Chasing an Elusive Virus: Robert F. Siliciano

“I was an MD-PhD student at The Johns Hopkins University School of Medicine in the early 1980s when the first articles were published describing this new disease, AIDS,” remembers Robert Siliciano, an HHMI Investigator since 2002. “It sounded like it came out of nowhere and had something to do with the immune system, possibly a new virus. That piqued my interest.” But it wasn’t until he started his postdoctoral work with Ellis L. Reinherz, a well-known researcher and expert in T cells, that Siliciano spent significant time studying HIV. Rather than working with a model antigen, as many immunologists do, Reinherz recommended that they study the relatively new pathogen that was driving an international crisis. That recommendation changed the course of Siciliano’s career. When he returned to Hopkins to start his own lab in 1988, he focused exclusively on the virus that was now dominating health news. “Initially I worked on HIV vaccines, I would have to say not very successfully,” he says. “We still don’t have one. But that got me thinking about how HIV could persist and evade the immune response. And I became interested in the idea of a latent infection.” A virus is latent when it remains in the body but does not produce symptoms. Siliciano points to herpes and shingles as common examples of viruses that can stay latent for years between outbreaks. When Siliciano zeroed in on studying HIV, it seemed unlikely that the virus would need to hide in the body this way, since its rapid mutations usually kept it one step ahead of the immune system. “It was a shot in the dark,” Siliciano says, but his lab discovered that HIV can in fact live in memory T cells – cells that “remember” previous infections and allow the body to respond more quickly if the infection returns. In the mid-1990s, Siliciano’s lab showed that the virus can remain latent in these cells, but so well hidden that it’s nearly impossible to tell an infected memory T cell from an uninfected one. This breakthrough showed just how far off a cure truly was. If a patient stopped taking their retroviral drugs, the virus would begin replicating at detectable levels within two weeks. An Enduring Focus The virus’s persistence helps explain why, two decades later, the Siliciano lab and their peers around the world are still working to find a vaccine or cure. But Siliciano says that the support of HHMI is essential to this work because of the Institute’s steadfast focus on basic science. “The HIV field is a bit insular,” he says, “but to really move forward we need scientists who know fundamental aspects of gene regulation and immune response. If you only think about HIV, you probably don’t have the best basic science grasp of the key areas. That’s why it’s so valuable to go to HHMI meetings and see people who are doing very fundamental work.” He mentions HHMI Investigator Bert Vogelstein, an oncology professor at Johns Hopkins who Siliciano interacts with through their mutual HHMI connection. Their discussions about cancer biology have informed some of Siliciano’s current work on latent HIV. Working with his wife and longtime collaborator Janet Silicianoexternal link, opens in a new tab, he is now trying to determine if individualized vaccines for patients would help address the problem of a virus that can hide in a latent form. “Through collaboration,” Siliciano says, “we can take advantage of all of the vaccine knowledge and infrastructure and technological capabilities that have grown in the last 40 years.”