HIV, the virus that causes AIDS, depends on more than 250 human genes to grow, a finding that reveals the lethal virus's weakness and may lead to new ways to attack it, scientists said.
By blocking genes in infected cells, scientists tied the virus's survival to processes of protein transport, entry to the nucleus, and cellular self-destruction, Harvard University scientists said in a study released Thursday by the journal Science.
With just nine genes that make 15 proteins, HIV must assume control of the protein-making machinery of infected cells to reproduce itself. Drugs that stop cells from cooperating with the lethal virus might be valuable alternatives to those that attack the ever-changing virus directly, said David Baltimore, a California Institute of Technology biologist and HIV researcher.
"This provides a very important class of leads for the synthesis of new drugs that can prevent HIV growth," said Baltimore, who wasn't involved in the study. "The nice thing is that these cellular targets mutate at a much slower rate than viral targets, so resistance is less likely to arise."
HIV attaches itself to proteins on the surfaces of immune cells, enters them, and hijacks their protein-making machinery to produce more viruses. In the process, it destroys the body's defenses, leaving patients vulnerable to infections, such a tuberculosis and cancer.
To be successful, it must commandeer the services of a wide variety of cellular genes, said Stephen Elledge, a Harvard Medical School geneticist who helped write the study.
"It's as if a small terrorist group attacks a town with a tank, and then converts the town into a tank factory," Elledge said in a telephone interview. "They would have to take over the existing infrastructure to get these things replicated."
He and Abraham Brass, another Harvard geneticist, used gene-blocking technology called RNA interference to see which cellular functions are most important in the viral attack. After screening about 21,000 genes this way, the researchers found clues as to how the virus takes over transport within the cell and gains entry to the DNA stronghold in the nucleus.
The virus also requires the services of genes that make a variety of proteins on the cell surface that weren't known to be involved in infection, Elledge said. Genes involved in a cellular self-disposal process, called autophagy, were also used by HIV. Blocking or inhibiting any of these may offer better ways to treat the disease.
While some of these genes and proteins may be too important to cell survival to be blocked or altered, others may be targets for drugs, researchers said.
"It's an open book," said Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, in a telephone interview. "We need to methodically go down each and every one of them and track down how they're involved."
HIV infects about 33.2 million people worldwide, according to the World Health Organization in Geneva, including about 1 million in the U.S. There is no vaccine against HIV, which mutates constantly to evade drugs, keeping researchers on a constant quest for new treatments.
Two drugs that attack the virus in previously unseen ways, Pfizer Inc.'s Selzentry and Merck & Co.'s Isentress, gained market clearance last year, while Panacos Pharmaceuticals Inc. is developing drugs that work by yet another mechanism. These new medications can save the lives of patients who no longer respond to existing treatments.
The study was supported by the Howard Hughes Medical Institute, the U.S. National Institutes of Health, and the Crohns and Colitis Foundation.