The immune system works 24/7 to fend off invading microbes and viruses, but when it comes to infection with human immunodeficiency virus (HIV), the virus has the clear advantage. Research by Dan Littman is shedding light on how HIV and other microbes evade detection by the immune system and interact with immune cells and proteins to ensure their survival. "By understanding the basic molecular mechanisms of microbial pathogenesis, we can design better ways to combat HIV infection," he explained. His study of immune system signaling and development is also providing clues to ways to manipulate immune cells to prevent or treat autoimmune diseases and to develop better vaccines against microbial pathogens or cancer.

Recent research by Littman and his colleagues at New York University Medical Center, in collaboration with a team of Dutch scientists, strongly suggests that HIV enters the body via a "Trojan horse"—immature immune cells, called dendritic cells. HIV does not infect and replicate in dendritic cells, but it is through these cells that the virus gains access to the immune system, invading and gradually disabling helper T cells. Without helper T cells, the body can't fight off HIV and also is vulnerable to other so-called opportunistic infections.

Littman has studied HIV since the early 1980s, soon after AIDS was first discovered. In 1984, while working as a postdoctoral fellow in the laboratory of HHMI investigator Richard Axel at Columbia University, Littman isolated the gene for CD4, the receptor to which HIV binds when it invades helper T cells. Later, as an HHMI investigator at the University of California, San Francisco, Littman identified the precise portion of CD4 targeted by HIV.

Then in 1996, Littman, working at New York University School of Medicine, identified a second receptor for HIV, called CC-chemokine receptor 5, or CCR5, which appears to play a key role in the transmission of the virus between individuals. In collaboration with Nathaniel Landau of the Aaron Diamond AIDS Research Center, he showed that CCR5 and CD4 proteins work together to fuse cells with the HIV virus, allowing the virus to release its genetic material.

Littman says he continues to be fascinated by the immune system. "While we know far more about the immune system than any other complex system in the body, I am astounded by how limited our knowledge really is," Littman said, noting that his laboratory recently found two types of immune cells in the intestine that are barely mentioned in the scientific literature and discovered that both have important new functions. "We are just at the tip of the iceberg in terms of understanding how the immune system works," he added.