A new route to stopping HIV from infecting cells? Credit: Getty

HIV enters human cells through a more complicated route than was previously believed, scientists report today.

The work, led by biophysicist Gregory Melikyan of the University of Maryland School of Medicine in Baltimore, has implications for drug treatments that aim to block the virus's entry into cells.

"The paper reveals another level of complexity associated with HIV fusion [and] entry" into the cell, says Thomas Hope of Northwestern University in Chicago, Illinois, who was not involved in the work. "It potentially answers important questions about the early steps of HIV infection."

Until now, researchers have thought that HIV first binds to cell-surface receptors, then fuses with the outer membrane and empties its contents, including the RNA the virus needs to replicate itself, into the cell, a process taking about 10 minutes.

Delayed entry

The new work, published in Cell, suggests the story is more involved1. After it binds to cell-surface receptors, Melikyan's team has found, HIV is engulfed by membranous sacks called endosomes, in a process called endocytosis. The endosomes then sequester the virus away from the cell's cytoplasm for as long as 30 minutes to an hour. Then, the virus's outer coat fuses with the endosomal membrane, allowing the virus to dump its genetic material into the cytoplasm.

"The main discovery is this unexpected strong preference for endosomal fusion, which wasn't really appreciated," Milikyan says. His team spent years on the work that led to this new finding, he says.

The team studied how the virus responded to inhibitors that blocked binding at the cell surface and inside the cell. The team also tracked single HIV particles as they travelled through cells by labelling the virus's membrane and internal components with different dyes. This allowed them to track what happened to HIV's genetic content and outer coat as the virus travelled through the cell cytoplasm.

When the team blocked an enzyme called dynamin, which is involved in endocytosis, it stopped HIV infecting cells. That suggests the virus needs help from human proteins to complete its invasion of the cell, Melikyan says.

New challenge

"This work definitely represents a paradigm shift of how HIV entry is viewed," said Yorgo Modis of Yale University, who was not involved with the work. "There are important implications for treatment of HIV using inhibitors of viral entry such as Fuzeon."

Fuzeon is the brand name of the drug enfuvirtide, sold by Swiss pharmaceutical company Roche. It belongs to a class of drugs called fusion or entry inhibitors, which are designed to prevent HIV from infecting cells by interfering with its ability to dock to cell-surface receptors.

Enfuvirtide, for instance, works by binding to an HIV protein, gp41, that penetrates cellular membranes. But the docking sites for enfuvirtide and other entry inhibitors are only exposed after HIV begins binding to cell-surface receptors, a process that forces the virus to change its shape slightly. If this binding process in fact happens inside endosomes, rather than on the cell's surface, it means that fusion inhibitors will work better if they can travel along with the virus into the endosome, Modis points out.

"The challenge will be to design new inhibitors that are able to bind weakly to the virus prior to endocytosis, and then bind tightly to conserved [parts of the virus] in the endosome" so preventing the virus fusing and releasing its deadly contents, Modis says.