Researchers have discovered how HIV might enter the tightly sealed nucleus of an infected cell, a necessary step for the virus to replicate. Somehow, the virus sabotages the nuclear membrane with numerous punctures. The finding could provide a new target for future AIDS drugs.
The human immunodeficiency virus (HIV) reproduces by entering a cell's nucleus and taking over. Once inside, HIV copies its RNA genome into DNA, which it slips into the cell's own DNA. Then, when the cell gets ready to divide, it inadvertently copies the viral genome into RNA, the template for making protein. These proteins then assemble into new HIV particles that can infect other cells. To make more than one copy, the virus employs a protein called Vpr that halts the cell's normal cell division cycle. Like a skipping record, the cell cannot progress into division but transcribes the viral genome into RNA over and over again.
Virologist Warner Greene and colleagues at the University of California, San Francisco, and Northwestern University Medical School, wanted to know how the virus arrests the cell cycle. The team used video fluorescence microscopy to follow the movement of cell-cycle-related proteins in and out of cell nuclei, watching how traffic varied with the presence of Vpr. "I was flabbergasted," Greene says. When Vpr was present, pimples appeared on the membrane enclosing the nucleus. Some bulged until they burst, breaking the seal between cytoplasm and nucleus through an unknown mechanism. Reporting in the 2 November issue of Science, the team suggests that these breaches may give HIV easy access to the nucleus. Normally, it's too large to fit through the membrane.
The finding only increases researchers' respect for HIV. "It's blowing holes in the nuclear envelope, and that's about as radical as you can get," says cell biologist Katherine Wilson of Johns Hopkins University School of Medicine. Wilson says the finding may encourage drug designers to consider Vpr as a potential antiviral target. "It's an important paper," she says, "because it's making us look in a new direction."