A new paper published in the journal Cell indicates that researchers have isolated yet another natural ingredient in human blood that effectively blocks the binding of HIV to CD4 cells. This latest discovery, reported by a team of scientists from a variety of institutes in Germany and at The New York Blood Center, could lead to the development of yet another class of antiretrovirals with activity against HIV resistant to approved agents.
For many years, researchers have suggested that a variety of molecules in human blood can inhibit HIV. Until recently, however, the hunt for the natural compounds with the greatest anti-HIV activity has not produced fruitful results.
To look more closely for these circulating molecules, the German and American group of academic, public health, and pharmaceutical researchers sifted through a comprehensive library of small peptides – protein fragments – that had been filtered from the blood of patients with chronic kidney failure during dialysis. After sorting through more than one million blood peptides, including several with HIV activity, the scientists ended up focusing on one that appeared to block HIV without toxic effects on cells.
The research team found that a fragment of a relatively abundant blood molecule, dubbed virus-inhibitory peptide (VIRIP), acts as a broad-based inhibitor of HIV. Laboratory studies suggested that VIRIP specifically targets a conserved region in the HIV 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.
As with the development of other compounds designed to inhibit HIV fusion and entry, VIRIP's unique mechanism should ultimately allow it to remain effective against HIV strains resistant to many antiretrovirals currently available (and possibly other fusion/entry inhibitors).
The researchers reported that, in test tube studies, HIV does not easily develop resistance to VIRIP. There was also evidence to suggest that some derivatives of the peptide are highly stable in human blood plasma and are nontoxic even at exceedingly high concentrations.
"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.
Source:
Münch J, Ständker L, Adermann K, et al. Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 129:263-75, 2007.
