Discovery of an HIV inhibitor in human blood points to new type of fusion inhibitor

Keith Alcorn
Published: 20 April 2007


Münch J et al. Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 129: 263-275, 2007. DOI 10.1016/j.cell.2007.02.042

German scientists have discovered a protein in human blood that can block HIV entry into immune system cells, potentially offering a new type of HIV fusion inhibitor that is non-toxic even at high concentrations. The findings are published in the April 20th, 2007 issue of the journal Cell.

The protein, named Virus Inhibitor Peptide, or VIRIP, is a fragment of a naturally occurring serine protease inhibitor whose main function is to protect the lungs against damage from neutrophils.

"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.

It was identified after 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; while the whole serine protease inhibitor reduced HIV infection of cells by around 70%, VIRIP reduced infection by 99%. 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 an HIV-1 envelope protein 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.

VIRIP was effective in the test tube in preventing HIV infection of CD4 cells regardless of whether they were CCR5 or CXCR4-tropic, and also effective across many HIV-1 subtypes.

Further investigation of the 20-residue sequence and synthetic derivatives showed that two substitutions, or changes, within the chemical sequence enhanced the antiviral effect of VIRIP approximately 100-fold, showing equivalent potency to enfuvirtide in blocking HIV infection. (Enfuvirtide, or T-20, is the only licensed fusion inhibitor).

The modified forms were equally active against all drug-resistant viruses tested, including those showing resistance to enfuvirtide. In lymphoid tissue explants derived from human tonsils VIRIP constructs blocked HIV replication at much lower concentrations than enfuvirtide (100nM vs 1µM for enfuvirtide), suggesting the potential for greater viral suppression in the site of greatest viral replication, the lymph nodes.

Serial passaging of various HIV isolates in the presence of VIRIP showed no emergence of resistance mutations after two months, in contrast to the rapid emergence of enfuvirtide resistance. The authors found that while mutations conferring resistance to T-20 were relatively well-tolerated by the virus, mutations in the region of gp41 targeted by VIRIP "showed grossly impaired infectivity,” or else did not result in resistance.

VIRIP, the investigators conclude, is a promising fusion inhibitor candidate. It is being developed by IPF PharmaCeuticals GmbH, a German company.

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