Scientists Discover Enzyme Crucial to HIV Replication
Scientists have discovered that a cellular enzyme helps ferry
HIV genetic instructions out of the cell nucleus where they can
then be translated into proteins to begin their most destructive
work. The cellular enzyme represents a potential new target for
developing improved HIV drugs, say the researchers from the National
Institute of Allergy and Infectious Diseases (NIAID), part of the
National Institutes of Health, and the McGill University AIDS Center.
Kuan-Teh Jeang, M.D., Ph.D., of NIAID led the research team reporting their discovery
in the Oct. 29 issue of Cell.
“This finding provides new insights into a crucial step in HIV replication,” says
Anthony S. Fauci, M.D., director of NIAID. “The discovery also provides
an attractive target for drug development which, if successful, might in time
give us a completely new type of HIV drug that circumvents the problem of drug
Dr. Jeang’s team found evidence that the virus co-opts an enzyme produced
by human cells to transport HIV’s genetic material out of the cell nucleus.
Once out of the nucleus, these messenger RNAs begin directing the cell to create
and assemble new virus particles.
The process of how HIV genetic material a long unedited strand of
the cell nucleus has long puzzled scientists. Human cells cut, edit and splice
RNA before it can leave the nucleus, but somehow HIV subverts that process and
exports from the nucleus the long version of RNA that encodes instructions for
making new viral particles.
Scientists knew that HIV makes a protein called Rev to help skirt the prohibition
on transporting the lengthy, unedited version of RNA from the nucleus. They also
knew that HIV commandeers a human protein known as CRM1 to aid in this process.
Rev and CRM1 together, however, are insufficient to explain how HIV flouts the
molecular machinery that cuts and splices RNA before it leaves the nucleus.
“Unspliced RNA is like an unwieldy ball of yarn,” explains Dr. Jeang. “We
found that the virus also uses a human enzyme known as DDX3 to straighten its
RNA before threading it through a small pore in the nucleus.” The team’s
experiments offer the first evidence that HIV uses DDX3 in the complex process
that moves its RNA out of the nucleus. They also demonstrated that DDX3, a human
RNA helicase enzyme, is essential to this process. RNA helicases are enzymes
that untwist RNA molecules.
The researchers now plan to look for inhibitors, small molecules that could either
lock or gum up DDX3’s ability to straighten a twisted strand of RNA. Although
it would take many years to develop, in the best scenario, an inhibitor for DDX3
could effectively block HIV replication. Researchers would need to find a balance
between a potential inhibitor’s action in shutting down viral replication
and any detriment it might cause to human cells.
In the past decade, two classes of HIV inhibitor drugs, protease inhibitors and
reverse transcriptase inhibitors, have greatly extended the lives of HIV-positive
individuals. While these drugs target HIV enzymes, a DDX3 inhibitor would target
a cellular enzyme. The researchers see a great therapeutic advantage to blocking
a cellular enzyme rather than a viral enzyme.
“Unlike viral enzymes, cellular enzymes can not mutate to escape from drugs,” says
Dr. Jeang. The problem of drug resistance that occurs with protease and reverse
transcriptase inhibitors might thus be eliminated with a successful DDX3 inhibitor.
NIAID is a component of the National Institutes of Health, an agency of the U.S.
Department of Health and Human Services. NIAID supports basic and applied research
to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other
sexually transmitted infections, influenza, tuberculosis, malaria and illness
from potential agents of bioterrorism. NIAID also supports research on transplantation
and immune-related illnesses, including autoimmune disorders, asthma and allergies.
News releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at http://www.niaid.nih.gov.
Reference: VSRK Yedavalli et al. Requirement of DDX3 dead box RNA
helicase for HIV-1 Rev-RRE export function. Cell 119:381-92 (2004).