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University of North Carolina researchers decode the structure of an entire HIV genome
08-24-2009
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CHAPEL HILL, N.C.—Viruses have always been a challenge for
pharmaceutical therapies, but HIV has been one of the more frustrating entities
against which researchers pit themselves—given that therapies quickly fall prey
to mutations giving rise to resistant strains of HIV, meaning that even
multi-drug cocktails fail to truly wipe out the infection.
So, the news coming out of the University of North Carolina
at Chapel Hill in early August that researchers have, for the first time,
decoded the structure of an entire HIV genome comes as welcome news to
researchers. It means that they may soon understand better the strategies that
HIV uses to infect humans and cause AIDS, may better understand other viruses'
tricks as well, and will be better equipped to come up with groundbreaking
therapies to use against them.
The HIV genome work, reported in the cover story of the Aug.
6 issue of the journal Nature, began
with work by Dr. Kevin Weeks and other chemists at UNC, whose lab focuses on
the chemical and structural biology of RNA. According to Weeks, he and his
colleagues thought that technologies created in their lab could help the HIV
research community. So, they worked out a plan to collaborate with UNC
virologists and the National Cancer Institute (NCI) and began study to solve
the structure of an entire HIV-1 genome.
The new results show that the HIV RNA genome contains
numerous RNA structures that influence how HIV proteins are made and how the
virus hides from the body's defenses. Moreover, the HIV genome structure
appears to be so extensive as to constitute "another level of the genetic
code," notes Weeks, a professor of chemistry in UNC's College of Arts and
Sciences and one of the lead authors of the study.
HIV, just like viruses that cause such other serious
diseases as influenza, hepatitis C and polio, carries its genetic information
as single-stranded RNA rather than double-stranded DNA. The information encoded
in RNA is more complex than in DNA, Weeks explains, with RNA able to "fold into
intricate patterns and structures." These structures are created when the
ribbon-like RNA genome folds back on itself to make three-dimensional objects.
Weeks says that prior to this new work, researchers had
modeled only small regions of the HIV RNA genome, in part because the HIV RNA
genome is so large, with two strands of nearly 10,000 nucleotides each.
"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. "We are also beginning to understand tricks the
genome uses to help the virus escape detection by the human host."
Weeks, who is also a member of the UNC Lineberger
Comprehensive Cancer Center, and Joseph M. Watts, a chemistry postdoctoral
fellow supported by the Lineberger Center, used technology developed by Weeks'
lab to analyze the architecture of HIV genomes isolated from infectious
cultures containing trillions of viral particles that were grown by Dr. Robert
Gorelick and Julian Bess of the NCI.
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."
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