With just over a year at The Wistar Institute under their respective scientific belts, innovator-scientists Amelia Escolano, Ph.D., and Daniel Claiborne, Ph.D., have been pushing the scientific envelope in Wistar laboratories using mouse models to pursue basic research and potential therapies for one of the toughest problems in medicine: HIV.
In line with the priorities of Wistar’s Bold Science // Global Impact Strategic Plan to advance the scientific enterprise at the Institute, they are making their mark as the newest members of The Vaccine & Immunotherapy Center (VIC) at The Wistar Institute.
Escolano joined Wistar from Rockefeller University, where she was a postdoctoral fellow. With a background in inflammatory diseases, Escolano began her postdoctoral work focusing on vaccine design. There, she was one of the first researchers to use a mouse model called immunoglobulin knock-in mice for HIV vaccine research. Escolano’s expertise with this mouse model, along with her experience developing sequential immunization protocols, make her a valuable addition to the VIC team.
A knock-in mouse is a mouse that has a specific DNA fragment inserted into a particular position on the mouse’s genome. In the case of immunoglobulin knock-in mice, genes that make antibodies are inserted into the genome. Escolano and her lab then use the mice to test whether their immunogen designs — proteins that induce an immune response, like in vaccines — activate the mouse’s B cells to produce those antibodies that fight disease.
“These mice are used to see how we can activate those B cells and how we can make them evolve to become broadly neutralizing antibodies,” said Escolano.
“Making antibodies evolve” is Escolano’s area of research, specifically designing a sequential immunization protocol to induce neutralizing antibodies against HIV. Sequential immunization involves a first injection with one immunogen, then a subsequent injection with a slightly different immunogen, and so on. The purpose is to gradually introduce mutations on the antibodies which make them evolve to neutralize against HIV more effectively so that the result is a potent and broadly neutralizing antibody. This sophisticated form of antibody is necessary to combat HIV and other viruses that mutate quickly and form many different strains.
“Here at Wistar, I’m continuing my efforts to design these types of sequential immunization protocols and make them work in model systems and eventually in humans,” said Escolano. Ultimately, she and her lab hope to answer the question of why some vaccines induce protection for years, while others only offer protection for months. With this knowledge, scientists will be able to design vaccines that induce protection for a long time — potentially even a lifetime.
Claiborne came to the VIC as a Caspar Wistar Fellow. This fellowship is awarded to early-stage investigators with outstanding research records who, as Claiborne puts it, “have unique angles on things.” His distinct expertise is using humanized mouse models to research T-cell dysfunction, specifically in pursuit of therapies that could cure HIV. “At the same time Wistar was just starting a humanized mouse program, I came in with knowledge on how to use that model well,” Claiborne shares.
In the context of vaccinology and immunology research, a humanized mouse is a mouse that is engineered to have a human immune system. Claiborne is a proponent of this model because it can be more readily translated to clinical settings. “I’m a basic scientist, but it’s always important to think about how this is going to advance human health,” he said. “In humanized mice, you can use authentic strains of HIV, which facilitates the translatability of anything you’re doing that’s a therapeutic intervention.”
In his own research, Claiborne is using humanized mice to try to answer the question of how T cells, a type of white blood cell, become dysfunctional when they see their target over and over again, like in chronic HIV or cancer. “Functional exhaustion” turns off T cells and protects them from becoming overactivated — a state in which T cells could kill you. However, when it comes to certain therapies for HIV and cancer, such as CAR T-cell therapies, T cells that turn off ruin the efficacy of the treatment.
In CAR T-cell therapies, T cells are removed from a patient’s blood. Then, a specific receptor is added to the T cells that helps them find the target the patient’s body needs to fight. The T cells — now called “chimeric antigen receptor” or “CAR” T cells — are injected back into the patient. However, these cells are only effective as long as they continue to find and fight that target. Researchers found that when CAR T cells encounter the same antigen repeatedly and do not clear it, as with HIV, they self-regulate and turn off. Claiborne and his lab are investigating how this process begins.
“At the end of the day, we’re trying to figure out how T cells start to go down that path of functional exhaustion so we can stop that from happening,” said Claiborne. “That would have implications for all CAR T-cell therapies.”