Researchers at Johns Hopkins Medical Institutions have discovered that the Human immunodeficiency virus (HIV) exploits a pre-existing transport system to leave one infected cell, and infect new ones.
Published in Plos Biology, the new findings counter the prevailing belief that HIV and other retroviruses can only leave and enter cells by virus-specific mechanisms.
Advertisement"It appears that cells make HIV and other retroviruses by a naturally occurring export mechanism," says Dr. Stephen Gould, Professor of Biological Chemistry at Johns Hopkins.
The researchers say that cells normally export certain membrane-bound molecules to the outside world by means of small sacs known as exosomes. They say that a study of human T-cells under a microscope helped them discover what is 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," says Gould, a researcher.
In one experiment, the researchers added chemicals to normal human cells that force nearby proteins together into a clump, which was enough to get them sent out of the cell in exosomes. When 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 sense in selecting exosomal cargoes.
Upon removal of the tethers or clumping signals from Gag, it could no longer get out of the cell. However, when they were replaced with synthetic membrane anchors and clumping domains, Gag regained its ability to get out of cells in exosomes.
Gould believes that cells might have initially developed exosomes as a quality control mechanism to get rid of clumped proteins, which are generally broken and useless. However, just as 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.
The researchers believe that drugs that interfere with exosome formation might be one way to inhibit HIV infections.
"Viruses like HIV use pathways we barely recognize, much less understand. 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," Gould says.
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