AIDS Vaccines: Y So Hard?

It’s 25 years and counting after the AIDS epidemic began, yet we still don’t have a good vaccine against HIV, the virus responsible. A Caltech team thinks that part of the reason may be that our body’s natural HIV antibodies simply don’t have a long enough reach.

Antibodies, which are Y-shaped, work best when both arms of the Y bind to their target proteins on the virus at more or less the same time. This can increase the antibody’s grip strength a hundred- or even a thousandfold. But double-armed binding can be easier said than done. Pamela Bjorkman, the Delbrück Professor of Biology and a Howard Hughes Medical Institute investigator, and grad student Joshua Klein looked at two antibodies that bind to proteins that stick out like spikes from HIV’s viral membrane.

“The story really starts to get interesting when we think about what the HIV virus actually looks like,” says Klein, the lead author of a paper published April 16 in the online early edition of the Proceedings of the National Academy of Sciences. Whereas a flu virus’s surface is studded with approximately 450 spikes, he explains, the similarly sized HIV may have fewer than 15. With spikes so few and far between, locating two that both fall within an antibody’s reach—generally between 12 and 15 nanometers, or billionths of a meter—becomes much more of a challenge. “HIV may have evolved a way to escape one of our immune system’s main strategies,” he says.

“I consider this a very important paper because it changes the focus of the discussion about why anti-HIV antibodies are so poor,” adds virologist David Baltimore, the Millikan Professor of Biology and a Nobel Prize winner. “It brings attention to a long-recognized but often forgotten aspect of antibody attack—that they attack with two hands. What this paper shows is that anti-HIV antibodies are restricted to using one hand at a time and that makes them bind much less well. Responding to this newly recognized challenge will be difficult because it identifies an intrinsic limitation on the effectiveness of almost any natural anti-HIV antibodies.”

As well as Bjorkman and Klein, the paper’s authors are research technicians Priyanthi Gnanapragasam, Rachel Galimidi, and Christopher Foglesong, and Member of the Professional Staff Anthony West, Jr. (PhD ’98). The work was supported by a Bill and Melinda Gates Foundation grant through the Grand Challenges in Global Health Initiative and the Collaboration for AIDS Vaccine Discovery. —LO