For millions of years, viruses have been waging an evolutionary arms race against the cells they infect. The human immunodeficiency virus (HIV) is an exquisite champion of this battle. It slips past many of our defenses, cloaked by its…
For millions of years, viruses have been waging an evolutionary arms race against the cells they infect. The human immunodeficiency virus (HIV) is an exquisite champion of this battle. It slips past many of our defenses, cloaked by its chameleon shell. Its genes wriggle their way into our DNA. And it infects and cripples the immune cells that are best equipped to defeat it. The modern arsenal of anti-HIV drugs can keep the virus in check for years, even decades. But decisively defeating HIV once it has gained a foothold is another matter. To do that, scientists need a deeper understanding of how it operates inside our cells—and how those cells try to beat it back. For nearly a decade, Paul Bieniasz has been leading the quest for a complete understanding of that host-virus relationship. Again and again, his discoveries have profoundly deepened our understanding of the intricate exchange between HIV and the white blood cells it infects. "Just seven or eight years ago, we didn't appreciate the complexity of the interactions between HIV and its host cells," says Bieniasz. "We've learned a lot since then." Much of that knowledge has sprung from Bieniasz's laboratory at the Aaron Diamond AIDS Research Center. Since 1999, he has elucidated important steps in HIV's life cycle—such as how the virus hijacks cellular machinery to form new viral particles. He's reconstructed an ancient retrovirus lying dormant inside human DNA to learn its secrets—and to gain insight into cellular defenses. He's resolved a long-running controversy regarding exactly where within cells new HIV particles assemble. And he's engineered a strain of HIV that can infect monkey cells—a crucial step toward developing a primate model of HIV infection, a sorely needed tool for studying host-virus interactions. In short, Bieniasz has repeatedly expanded the boundaries of knowledge of this important human pathogen. Each new discovery brings him a thrill, a frisson he first felt as a college student during a stint doing research at the pharmaceutical company Sandoz. "We were tackling problems that nobody knew the answers to—and that was instantly exciting," he says. Most recently, Bieniasz discovered that human cells possess a heretofore unknown viral defense mechanism. As a last-ditch attempt to stop infections from spreading, infected cells crank up production of a protein Bieniasz dubbed tetherin. This sticky substance migrates to the outer surface of the cell, where it snags newly spawned viral particles as they bud from the cell membrane. Ensnared by tetherin, the new viral particles can't float free to infect other cells. Tetherin inhibits every retrovirus Bieniasz has tested—except for HIV. Ever shifty, HIV has a protein called Vpu (viral protein U) that defeats tetherin and helps the virus wriggle free. Previously, Vpu was considered an "accessory" protein for HIV—nobody knew what it did. "In a series of experiments, we found a new host defense against viruses and explained the function of an HIV gene. I'm particularly proud of this story—we worked it out from first principles," says Bieniasz. Bieniasz is continuing to explore exactly how Vpu helps HIV escape tetherin. "It's conceivable that after we learn how this works it could be a new target for HIV therapeutics," he says. And ultimately, the quest for new treatments is why Bieniasz became an HIV researcher in the first place. When the AIDS epidemic first exploded across the globe, Bieniasz, who was then a student at the University of Bath, realized that stanching the disease was going to be a "massive intellectual challenge." That challenge keeps leading him down myriad scientific paths. "Young investigators are often told to focus on one or two problems," Bieniasz says. "My philosophy is slightly different; I tend to follow my nose. If I find something interesting and I think I can solve a problem, I'll go ahead and tackle it." As a result, our understanding of HIV is much deeper.