BioEd Online

A natural component of human blood has been found to block the HIV virus from infecting cells. And fortunately, tweaking just a few of the amino acids that form the molecule somehow makes its effects 100 times more potent.

Because it works in a different way to existing therapies, the peptide could lead to a novel class of drugs to fight AIDS. There is also evidence that HIV doesn't easily develop resistance to the new compound, which is a major problem with many current HIV treatments.

The molecule, known as VIRIP (virus-inhibitory peptide), binds to a spiky protein on the surface of the HIV virus called gp41. HIV normally uses this protein to make the first contact with and latch onto a human cell, after which it would infect it. But the intervention of VIRIP stops that contact from happening.

The molecule was found by Frank Kirchhoff of the University of Ulm in Germany and his colleagues, who report their work in the journal Cell¹. They screened a massive library of compounds isolated from 10,000 litres of filtered human blood, looking for substances that could naturally inhibit HIV. Human blood has yielded some HIV-inhibiting substances before.

Pinpointing exactly which compounds have an effect is difficult — lots of blood is needed to be able to single out and test enough of each compound found. Kirchhoff's team had access to a large library of blood compounds at IPF PharmaCeuticals, a pharmaceutical company in Germany keen to develop the work.

Tweak till perfect

Once they had isolated the protein, the team set about adjusting it to explore which changes to its structure might alter its function, by fiddling with the amino acids in its 20-amino-acid chain. In one instance, they found that adding just one specific amino-acid building block rendered the protein useless in protecting against HIV. "We were surprised it was so specific," says Kirchhoff. "It is really striking."

Of the mass number of alterations the team tested, they found one instance in which altering just three specific amino acids made the compound 100 times more effective at inhibiting HIV — a potent drug candidate.

The group has already tested this modified version in animal models, including rats, dogs and monkeys, to make sure it is not toxic. The unpublished results look promising, Kirchhoff says, and the molecule could be ready for clinical trials by the end of this year.

Stable surface

Another bonus is that HIV should not be able to develop resistance to VIRIP as easily as it can with other drug compounds. Half of patients given a drug called T20, for example, which also acts to prevent HIV entering the cell, develop resistance to it, says Neelanjana Ray, a virologist at the University of Pennsylvania in Philadelphia.

This is because HIV has proven to be very adaptable; many of its surface proteins constantly change. But VIRIP picks on a fairly stable surface protein, which does not change so much — it works in conjunction with another protein, called gp120, which was recently discovered to be conserved over time (see 'HIV reveals site of vulnerability)'. This means that a drug using it should remain effective. "The really good thing is that it targets a very conserved area," says Ray. "It does seem to be a promising candidate."

But one question that the researchers can't yet answer is: what does VIRIP usually do in the body? If the protein had a significant role in inhibiting HIV, it would be expected that more people would be naturally immune. "We honestly really don't know how important it is in the control of HIV," Kirchhoff says.

One way to find out, he says, would be to test people who have HIV; it would be interesting to know whether those who are naturally deficient in VIRIP develop AIDS more rapidly than those who have the protective protein in normal quantities. It would also be useful to know whether those people who have proven naturally resistant to the syndrome have VIRIP in super-abundant quantities.