Understanding Immunity: Jeannette Tenthorey

Jeannette Tenthorey was deep into her studies of infectious diseases before HIV even occurred to her as a potential subject. Born in 1986, Tenthorey came of age as a molecular biologist after the first wave of meaningful breakthroughs in the fight against HIV had already been made. Tenthorey, who became an HHMI Hanna Gray Fellow in 2018, says, “I don’t think I even learned what HIV was until we already had pretty good drugs for it.” But as a postdoc studying immune-system response to pathogens, she realized that HIV was still a fruitful field of research, especially given her growing interest in the evolution of the immune system. Her journey and her current work show how much is left to understand about the virus, and where the research field might go in the future. “HIV evolved from these immunodeficiency viruses that circulate through monkeys,” she says. “There is clear evidence that the viruses that gave rise to HIV really changed the evolution of those host genomes. That made me curious to study HIV and other viruses like it to understand how our own genomes have evolved in response to viral infections.” Building on the Foundation of Basic Science Tenthorey started her own lab at the University of California, San Francisco, in 2023. She focuses on so-called “innate immune responses,” which she describes as the “frontline response to infection, before your antibodies and your T cells really ramp up.” HIV is a useful model organism for exploring this response, since so many variants arise in each individual. Tenthorey is currently studying the virus “to try and understand if there might be ‘evolutionary holes’ in HIV, places in the evolutionary process where the innate immune system could find a foothold.” That finding could improve our understanding of how the immune system can evolve to meet deadly threats, not only HIV. Tenthorey says that HHMI’s focus on basic science research is important for the contemporary study of HIV and AIDS. “HHMI scientists are encouraged to ask different questions than other people in our fields. We’re free to understand our work from a different angle, which in HIV and AIDS means we can study broader elements of the virus without feeling pressure to find a cure and create a drug. That is obviously still an important goal, but HHMI researchers can pursue additional ideas as well, with the understanding that no research goes to waste.” An evolutionary focus, for example, will hopefully give Tenthorey’s lab a sense of how to improve HIV drug therapies. “We’re looking at the innate immune response and what it can and cannot do, and how it recognizes HIV," she says. "But we can apply that kind of framework to all different kinds of viral infectious diseases. Even when we get a sad answer, like, ‘This vaccine didn’t work against HIV,’ we learn a lot about why it didn’t work. And that gives us more targeted strategies and a lot more insight about what to do when the next virus comes up.” Tenthorey adds that HHMI’s newer programs for early-career scientists, like the Hanna H. Gray Fellows Program, have helped expand the HIV field at a crucial time. “There are giants in this field who have studied the virus since the beginning, which can make it a little difficult to feel like there’s an angle for you as a younger person,” she says. “But these new funding opportunities, including the Freeman Hrabowski Scholars and Gilliam Fellows programs, give us a little more standing in those established communities. So I’ve been incredibly appreciative of that opportunity from HHMI.”