Stopping HIV with an artificial protein
By Jon Cohen
For 30 years, researchers have struggled to determine which immune responses best foil HIV, information that has guided the design of AIDS vaccines and other prevention approaches. Now, a research team has shown that a lab-made molecule that mimics an antibody from our immune system may have more protective power than anything the body produces, keeping four monkeys free of HIV infection despite injection of large doses of the virus.
Intensive hunts are under way for natural HIV antibodies that can stop—or “neutralize”—the many variants of the constantly mutating AIDS virus. Researchers have recently found several dozen broadly neutralizing antibodies (bNAbs) that are highly potent and work at low doses. But viral immunologist Michael Farzan of the Scripps Research Institute in Jupiter, Florida, and 33 co-workers have recently taken a different strategy, building a novel molecule based on our knowledge of how HIV infects cells. HIV infects white blood cells by sequentially attaching to two receptors on their surfaces. First, HIV’s own surface protein, gp120, docks on the cell’s CD4 receptor. This attachment twists gp120 such that it exposes a region on the virus that can attach to the second cellular receptor, CCR5. The new construct combines a piece of CD4 with a smidgen of CCR5 and attaches both receptors to a piece of an antibody. In essence, the AIDS virus locks onto the construct, dubbed eCD4-Ig, as though it were attaching to a cell and thus is neutralized.
In test-tube experiments, eCD4-Ig outperformed all known natural HIV antibodies at stopping the virus from infecting cells, Farzan’s team reports in this week’s issue of Nature. To test how it works in animals, they then put a gene for eCD4-Ig into a harmless virus and infected four monkeys; the virus forces the monkey’s cells to mass produce the construct. When they “challenged” these monkeys and four controls with successively higher doses of an AIDS virus for up to 34 weeks, none of the animals that received eCD4-Ig became infected, whereas all of the untreated ones did.
The new study ups the ante on a similar gene therapy approach with natural antibodies that 6 years ago showed promise in monkey experiments, says an accompanying Nature editorial by AIDS vaccine researcher Nancy Haigwood of Oregon Health & Science University in Beaverton. “I am a huge fan of this paper,” Haigwood says. “It’s really very creative and a breakthrough as far as I am concerned.” Pediatrician Philip Johnson of the Children’s Hospital of Philadelphia in Pennsylvania, whose lab in 2009 showed success with a gene therapy that delivers an HIV bNAb, adds that eCD4-Ig “is a beautiful thing.”
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http://news.sciencemag.org/biology/2015/02/stopping-hiv-artificial-protein