U.S.
researchers using a new genetic screening toll report identified 273 new human
proteins that, if blocked, keep the AIDS virus from multiplying and spreading
through the human body.
HIV
requires more than 250 proteins in the human host cell to complete its lifecycle,
and any of these may represent possible targets for antiretroviral
therapy, according to a study published in the January 10, 2008 advance online
edition of Science magazine.
Stephen
Elledge and colleagues at Harvard Medical School performed a genome-wide scan,
or large-scale screen using thousands of short interfering RNA (siRNA) sequences,
to identify human host factors required for HIV-1 replication; siRNAs are bits
of genetic material that block production of a single protein.
The researchers
then introduced HIV to some 21,000 human cell samples, each with a specific blocked
protein, to see whether the virus could still enter the cells and produce new
viral particles.
On the basis of failed virus replication, they identified
273 proteins they dubbed "HIV-dependency factors," or HDFs. Only a fraction
-- 36 proteins -- had a previously recognized role in HIV replication, including
the CCR5 and CXCR4 co-receptors.
Identified proteins with previously unknown
roles in relation to HIV include:
•
Retrograde Golgi transport proteins (Rab6 and Vps53) play
a role in viral entry;
•
A karyopherin called TNPO3 is involved in viral integration;
•
The mediator complex (Med28) plays a role in viral transcription.
"These
proteins participate in a broad array of cellular functions and implicate new
pathways in the viral life cycle," the researchers wrote.
The
added that transcriptional analysis revealed that HDF genes had higher levels
of expression in immune cells, suggesting that HIV and other viruses evolve in
specific host cells that "optimally perform the functions required for their
lifecycle."
"This effort illustrates the power with which RNA
interference and forward genetics can be used to expose the dependencies of human
pathogens such as HIV, and in so doing identify potential targets for therapy,"
the authors concluded. Targeting essential human proteins makes it more difficult
or impossible for HIV to develop resistance, but may also interfere with normal
cell function.
"It
remains to be seen if any of these proteins they identified are useful clinically,"
National Institute of Allergy and Infectious Disease director Anthony Fauci told
The New York Times, noting that researchers must still conduct laborious
studies of each potential target. "This [research] is hypothesis-generating,
not hypothesis-solving."
Department of Genetics, Center for Genetics
and Genomics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard
Medical School, Boston, MA; Gastrointestinal Unit, Massachusetts General Hospital,
Harvard Medical School, Boston, MA.
01/15/08
Sources
AL
Brass, DM Dykxhoorn, Y Benita, and others. Identification of Host Proteins Required
for HIV Infection Through a Functional Genomic Screen. Science. January
10, 2008 [Epub ahead of print].
DG McNeil. Study Finds Possible Targets
for AIDS Drugs. The New York Times. January 10, 2008.
