LA JOLLA, CALIF. - HIV selectively inserts itself into active areas of a host cell's genome, Salk Institute researchers have found for the first time. The fact that the virus hooks itself up to areas of the cell's genome that are busy expressing themselves may help explain why HIV can replicate, or reproduce itself, so rapidly. The findings are being published as the cover article in the Friday, August 23, issue of the journal Cell. "HIV seems to be targeting not just genes, but active genes," said Salk researcher Frederic Bushman, a specialist in infectious diseases who headed the research team. "That makes a lot of biological sense if the targeting has evolved to promote efficient expression of the viral genome once it integrates into the cell."
The findings may have implications for developing more effective gene therapies, said Bushman, Associate Professor in the Infectious Disease Laboratory. Gene therapy involves treating genetic disorders by using a mutated retrovirus to insert a new gene into a defective genome. Gene therapy could be made safer and more effective by knowing more about and taking advantage of a retrovirus's targeting specificity, he said.
Retroviruses like HIV reproduce themselves by infecting a cell, making a DNA copy of the virus's RNA genome, and integrating that DNA copy into a chromosome of the host. When the genome of the host is "read" to produce proteins and gene products, so is the genome of the virus-which reproduces itself. The question Bushman and his team sought to answer was, where in the human chromosome does the virus integrate itself?
The team took advantage of the recently published human genome sequence. The researchers infected human cells in tissue culture with the HIV virus, and then broke open the cells and sequenced pieces of DNA to find out where the viral DNA ended up. By matching DNA segments with the published human genome sequence, they found that that the viral DNA mostly ended up in areas of the chromosomes where there are human genes, rather than places in between.
The researchers then asked, "What is it about these genes? Are they active genes, or is it something else about being a gene that's good?" Using another new technology, gene chips that help screen for products made by active genes, the researchers found that the genes that were targeted were disproportionately active ones.
In fact, Bushman said, the genes that are targeted are specifically ones that are turned on by infection with HIV itself. When the virus enters a cell, it triggers a response by the cell that includes making new proteins in response to the infection. So in essence, the HIV virus wields a double-edged sword, creating a weakness and then taking advantage of it.
Most HIV-infected cells die relatively quickly, within a day or two, Bushman said, so it's to the virus's advantage to be able to reproduce quickly. "Viruses that integrate into different points of the human genome inside a cell replicate with very different efficiencies," Bushman said. "There are bad places to be, where it's hard to express your genome, and there are other places where you can express very efficiently." HIV, it appears, is extremely efficient.
HIV differs from other types of genomic pathogens, Bushman said, that have evolved to live with their host on a long-term basis. These may target relatively benign regions of the genome where they don't hurt the host, and they reproduce because the cells continue to live, grow and divide, reproducing the pathogen as the cell itself reproduces.
"Not so with HIV," Bushman said. "HIV has aggressive targeting. That targeting is damaging to the host, but for an aggressive parasite in a cell that's only going to live for a day or so, it makes a sensible evolutionary strategy."
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