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
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
"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
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
"And I had lots of collaborators and very dedicated people," he
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