Proteins That Could Be
Used to Halt HIV Are Identified
A research team announced yesterday that it
has identified about 270 human proteins that the AIDS virus apparently needs to
infect a person, instantly providing researchers with dozens of new strategies
for blocking or aborting HIV infection.
The vast majority -- more than 200 -- were
not previously known to play a role in the complicated choreography by which
the virus attaches to a cell, enters it, gets copied and establishes permanent
residence.
The discovery was made with a technique
called a "genome-wide scan," which is only a few years old. Current
AIDS drugs work by interrupting one of four main steps in HIV's life cycle. The
new study suggests that there are many more to target.
"This is likely destined to be one of
the best papers on HIV for this coming decade," said Robert C. Gallo,
co-discoverer of the AIDS virus, who was not involved in the study. "I
think it is terrific."
Anthony S. Fauci,
an AIDS researcher and director of the National Institute of Allergy and
Infectious Diseases, said the study "puts on the table many, many more
processes that up to this point were unrecognized." He added quickly:
"Now they have their work ahead of them."
The research, led by Stephen J. Elledge of
"We hope this leads to an acceleration
of research for cures for AIDS," Elledge said.
"It seems like people are starting to forget about AIDS. It is still an
incredibly important human health problem."
The genome-wide scan is not the last word on
what HIV needs to infect and destroy human cells, but it is a much more
comprehensive inventory than has existed before.
"We'll miss a few things, but the
remarkable thing is how much we did find," Elledge
said.
Like all viruses, HIV is incapable of
growing and doing damage on its own. For that, it must first enter a living
cell and hijack some of the molecular and chemical machinery inside. The virus
takes specific enzymes, structures and pieces of membrane that the cell uses
and turns them to its own purposes. Those include making new copies of itself, bursting out of the cell to infect more cells and,
in the case of HIV, not killing some but, instead, stitching its own genes into
them.
Seeking to discover all the proteins HIV
employs to complete these tasks, Elledge and his
co-workers scanned all 21,000 human genes that encode proteins, blocking them
one at a time and seeing what effect that had on the virus's ability to infect
a cell. They found 273 proteins that the virus seemed to need.
Of that number, 36 had been previously
identified. Those proteins include such long-known and well-studied proteins as
the CD4 and CCR5 receptors that HIV uses to attach to a cell's surface.
But the researchers also found 237 proteins that
had not been known to be necessary for HIV to attack,
grow and destroy cells. While not every protein will turn out to be absolutely
essential to the virus, most appear to be.
Some proteins are active in steps of HIV's
life cycle already targeted by AIDS drugs.
For example, the researchers found a group
of proteins involved in letting HIV enter the cell. "Entry
inhibitors" are a relatively new class of medications; the first was
approved for use in 2003.
The researchers also found proteins involved
in helping the virus's long strand of genetic material, called RNA, attach
itself to the cellular structure that then copies it. The oldest AIDS drugs,
such as AZT, block a stage of this copying process. But the Harvard team found
proteins involved in stages not blocked by those drugs but that might
theoretically be blocked by future compounds.
The scientists also identified proteins at
work in deeper, more mysterious phases of HIV's sojourn in the human cell.
Until now, such proteins have been off the pharmaceutical radar screen.
One group is involved in helping the virus
get through windows of the cell's nucleus, where the gene-encoding DNA resides.
Once HIV gets there, it integrates its genes into the human host's -- ensuring
the virus's permanence.
Another group of proteins is involved in
studding the outer surface of a newly minted virus with sugar molecules, a
process called "glycosylation." Without
those sugars, HIV cannot infect a human cell. A drug blocking glycosylation could theoretically make AIDS viruses
impotent.
"We found a large number of proteins
that were involved in shuttling the virus around the cell," Elledge said. Although they appear necessary for HIV's
survival, precisely what they do that the virus needs is unknown.
The new study also shed light on why HIV
causes a disease of the immune system.
One-third of the genes identified by Elledge's team are highly active in cells of the immune system
-- much more active than in other organs and tissues.
HIV homes in on immune system cells because
they offer what it needs.
The study is another example of the
potential payoff of the Human Genome Project, the international effort to
identify and record the entire human genetic message. This job was largely
finished in 2003 and has been refined since then.
The project identified about 21,000 genes
and allowed commercial companies to produce "small interfering RNAs," which can selectively block the action of one
gene at a time. Scientists are using them to understand, among other things,
what genes are involved in disease processes.
Gallo, who is director of the Institute of
Human Virology in Baltimore, called the Harvard research "simply an
elegant combination of modern molecular biology, new technology and
bioinformatics that was used in a manner that has truly led somewhere."
Fauci, whose National Institutes of Health-affiliated
laboratory also studies HIV's interaction with cells, said he is impressed by
the strategy of selectively inhibiting cellular processes and then watching to
see the effects.
"There is nothing that is completely
new under the sun, but that is relatively novel," he said.