May 7, 2007

Molecule in Human Blood Inhibits HIV

Yellow sphere with small blunt blue spikes spread around its surface Computer model of HIV. Richard Feldmann.

Researchers have found a compound in human blood that effectively blocks HIV-1, the most common strain of the virus that causes AIDS in the U.S., from infecting immune cells and multiplying. With a couple of changes, the researchers were able to significantly increase the compound's potency. Because it works differently than existing HIV inhibitors, this discovery could lead to another class of drugs to fight AIDS.

Acquired immunodeficiency syndrome, or AIDS, was first recognized in 1981 and has since become a major worldwide pandemic. The virus that causes it was discovered in 1983. HIV kills or damages cells in the body's immune system, progressively destroying the body's ability to fight infections and certain cancers. People with AIDS can get life-threatening diseases called opportunistic infections, caused by microbes that usually don't make healthy people sick.

Compounds in human blood were known to inhibit HIV-1 to some extent. However, it has been difficult to purify and characterize compounds from blood to know which are most effective. Dr. Frank Kirchhoff of the University of Ulm in Germany and his colleagues turned to a recently developed technology to systematically screen for compounds in blood that could inhibit HIV-1. Funding for their work came from several organizations, including NIH's National Institute of Allergy and Infectious Diseases (NIAID).

The researchers took advantage of a process called hemofiltration, in which patients who have kidney failure have their blood passed through a set of tubing and filtered. Small protein chains called peptides can be collected from what's filtered out and usually discarded to make a "library" encompassing more than 1 million different peptides from blood. The researchers screened this type of peptide library for factors that block HIV-1 from multiplying in human cells. They published their work in the April 20, 2007, issue of the journal Cell.

The most potent peptide they found was named Virus-Inhibitory Peptide (VIRIP). VIRIP turns out to be a section of a protein produced by the liver called a1-antitrypsin. It's from a class of proteins called serine protease inhibitors. The full protein, the researchers found, didn't inhibit HIV-1 nearly as well as VIRIP.

The researchers chemically synthesized VIRIP and found that it blocked every HIV-1 strain they tested from infecting cells, including those resistant to current AIDS drugs. VIRIP showed little or no potency against several other viruses, including HIV-2.

The researchers next systematically designed and created more than 600 variations of VIRIP and showed that some changes increased its potency against HIV-1 by about 2 orders of magnitude. They also found that, in cells growing in the laboratory, the virus does not easily develop resistance to the peptide.

Experiments showed that VIRIP blocks HIV-1 by interacting with a specific part of a protein called gp41 that the virus needs to enter cells. As this is a different target than existing AIDS medications, this discovery may lead to the development of a new class of AIDS drug.

— by Harrison Wein, Ph.D.

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