Proteins That Could Be Used to Halt HIV Are Identified

oops1

Proteins That Could Be Used to Halt HIV Are Identified

By David Brown
Washington Post Staff Writer
Friday, January 11, 2008; Page A02

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 Harvard Medical School and the Howard Hughes Medical Institute, was published online yesterday by the journal Science.

\"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.