×îÐÂÂ鶹ÊÓƵ

Scientists Uncover Structure of HIV Genome

A portion of the HIV-1 genome's secondary structure, including stems and loops in protein-coding regions. Colored dots represent nucleotide building blocks, and different colors correspond to varying degrees of flexibility. Nature and Dr. Kevin Weeks.

Researchers have created the first comprehensive picture of how the entire HIV genome bends and folds. The finding may point to new options for treating or blocking HIV and other viral infections.

Unlike the double-stranded DNA that makes up the genomes of humans and other organisms, many viruses—like those that cause AIDS, rabies and the flu—carry their genetic information in a single strand of RNA. While double-stranded DNA generally forms into the familiar double helix shape, RNA genomes fold themselves into unusual kinks, loops and knots.

Scientists have long known that the folding of viral RNA affects the virus's ability to infect cells, make proteins and replicate. However, the complex structures of RNA genomes have been difficult to analyze with available technologies. Less than 20% of the structure of the HIV genome has been previously characterized, mostly at each end of the RNA strand.

To gain a better understanding of the genome structure of HIV-1, the most common type of HIV worldwide, Dr. Kevin M. Weeks and his colleagues at the University of North Carolina at Chapel Hill developed an automated, high-throughput technique called SHAPE. The new method analyzes chemical reactions along the entire RNA strand to distinguish which regions of the genome are mostly non-reactive and stable, and which are highly reactive. Stable regions correspond to structured stems and other defined shapes. Highly reactive regions indicate flexible, unstructured areas of the genome. Computer analysis then translates these variations into a model of the RNA strand's folded, or "secondary," structure.

Working with scientists at NIH's ×îÐÂÂ鶹ÊÓƵ Cancer Institute (NCI), Weeks and his team used the SHAPE method to analyze the secondary structure of the entire HIV-1 genome. Primary funding for the study came from NIH's ×îÐÂÂ鶹ÊÓƵ Institute of Allergy and Infectious Diseases (NIAID).

The team reported in the August 6, 2009, issue of Nature that the SHAPE method detected more than a dozen previously unrecognized structured and unstructured regions of the HIV-genome. The technique also successfully identified the few already-known structured areas at the ends of the HIV-genome, which regulate viral replication and packaging of viral particles.

The researchers showed that many newly discovered structured RNA regions were associated with regulatory regions of the genome. In addition, they found a correlation between highly structured segments of the genome and looped regions in the viral proteins that are coded by those segments. This finding suggests that the virus's RNA structure affects the way viral proteins are folded during formation inside host cells.

The scientists say these new discoveries can serve as starting points for additional investigations into the genomes of RNA viruses. "There is so much structure in the HIV RNA genome that it almost certainly plays a previously unappreciated role in the expression of the genetic code," Weeks says.

—by Vicki Contie