|Inside human cells, HIV often resides in active genes|
August 30, 2002
The virus that causes AIDS has preferred places in the human genome where it takes up residence after invading human cells, a new study has found. Researchers mapped the chromosomal locations of so-called insertion sites for hundreds of HIV-infected cells, and most of the sites turned out to be in active genes or specific chromosomal regions.
This preference may help explain why HIV reproduces so efficiently in humans. Once inside a cell, the virus burrows into a host chromosome and makes a copy of its own genome. The viral genome is reproduced as human DNA is transcribed, so active regions may be the ideal place for a virus trying to replicate many times before the cell dies.
"HIV wants to blast out as many copies of itself as it can before the cell is destroyed by the host immune system," says Frederic Bushman of the Salk Institute in La Jolla, California, who led the study. Joseph R. Ecker, also at Salk, provided expertise on the mapping and sequencing aspects of the research.
The prevailing view in the field has been that active genomic regions are not favored as insertion sites by retroviruses, such as HIV. But most of the data on this topic involve relatively small studies, in part because of the time and effort involved in determining the locations of insertion sites.
The new study, published in Cell, is the first to map insertion sites to a complete genome sequence. The researchers infected more than 500 human lymphoid cells with HIV and opened the cells to determine where the virus ended up. The junctures of viral and human DNA were sequenced and mapped to the human genome sequence.
The specificity of the viral targets in the human genome was unexpected. The pathogen integrated most often in genes and seemed to prefer genes that were active, including genes that switch on in response to a viral attack. The list of preferred regions included so-called hotspots, which may contain distinct structural features.
One such hotspot is an unstable stretch of chromosome 11. The region, called 11q13, is often duplicated in tumor cells and has been linked to a number of cancers. No one knows why HIV seems to prefer this hotspot.
In the coming months the Salk team plans to study insertion sites in different cell types and identify commonly targeted regions in order to understand what makes them special. "The importance of this work is that it will help us understand the life cycle of the virus," says Bushman.
He points out that HIV uses and destroys cells in ways that other viruses do not, killing the host cell usually within a day or two. Many viruses, in contrast, insert themselves in genomic regions that do not negatively affect the host cell. They live and reproduce along with their host; killing the host cell would be the equivalent of committing suicide.
HIV insertion sites are a hot topic among researchers in the field. This was demonstrated several months ago when Bushman presented these data at a scientific meeting. "The presentation probably set a record for the number of questions asked by the audience afterward," he recalls.
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