Study Finds Possible Targets for H.I.V. Drugs
By DONALD G. McNEIL Jr.
NY Times Published: January 11, 2008
Using a new type of genetic screen, researchers at Harvard Medical School have
identified 273 proteins that the AIDS virus needs to survive in human cells,
opening up new potential targets for drugs.
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Searching for Proteins Needed by H.I.V.
Related
Times Health Guide: AIDS
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Identification of Host Proteins Required for HIV Infection Through a Functional
Genomic Screen (Science)
Their work, published online on Thursday by Science magazine, used RNA
interference to screen thousands of protein-making genes; previously,
scientists had identified only 36 human proteins that the virus uses to break
into cells, hijack their machinery and start reproducing.
“This is just terrific work,” said Dr. Robert C. Gallo, director of the
Institute of Human Virology at the University of Maryland and a co-discoverer
of the virus. “I think it’s destined to be one of the top papers in this field
for the decade.”
Dr. Anthony S. Fauci, director of the National Institute of Allergy and
Infectious Diseases and the government’s top AIDS expert, called the Harvard
team’s work “elegant science,” but added a caution.
“It remains to be seen if any of these proteins they identified are useful
clinically,” Dr. Fauci said. “This is hypothesis-generating, not
hypothesis-solving. It creates a lot of work — someone has to go down each of
these pathways.”
The lead author on the paper, Dr. Stephen J. Elledge, is a geneticist, and this
is his first work on the human immunodeficiency virus, which causes AIDS. His
previous work has been on cancer, Dr. Elledge said, trying to figure out how
cells sense when their chromosomes are broken, and this paper was a
collaborative effort.
“I can’t even grow H.I.V. in my lab,” Dr. Elledge said, so he had to use virus
grown by Dr. Judy Lieberman, director of the medical school’s AIDS division and
one of the co-authors.
Dr. Elledge’s team used a library of tens of thousands of different short
interfering RNAs, bits of genetic code — each of which, when introduced into a
cell, knocks out the cell’s ability to make a single protein.
Next, about 21,000 samples of cells, each crippled in its ability to produce
one protein, were placed in separate wells on laboratory plates and dosed with
the virus.
If the virus could not reproduce normally in a given well, it suggested that
the missing protein was one of those it needed.
Of the 273 human proteins identified, only 36 had been previously found by
other methods.
The virus, which is itself only a short string of genetic material inside a
protective capsule, can make only 15 proteins, so it has to adopt human
proteins to its own use.
The advantage of targeting human proteins is that the virus would presumably
not be able to mutate to avoid drugs that block them, Dr. Elledge said. Right
now, virus strains evolve resistance to antiretroviral drugs, which attack the
15 proteins made by the virus itself, like reverse transcriptase and protease.
The mutations force AIDS patients to switch drug regimens — not always
successfully.
The disadvantage is that blocking human proteins can, obviously, be fatal to
humans. But, as Dr. Gallo pointed out, cancer therapy works that way — doctors
try to block proteins that feed fast-growing tumor cells without killing too
many other fast-growing cells, like those in the bone marrow.
Right now, Dr. Elledge said, only one drug that targets one of the known human
proteins, a receptor called CCR5, has been developed, and it has just won
approval.
The new screening technology, known as siRNA, is now used in many laboratories,
so this work could theoretically have been done elsewhere, or by using older,
more laborious methods.
Dr. Elledge said he benefited from working at Harvard, which could afford the
expensive robotics and imaging technology needed.
“And I had lots of collaborators and very dedicated people,” he said.
To confirm that the newly identified proteins were important to the life cycle
of the virus — which Dr. Elledge described as “opaque” — the team ran further
tests on three of them.
Many of the proteins identified by the screen are already known to be important
to cells in the immune system, which is the port of entry for H.I.V.
Dr. Abraham L. Brass, a co-author, said the screening method undoubtedly missed
other proteins the virus needs, “but the majority of the ones we found are
highly likely to play a role in H.I.V. propagation.”
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