They then teamed up with UNC researchers in the College and the School of Medicine for further analysis: Christopher Leonard in the Department of Chemistry; Dr. Kristen Dang from the Department of Biomedical Engineering; Dr. Ron Swanstrom, a professor of microbiology and immunology at UNC Lineberger; and Dr. Christina Burch, an associate professor of biology. They found that the RNA structures influence multiple steps in the HIV infectivity cycle.  

 

Swanstrom and Weeks note that the study is the key to unlocking additional roles of RNA genomes that are important to the lifecycle of these viruses in future investigations.

 

"One approach is to change the RNA sequence and see if the virus notices," says Swanstrom, who is also director of the UNC Center for AIDS Research. "If it doesn't grow as well when you disrupt the virus with mutations, then you know you've mutated or affected something that was important to the virus."  

 

In a comment about the UNC study in Nature, Hashim M. Al-Hashimi of the Department of Chemistry and Biophysics at the University of Michigan in Ann Arbor, Mich., notes that the approach of the UNC team was unique because so many researchers zoom in on "stems and loops" in viral genomes that contain motifs to direct various steps of viral replication so that they can better understand their function. The UNC team instead "zoomed out."

 

Watts, Weeks and the other researchers used instead a technique called SHAPE (selective 2ʹ-hydroxyl acylation analyzed by primer extension) that provides images of lower resolution than those traditionally obtained by NMR spectroscopy and X-ray crystallography. But as Al-Hashimi points out, this bird's eye-style view "span a much larger area of the genome. The technique is thus akin to zooming out on a map and getting a broader view of the landscape at the expense of fine details."

 

"SHAPE may be generally useful for identifying new regulatory elements in large RNAs. All of these elements represent hypotheses and starting points that we hope will stimulate further detailed examination," the UNC researchers explain in their Nature article. Structural biologists will be able to use this kind of genomic map to "judiciously" zoom in on pieces of the HIV-1 genome in order to determine architectural and functional principles at the atomic level, Al-Hashimi indicates.

 

"Bridging these disparate RNA structure-function scales as well as moving towards movies of the genome in functional motion will be challenges for the future," he writes. "But for now, it seems that the quest for a high-resolution structure of the entire HIV-1 RNA genome has begun in earnest."