After infecting a susceptible cell, the human immunodeficiency virus hijacks that cell's normal machinery to produce carbon copies of itself. New HIV particles roll off the cellular assembly lines, burst like bubbles out of the cell, and float off to invade other cellular factories. Vanderbilt University Medical Center investigators have now identified an early step in HIV particle assembly.
The findings, published March 11 in Cell, could lead to new drugs that combat HIV infection by shutting down the virus's assembly lines.
For several years, Paul W. Spearman, M.D., associate professor of Pediatrics and Microbiology & Immunology, and colleagues have been studying the assembly of HIV particles, specifically the distinct steps HIV structural proteins take in order to come together and create a viral particle.
"The assembly process is just one part of the whole HIV life cycle," Spearman noted, "but it's an important part in that each step along the way is required to make an infectious viral particle."
Spearman's team has focused on a protein called "Gag," the major HIV structural protein. In recent years, Spearman said, it has become apparent that Gag moves to a compartment in the cell called the multivesicular body, or late endosome. In some cell types, Gag and the HIV viral envelope protein form particles in the multivesicular body; in other cell types, Gag makes its way from this site to the cell membrane before assembling into particles.
Although many studies have demonstrated that Gag is present in the late endosome and have focused on particle assembly at that point, none have tackled how the Gag protein gets there in the first place. The current work fills this gap.
Spearman and colleagues used the HIV-1 Gag protein as bait to "fish" for Gag binding partners. They identified several known and novel interacting proteins and selected one, the delta subunit of AP-3, for further evaluation. AP-3 is an "adaptor protein complex," a group of four proteins known to sort cargo proteins to specific compartments in the cell.