RNA viruses sneak into host DNA

Endogenous retroviruses, ancient viruses embedded throughout mammalian genomes, might help RNA viruses permanently integrate into the genomes of their hosts, according to a report in linkurl:__Science__;http://www.sciencemag.org/ this week. The findings overturn the long-held idea that most types of RNA viruses are incapable of DNA integration and raise another safety concern in the use of RNA-based gene therapy. "It's a very interesting paper," said Jens Mayer from the University of Saarland, who was not involved in the research, adding that it "touches a number of fields." linkurl:Lars Hangartner;http://www.virology.uzh.ch/research/hangartnerGroupENid_en.html from the University of Zurich started his investigation with a 1997 paper, in which colleague linkurl:Paul Klenerman,;http://www.jenner.ac.uk/invest_biog_p_klenerman.html then at the University Hospital Zurich, noticed that a small fraction of mouse cells contained DNA that was complementary to a mouse RNA virus. That study reported that the RNA virus called lymphocytic choriomeningitis virus (LCMV) had somehow integrated into the mouse genome -- surprising because with the exception of retroviruses like HIV, RNA viruses are not thought to integrate in host DNA. That's one of the reasons that RNA viruses have been attractive candidates for gene therapy and vaccines: no risk of permanent integration. The cells that had this DNA insertion were so rare, however, only occurring once every 1,000 or 10,000 cells, that the group thought it would be impossible to test the phenomenon. "We thought we will never find the mechanism," said Hangartner. During a short break from his own PhD project, Hangartner decided to pick up the problem and see if he could make any headway. After four months of work, he had created two cell lines which contained DNA copies of the RNA mouse virus. He amplified the inserted sequences for traces of genetic material that would suggest how the RNA integrated. He suspected that the LCMV might be interacting with mouse endogenous retroviruses. Endogenous retroviruses are ancient pieces of viral DNA embedded throughout mammalian genome. Thought to be relatively inert, they are not infectious, because they lack the full complement of viral genes. They do, however, contain reverse transcriptase, the enzyme required for turning RNA into DNA, a critical step for inserting RNA into the genome. "If it walks like a duck and talks like a duck maybe it is one," said Hangartner. Indeed, the DNA of his cell lines contained traces of one of the common endogenous retroviruses in mice called the Intracisternal A-type particle (IAP). Hangartner and colleagues, including co-PI Nobel Prize winner Rolf Zinkernagel, wanted to confirm that IAP was indeed necessary for LCMV integration. They took a plasmid that contained the IAP element and cultured it with a cell type that didn't normally contain IAPs. They then infected the cells with with the LCMV, and tested for conversion to DNA and subsequent integration. With IAP particles present, the RNA viruses integrated into the genomic DNA. "I think this paper opens up avenues for new investigation," said John Goodier, a geneticist at the University of Pennsylvania. "This is another example of things people will have to consider when working with RNA molecules," said Mayer. He noted that it remains to be seen whether this is a mechanism that is prevalent throughout human and viral evolution or one that is specific to this system. "We have entered a big dark room and only have a small spotlight at this point. We don't know the whole surroundings of the findings just yet," said Hangartner.
**__Related stories:__***linkurl:Researchers find no clear path on road to unraveling schizophrenia;http://www.the-scientist.com/article/display/13097/
[10th June 2002]*linkurl:Gene therapy's fall and rise (again);http://www.the-scientist.com/article/display/14947/
[27th September 2004]

RNA viruses sneak into host DNA

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