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Looking At How HIV Spreads Rather Than How It Grows

This year, as many as a sixth of Americans newly infected with HIV will acquire a strain of the virus that is resistant to existing drugs, and that proportion continues to grow.

Researchers are constantly looking for new ways to attack the virus. Wesley. I Sundquist and colleagues at the University of Utah School of Medicine report in today's issue of the journal Cell about one new approach that could well bear fruit.

Rather than focusing on the way HIV multiplies, Sundquist's team looked at the way it spreads from cell to cell within the body.

HIV reproduces itself within a cell, and then new viruses bud off from the surface of that cell to go and infect others. Formation of virus particles requires transport of specific viral proteins to the cell surface, where they act in budding and are incorporated into the virus particles. One such viral protein is called Group specific antigen, or Gag.

Based on previous research, Sundquist and colleagues reasoned that Gag likely acts by hijacking normal cellular proteins to help it function. They looked for proteins able to bind to the p6 domain of the HIV-1 Gag protein, focusing on this region because point mutations in it are known to stop HIV-1 from spreading.

One of the proteins they found was Tsg101, so called because it was originally identified as a tumor susceptibility gene. In further tests, the team found that the virus could not spread among cells in which Tsg101 is depleted: Instead of budding off from infected cells, viral particles collected in tails that branched off within the cell membrane.

Along with another protein called Vacuolar protein sorting 4 (Vps4), Tsg101 is part of the normal cellular machinery that targets proteins to an intracellular organelle called the multivesicular body. Like the virus particles, this forms by a budding process.

Further tests on cells with a mutation in Vps4 showed that it and another protein required for targeting to the multivesicular body were both vital for the budding of viral particles.

Overall, therefore, this study tells us that budding of HIV virus particles involves a process similar to multivesicular body formation.

By coincidence, another paper from Scott Emr and colleagues published in the July 27th issue of Cell provides important information about how this pathway normally works in cells, giving us even more insight into the biology of HIV.

“This is a reasonable new approach for therapeutics,” says Sundquist, “although it's not clear how much you could inhibit Tsg101 in an adult human.”

He now hopes to elucidate the whole pathway involving Vps4, where there could be other therapeutic targets. If either Tsg101 or the Vps pathway can be inhibited in patients without too many side effects, HIV could be marooned in the cells it has already infected, but unable to spread to others. That would probably leave the HIV infection unable to progress to full-blown AIDS.

[Contact: Wesley. I Sundquist]

06-Oct-2001

 

 

 

 

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