Likening HIV to "hobos on a train," researchers at Johns Hopkins University School of Medicine have found that the virus uses a pre-existing transport system to leave one infected CD4 cell and move on to infect news ones. Their findings, published in the June issue of PLoS Biology, counter the prevailing theory that HIV only uses virus-specific mechanisms to leave and enter cells, and may pave the way for development of yet another class of antiretrovirals.
"It appears that cells make HIV and other retroviruses by a naturally occurring export mechanism," says Stephen Gould, PhD, Professor of Biological Chemistry at Johns Hopkins. Cells normally export certain membrane-bound molecules to the outside world by means of small sacs known as exosomes. By studying human CD4 cells under a microscope, Dr. Gould and his colleagues discovered what's needed to qualify proteins for exosomal travel.
"Surprisingly, all that's needed for a protein to get out of the cell in exosomes are the ability to clump together and attach to the cell's membrane," Dr. Gould says.
In one experiment, Dr. Gould's team added chemicals to normal human cells that force nearby proteins together into a clump, and this was enough to get them sent out of the cell in exosomes. If they added a tether to force naturally-clumping proteins inside the cell to the membrane, the proteins met a similar exosomal deportation fate.
The major HIV protein ‘Gag' has both of these properties that cells can sense in selecting exosomal cargoes. When the researchers removed the tethers or clumping signals from Gag, it could no longer get out of the cell. However, if they were replaced with synthetic membrane anchors and clumping domains Gag regained its ability to get out of cells in exosomes.
According to Dr. Gould, cells may have initially developed exosomes as a quality control mechanism to get rid of clumped proteins, which are generally broken and useless. However, just as HIV and other retroviruses exploit other cell processes for their own ends, it now appears they rely on exosomes to get out of infected cells and infect fresh cells.
Dr. Gould's group speculates that drugs interfering with exosome formation might be another way to treat HIV disease.
"Viruses like HIV use pathways we barely recognize, much less understand," Dr. Gould says. "Our paper highlights the importance of studying their basic biochemistry and cell biology, which can yield a better understanding of normal human biology as well as identify new avenues in the fight against human disease."
Source:
Fang Y, Wu N, Yan W, et al. Higher-order oligomerization targets plasma membrane proteins and HIV Gag to exposomes. PLoS Biol 5(6):e158. Accessed June 6, 2007 at: PLoS Biology.
