Dr. Ralph Pantophlet, from Simon Fraser University, has come to HIV research in a roundabout way. Travelling from his home in Aruba to the Netherlands, Germany, the US and now Canada for his research has led him to think broadly about the complex relationship between viral antigens and immune system antibodies. He is now a leading expert in antiviral-antibody responses, particularly from an antigen angle.
But antigens weren’t always what he had intended to study. After his graduate work on the development of antibodies to better identify a group of hospital-acquired gram-negative bacteria, Dr. Pantophlet became interested in antibody engineering. But when he showed up at an HIV lab at The Scripps Research Institute in La Jolla, California, as a postdoctoral fellow ready to work on HIV antibodies he was told the project was already taken. “But they said ‘We have a project on modifying an HIV protein to better elicit anti-viral responses; why don’t you get started on that?’” says Dr. Pantophlet. “Initially I was disappointed, but over time I recognized the broad implications of being able to modify an antigen to bring about different antibody types and specificities.”
Supported now by CIHR team grants and a MSFHR Scholar Award, Dr. Pantophlet continues to work on understanding how to modify the HIV target protein with the ultimate goal of contributing to the development of an HIV vaccine. In unmodified form, the protein doesn’t elicit protective antibodies but it does harbour regions that could. “The idea that we are pursuing is that we can cover up sites that we do not want antibody responses to and leave others, to which we do want responses, accessible to the immune system,” says Dr. Pantophlet. “We’ve been looking not just at modifying the protein, but whether there are additional factors needed to get a desired response.” Though his research has largely succeeded in eliminating undesired antibody responses, increasing the desired response has been elusive. “Could it be a problem with the modifications we are doing? Are we doing too many and are we therefore creating new regions that initially weren’t there? Or could it also be that we need additional components of the immune system to be in place for everything to work? It’s not as straightforward as we had initially hoped!” says Dr. Pantophlet. “Certainly the latter question has us interested in T cells—they appear to be important for eliciting and achieving protective antibody responses and there are indications that having robust T-cells is somehow important.”
Coming full circle from his graduate work on bacteria, Dr. Pantophlet’s lab, in collaboration with researchers in Italy and with support from CIHR, recently discovered a plant bacterium that carries a surface sugar molecule similar to what you would find on HIV. Some HIV-infected individuals, for reasons that are still unclear, make antibodies that are able to recognize the sugar molecules on HIV and these antibodies have been shown to potently inhibit HIV infectivity in the lab. “But, if you take these sugar molecules in isolation and inject them [into an animal], you don’t get appropriate immune responses,” explains Dr. Pantophlet. “There is a difference in the way that our immune system recognizes these sugar molecules if they are on the surface of HIV versus in isolation. One of our ideas is to see if we can chemically synthesize this bacterial sugar molecule and derivatives, and determine, in animal models, whether they can encourage the desired immune response.”
Whether working on bacteria or HIV the ultimate goal of his research is big—understanding and using the complex interrelationship of the immune system and the pathogen to make better vaccines. “The idea is that one can make an antigen to trigger a desired response. That goal is illusive, but there are certain laws and elements in place. As such, it may be possible to unravel things and understand how they work together and there is general belief among vaccine researchers that it will be possible to modify and present proteins and other structures, and get the desired response,” says Dr. Pantophlet.
And Dr. Pantophlet loves both the big challenge and the opportunity. “I hope we can truly be part of a new era of vaccine development, where we move away from the more traditional methods to ones informed by molecular biology, informatics, and deep knowledge,” says Dr. Pantophlet. “To know what we are targeting and why we are targeting it. I’d like to be part of that.”
The Canadian Association for HIV Research (CAHR), the CIHR HIV/AIDS Research Initiative, the Canadian Foundation for AIDS Research (CANFAR), the CIHR Canadian HIV Trials Network (CTN) and the Canadian HIV Vaccine Initiative (CHVI) Research and Development Alliance Coordinating Office (ACO) would like to congratulate Dr. Pantophlet for his significant contributions to our understanding of HIV. His work is part of a larger Canadian research effort that is making a difference in the lives of those affected by HIV in Canada and around the world.