related deaths among people 13 years and older in the United States fell by nearly half according to a study from the Center for Disease Control and Prevention.

Much has been accomplished in the HIV research field, however there is still so much more to do, including the continued pursuit of a successful HIV vaccine and ultimately a cure for HIV. In this pursuit for a cure, Dr. Montaner currently leads one of the largest coalitions of NIH-funded, HIV cure-directed research under the BEAT-HIV Delaney Collaboratory. This enormous consortium brings together more than 70 top HIV researchers from academic research institutions around the world working with government, nonprofit organizations, and industry partners to test combinations of several novel immunotherapies under new preclinical research and clinical trials. The common goal of the Collaboratory is to achieve an accessible and safe strategy that can either sustain control of HIV without the continued use of current therapies and/or eradicate HIV.

While global collaborations are important, Luis has always been a huge proponent of the power of local collaborations. Within Philadelphia, his lab has a long-standing partnership with Philadelphia FIGHT, a comprehensive health services organization providing primary care, consumer education, research and advocacy for people living with HIV/AIDS and those at high risk. Representing an academic-community partnership that is unique in HIV research, Philadelphia FIGHT and the University of Pennsylvania along with the Robert I. Jacobs Fund of The Philadelphia Foundation, developed the HIV-1 Patient Partnership Program to provide clinical material for basic research and to sponsor the Jonathan Lax Memorial Lecture. Research with clinical material obtained from this Program is focused on mechanisms of AIDS immunopathology. This collaborative link between Montaner’s research team and more than 5,000 people living with HIV/AIDS in the Philadelphia region has led to the largest HIV Cure clinical trial to date — the BEAT-HIV Study. Their partnership with Philadelphia FIGHT strives to develop trusted relationships and maintain meaningful, bi-directional lines of communication between scientists and communities most affected by HIV. HIV Social Science has been a recent addition to the Montaner lab program to enhance both their preclinical and community engagement efforts.

Opportunity for progress is unique and unparalleled at present but so is Wistar’s collective responsibility to deliver.

Despite an unprecedented volume of research, there are still many unanswered questions on COVID-19, especially regarding the extremely varied clinical course the disease takes, ranging from asymptomatic to severe, even fatal. The evidence collected so far points to the so called “cytokine storm” as a major factor determining the final outcome.

Given the large volume of knowledge accumulated to date, Dr. Luis Montaner, director of Wistar’s HIV Immunopathogenesis laboratory, vice president of Scientific Operations, the Herbert Kean, M.D., Family Endowed Chaired Professor, and editor-in-chief of the Journal of Leukocyte Biology, teamed up with other editors to prepare a comprehensive review of COVID-19 publications from around the world with a focus on obtaining a better understanding of what creates a cytokine storm in some people and not others when infected with SARS-CoV-2. Here’s the conversation.

Define a cytokine storm.

Montaner: A person’s uncontrolled inflammatory response to a pathogen, which causes a cascade of negative events that may lead to multiple organ failure and premature death.

Break down and define in simple terms leukocytes and cytokines.

Montaner: Leukocyte, or white blood cells, are immune cells in the blood that also go into tissues. Cytokines are the messenger proteins made by leukocytes to communicate with other leukocytes and other cell types in the body. Both leukocytes and their cytokines are being evaluated as triggering factors contributing to disease severity and death in COVID-19.

What role do leukocytes and cytokines play in the immune response and disease progression?

Montaner: After a person becomes infected, leukocytes are the first cells to respond through the production of cytokines. This is a normal occurrence that is meant to jump start your immune response, but it becomes abnormal as the magnitude and rate of a person’s response to the infection increases.

Why does the immune system go wild and create a cytokine storm with COVID-19?

Montaner: That’s what this review is probing at by putting forth potential mechanisms that may trigger a cytokine storm. We are trying to understand what is changing with this disease and piece the moving parts together. We don’t know what the key triggers are for a cytokine storm or the quick onset of organ failure and death or in what order they act, but we are putting these pieces together.

Is this unique to SARS-CoV-2? If not, what other diseases bring this reaction on?

Montaner: Autoimmune diseases and other diseases can cause cytokine storms. Other coronaviruses like SARS and MERS also increase immune activation.

How did you come to study the data of 3939 patients from China? Tell me about this collaboration.

Montaner: As editor-in-chief of the Journal of Leukocyte Biology, I work closely with editors across the globe. Editors from China wanted to review the data and include integration of immune changes together with therapies being tested in the U.S. and China.

Did you find potential treatments that could be useful to dampen the storm?

Montaner: All of the strategies we reviewed are under analysis, as no FDA (or foreign equivalent) approved therapies are yet available. Clinical studies are now testing immune modulation, transfer of immunosuppressive stem cells, convalescent plasma transfusion, steroids, and traditional medicinal treatments.

What was the goal of your review?

Montaner: There have been numerous independent discussions of specific leukocytes or cytokines but no single, comprehensive review of all leukocytes and what their collective role in disease progression. I think this Review will serve to help define the clearest path forward for defining future research efforts to be explored in this global effort to create vaccines, therapeutics and diagnostics for SARS-CoV-2.

What were your final conclusions?

Montaner: While we all want to find a medicine that will be a “magic bullet” to treat all – the data indicates that the disease, leukocytes and the type of trigger for a cytokine storm may not be the same for all. In addition, diagnosis efforts to predict the risk of a cytokine storm and multi organ failure may require monitoring how the person is responding to infection as opposed to monitoring the amount of virus alone. Accordingly, our COVID-19 Wistar research is developing separate therapies to control the virus and the host response during a cytokine storm.

New infectious diseases are on the rise: In 2015 and 2016, there was an upswing in Zika outbreaks in the U.S., and the virus still impacts many parts of the world. The Ebola epidemic in the Democratic Republic of Congo (DRC) is the second largest in history, according to the CDC. HIV remains an incurable disease.

All of these epidemics beg one question that members of Wistar’s Vaccine & Immunotherapy Center are interested in solving: can we create a cure for infectious diseases?  

In particular, Kar Muthumani, Ph.D., assistant professor in Wistar’s Vaccine & Immunotherapy Center and director of the Laboratory of Emerging Infectious Diseases, is pursuing whether we can develop antibody therapeutics to help people recover from infection.

“Historically, vaccines have been our answer to global disease prevention but look at Ebola in the DRC — when an outbreak has already started, people with the disease need a therapeutic not a preventative answer,” said Muthumani. “In my lab at Wistar we are focused on therapeutics that could be given to anyone who comes down with symptoms; patients would receive a blood test to confirm the type of disease and take the therapy for that specific disease.” 

Muthumani’s expertise is in design and creation of synthetic DNA-based vaccines and therapeutics. His work crosses over between infectious diseases and cancers. He’s actively working on Zika virus, Mayaro virus, chikungunya, Middle East respiratory syndrome (MERS), Nipah virus, Junín virus (JUNV), Crimean-Congo hemorrhagic fever (CCHF), dengue virus, and HIV.

Muthumani is strongly committed to antibody therapy as a strategy to provide relief for emerging disease situations. Antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind to specific cells or proteins that will prevent infection and/or stimulate an individual’s immune system to attack the harmful cells. He is currently working with partners to characterize immune cells and antibodies from survivors of South India’s 2018 Nipah outbreak in Kerala, with the goal of engineering these antibodies, leveraging synthetic DNA technology and delivering them directly to patients. These antibody therapies would be ready to attack the virus and boost the body’s ability to fight infection. The goal is to provide an immediate protection while the body builds a long-lasting immune response to immunization.

Just two floors away at Wistar is the lab of Luis J. Montaner, D.V.M., D.Phil., director of the HIV-1 Immunopathogenesis Laboratory and HIV Program leader, who is also focused on a cure, but for another infectious disease – HIV/AIDS.

There are approximately 37 million people living with HIV worldwide and 21.7 million are receiving antiretroviral therapy (ART), according to the World Health Organization. ART suppresses the HIV virus and reduces disease progression, helping people with HIV live longer and preventing onward transmission. However, ART does not eliminate infection and has to be taken daily for life, thus the priority to move HIV cure research forward. 

Montaner’s 20+ years of HIV/AIDS research at Wistar has propelled him into his largest research project: the BEAT-HIV Delaney Collaboratory. He oversees a consortium of more than 80 top researchers from academia, government, nonprofit, and industry working to define the most effective way to combine immunotherapy regimens to advance new cure-directed efforts against HIV through new preclinical research and clinical trials. Their work centers on investigating where HIV hides after therapy and testing novel clinical strategies ultimately aimed at a cure that eliminates the hidden virus.

The consortium has three important goals, including two first-in-class clinical HIV cure-directed studies: 

1) identifying where and how HIV hides in the body of people on antiretroviral therapy to better determine new strategies to kill the virus; 
2) stimulating the innate immune system to be stronger against HIV, combining a medication called pegylated interferon alpha 2b, which may help control viruses, and potent antibodies that can neutralize HIV; and 
3) introducing new “killer T cells” by bringing together two promising gene therapy strategies, independently tested in humans, with the goal of engineering, growing and administering killer T cells that are uniquely empowered to find and kill HIV-infected cells.

“Lifelong stigma, economic burden on society, strain on healthcare resources, and sheer toll on human life across the globe makes finding a cure a top priority,” said Montaner. “Together, we’re building on our teams’ extensive and established efforts to move forward and make those next transformative steps that will bring us closer to an HIV cure within our lifetime.”

Wistar scientists are dedicated to the design and creation of vaccines and therapies to stem the tide of the global burden of disease. Research is one major piece of an integrated push across communities, governments and countries for the best global health outcomes. 

“Hope is a state of mind, not a state of the world. Either we have hope within us or we don’t; it is a dimension of the soul not essentially dependent on some particular observation of the world or estimate of the situation. It is an orientation of the spirit, an orientation of the heart […] Hope is an ability to work for something because it is good, not just because it stands a chance to succeed. The more unpropitious the situation in which we demonstrate hope, the deeper the hope is.”

This quote by Czech statesman and writer Václav Havel was posted on the fridge in the home of Jonathan Lax, one of the most transformative AIDS activists in Philadelphia. Lax volunteered his time to provide medical care through drug access to treatments not available in the U.S., and helped many young, HIV-positive men connect with doctors to find medical help.

After his passing in 1996, The Wistar Institute, Philadelphia FIGHT and other scientific and community partners came together and established the Annual Jonathan Lax Memorial Lecture to honor his memory and create a direct channel of communication between the scientific process of studying HIV and the community it serves.

The Lecture has reached its 24th year, fittingly celebrated on Monday, June 24.

“Every year, this event carries forward our mission of making HIV science accessible to everyone, while researching better therapies for HIV,” said Luis J. Montaner, D.V.M., D.Phil., Herbert Kean, M.D., Family Professor and director of the HIV-1 Immunopathogenesis Laboratory at Wistar, and one of the founders of the Lax Memorial Lecture.

During the opening remarks, Jane Shull, executive director of Philadelphia FIGHT, commented that in the early days of the HIV epidemic, ordinary people had to stand up in the face of silence from government institutions and lack of resources to tackle AIDS. It was a growing public health emergency and people took it into their own hands to stop the epidemic.

“Although he was a rather extraordinary person, Jon was one of these ordinary people that made a difference,” said Shull. “Those activists won their battle and we are all the better for that.”

“We must remember the days when the barrier between science and the community came down,” added Shull. “This Lecture keeps that spirit going.”

Montaner remarked on how this event is meant to be an opportunity for the local community to be exposed to new trajectories of research and remain abreast of scientific advances in the HIV field.

The audience, including community members, HIV advocates and researchers, heard from Michel C. Nussenzweig, M.D., Ph.D., Zanvil A. Cohn and Ralph M. Steinman Professor at The Rockefeller University and Howard Hughes Medical Institute investigator, who studies the immune response to HIV infection with particular focus on antibodies and is advancing promising novel approaches.

Nussenzweig discussed the characteristics of HIV infection that make the immune response to this virus atypical compared with other infectious agents. In fact, only a small fraction of HIV-infected individuals develops effective antibodies, known as broadly neutralizing antibodies (bNAbs), able to neutralize the majority of circulating HIV virus variants. In addition, it takes their immune system a very long time — two to three years — to do so.

Only five of these antibodies were isolated between 1981 and 2009, and these were not very potent, reported Nussenzweig. This aspect, and the fact that HIV can shield itself with host-derived molecules to go undetected by the immune system, have made the process of developing an effective HIV vaccine extremely challenging.

His and other laboratories have recently developed more effective methods to isolate bNAbs from HIV-positive individuals.

“By looking to the people that develop bNAbs, we gain information that can assist us in designing future vaccines,” said Nussenzweig. “We also asked, what can we do with these potent antibodies for therapy and prevention?”

Therefore, they tested the possibility of passive immunization with bNAbs in animal models. These studies showed that bNAbs are able to suppress viremia, or presence of the virus in the blood, and preserve the host T cells, giving the immune system time to build a good response to the virus.

Based on these encouraging results, this approach has been moved to clinical testing. More than 200 people have been involved so far, confirming that bNAbs are very safe and can delay viremia rebounding in individuals that discontinue antiretroviral therapy (ART).

In particular, Nussenzweig and his collaborators tested in nine individuals a combination of two broadly neutralizing antibodies called 3BNC117 and 10-1074, which bind different portions of the HIV virus. All nine maintained long-term viral suppression in the absence of ART and none developed resistant viruses.

Nussenzweig said he is very optimistic that passive administration of potent bNAbs represents a potential alternative to ART therapy. “Not only can bNAbs neutralize the virus, they also engage the host immune system, something that ART cannot do.”

Answering a question from the audience regarding the cost of this approach, he said that it would be acceptable and believes that “bNAbs could be produced with acceptable costs and would be broadly available to the HIV community, including in developing countries.”

In this day and age in the fight against HIV, what we hope for and how far scientists have come are getting closer and closer.