SicilianoRobert F. Siliciano, M.D., Ph.D.

Robert F. Siliciano’s childhood love of chemistry was literally fueled by his mother, Ann, an anatomy and physiology professor at Elmira College.

“I had a lab in the attic, and my mom would get chemicals for me,” he said. “I had liters of ether and benzene, concentrated hydrochloric acid, toluene. I had a Bunsen burner with a propane tank. My ‘hood’ was basically a large fan that blew the fumes outside!”

Siliciano (pronounced Sill-ih-CAH-noh) went on to major in chemistry at Princeton. Then, following his interest in medicine, he entered the M.D./Ph.D. program at Johns Hopkins. He earned his doctorate in immunology, studying how T cells recognize antigens (foreign particles). During a postdoc at Harvard, Siliciano was studying T cell responses to a synthetic antigen. His advisor, Ellis Reinhertz, urged him to “stop studying model systems and start studying a real antigen.”

Siliciano chose HIV. He began studying the virus in the mid-1980s, just after it was identified. His discoveries about HIV have changed the way treatment is given.

HIV drug therapy—called highly active antiretroviral therapy, or HAART—has reduced AIDS mortality dramatically and morphed HIV infection from an acute disease to a chronic condition for many. The drugs can reduce the amount of circulating HIV to such low levels that it appears patients are cured. But the virus is still there. Where these few viral particles originate is still something of a puzzle, but Siliciano and colleagues have discovered two of the major pieces.

In 1997, Siliciano’s group identified a population of HIV-infected memory T cells that persist in patients on antiviral drug therapy. T cells are activated to defend the body against viruses or bacteria. Though most activated T cells die fighting the threat, a small subset return to a resting state and become memory T cells. This subset serves as the immune system’s lifelong “memory” against that particular threat. Interestingly, in these memory cells, HIV turns off and goes into a silent or latent state.

Because antiviral drugs block HIV only when it replicates, the latent virus in infected memory T cells is not affected by drug therapy unless the T cell becomes reactivated.

Memory T cell populations do change over time, but the changes are slow. Siliciano has estimated that these subsets of HIV-infected memory T cells could persist in one person for 70 years or more.

“Our findings made it clear that antiviral drugs alone won’t be enough to cure the infection,” Siliciano said.

Although HAART can effectively control viral replication, the infection cannot be cured unless this “latent reservoir,” identified by Siliciano’s group, is eliminated. Targeting the reservoir has become the focus of a major international research effort. Siliciano’s laboratory is currently searching for drugs that will wake up this latent virus so that the infected cells can be identified and eliminated. His group is also working on ways to measure this reservoir in patients, something that is very difficult to do because the number of latently infected cells is very low (about one in a million).

Siliciano is also searching for other viral reservoirs that prevent curing HIV infection and trying to better understand how the T cell reservoir is established and maintained. This knowledge may help develop new therapies against HIV-1 infection. His group is also working on drug resistance, a major problem in the treatment of HIV infection.