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Discovery of an HIV inhibitor in human blood points to new drug class

A new study has pinpointed a natural ingredient of human blood that effectively blocks HIV-1, the virus predominantly responsible for human AIDS, from infecting immune cells and multiplying. The virus blocker might play a role in the progression of HIV to full-blown AIDS and—because it works in a different way than existing antiretroviral inhibitors—could lead to the development of another class of drugs in the fight against the pandemic disease, researchers reported in the April 20, 2007 issue of the journal Cell, a publication of Cell Press.

The research team found that fragments of a relatively abundant blood molecule, which they call VIRUS-INHIBITORY PEPTIDE, or VIRIP, acts as a broad-based inhibitor of HIV-1. Moreover, they showed that a few amino acid changes in the fragment enhanced its antiretroviral potency by two orders of magnitude. VIRIP and its derivatives remained effective against drug-resistant HIV strains, making them "highly promising for further clinical development," according to the researchers.

"The findings reveal a new target for inhibiting HIV that remains fully active against viral strains that are resistant to other drugs," said study author Frank Kirchhoff of the University of Ulm in Germany. "That's a big advantage."

Kirchhoff's group also provided evidence that HIV-1 does not easily develop resistance to VIRIP, at least in cell culture. Furthermore, their collaborators led by Wolf-Georg Forssmann of IPF PharmaCeuticals GmbH and Hannover Medical School found preliminary evidence showing that some derivatives of the peptide are highly stable in human blood plasma and are nontoxic even at exceedingly high concentrations.

According to the latest World Health Organization estimates, nearly 40 million people worldwide are living with HIV/AIDS, including more than 2 million children. Close to 4 million people became infected with HIV in 2006, and the virus was responsible for about 3 million deaths last yea r alone.

A variety of molecules in human blood have been implicated in the inhibition of HIV-1, the researchers noted. However, it had remained elusive which circulating natural compounds are most effective in controlling viral replication in the body.

In the new study, the researchers sifted through a comprehensive library of small peptides that had been filtered from the blood of patients with chronic kidney failure during dialysis, in search of those with anti-HIV activity. After sorting the more than one million blood peptides into 300 fractions, they focused on one that blocked HIV without toxic effects on cells.

Further examination revealed VIRIP as the active ingredient. A synthetic version of the peptide maintained its anti-HIV activity, excluding the possibility that some other factor was responsible.

VIRIP specifically targets a conserved region in the HIV-1 transmembrane glycoprotein known as "gp41 fusion peptide." This peptide, which is normally buried in the viral envelope, becomes exposed during the process of viral entry and makes the first direct contact between the viral particle and host cell.

Thus, they showed, VIRIP plays an essential role in the ability of HIV to fuse with and infect its host's immune cells. That unique underlying mechanism allowed the inhibitor to remain effective against viral strains that are resistant to other antiretroviral drugs, they found.

"Our data support the possibility that VIRIP may contribute to controlling HIV-1 replication in infected individuals and that derivates thereof are highly suitable for development of a new class of HIV-1 inhibitors targeting the highly conserved gp41 fusion protein," the researchers concluded.

There are now some 20 different HIV drugs in use, Kirchhoff said. However, the treatments all fall into one of four categories based on their modes of action, and a growing number of HIV strains are becoming drug resistant.

HIV resistance to one drug can lead to resistance to other drugs in the same class, a phenomenon known as crossresistance.

"You want a lot of drug classes because multi-drug resistant viruses are starting to show up more and more," Kirchhoff said. "In at least some industrialized countries, it is already a severe problem."


Source:Cell Press

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