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UNC-Led Team Exposes HIV Genome Structure

NEW YORK (GenomeWeb News) – In a paper appearing online today in Nature, an American research team described the full genome structure of HIV-1 for the first time.

The researchers used a high-throughput method called "selective 2'-hydroxyl acylation analyzed by primer extension" (SHAPE) to glean structural information for nearly every nucleotide in the HIV-1 genome. The team also started identifying structural patterns that may offer clues about the virus' function and potential vulnerabilities — including an apparent link between RNA and protein structure.

"There are a lot of structures in the HIV genome," senior author Kevin Weeks, a chemist at the University of North Carolina, told GenomeWeb Daily News. "What we discovered is that there's a very strong correlation between the structure of RNA and the structure of a protein."

The HIV-1 genome is comprised of roughly 10,000 bases of RNA arranged in nine open reading frames coding for 15 proteins. Some 15 percent of HIV's genome structure had been cobbled together from structural predictions and a few NMR and crystallography studies, Weeks explained. But RNA structural analysis is challenging, he added, and many thought that the benefits of discerning the entire HIV genome structure were outweighed by the effort required to accomplish this feat.

In an effort to simplify the structural analysis of HIV-1, Weeks and his co-workers applied an approach called SHAPE, which exploits the 2' hydroxyl group that distinguishes RNA from DNA using a chemical reaction that occurs at each nucleotide.

RNA bases that are involved in structures are not reactive, Weeks explained, while those that are not are free to react. By doing primer extension experiments, the researchers can then figure out which 2'-hydroxyl groups have reacted.

Earlier this year, the team published a paper in the Proceedings of the National Academy of Sciences outlining a computational approach for translating the chemical reaction patterns into RNA secondary structure.

When the team applied the SHAPE method to HIV-1, they found that they could get information for more than 99 percent of the 9,173 nucleotides in the virus' genome.

Their results suggest that the HIV-1 genome contains many structural patterns, Weeks said, representing regions of high and low structure. At least ten structured and seven unstructured regions popped out of their analysis.

When they looked more closely at the connection between RNA and protein structure, the researchers found that highly structured RNA often occurred in and around sites coding for parts of proteins with unstructured loops and protein junctions.

The team speculated that this relationship could contribute to ribosome function. By prompting ribosomes to move more slowly over highly structured RNA, Weeks explained, the RNA structure might create something akin to ribosome pause sites. That, in turn, suggests that both RNA sequence and structure help to guide protein development.

"It kind of means that the instructions in RNA for making proteins occur at two levels," Weeks said.

So far, though, the researchers have only looked at one HIV-1 strain, Weeks cautioned. In the future, they plan to look at additional HIV genomes as well as the genomes of other RNA viruses. By uncovering viral genome structures, the team hopes to not only gain insights into RNA virus biology but clues about parts of the genome that could make good targets for new antivirals.

"The extraordinary density of information encoded in the structure of large RNA molecular represents another level of the genetic code, one which we understand the least at present," Weeks and his co-authors concluded. "This work makes clear that there is much to be discovered by broad structural analyses of RNA genomes and intact mRNAs."

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