If current dreams of an AIDS-free generation are to be realized, it will be necessary to develop an effective vaccine against HIV. And such a vaccine will need to induce a broadly neutralizing antibody.

About 1 in five HIV-infected individuals ultimately develops such antibodies – not that it does them any good. "These antibodies have unusual traits," Barton Haynes, of Duke University, told BioWorld Today, and developing those traits takes time, and a long journey from the naïve germline antibodies that first start fighting HIV in a newly infected individual.

Such antibodies take two to four years to develop, at which point the virus is firmly established in its host, hiding out in reservoirs where it is impervious to both the drugs used to treat it and the human immune system.

If those same broadly neutralizing antibodies were induced prophylactically, the arms race between host and virus would be shifted in favor of the former. But developing antigens that can induce such antibodies has so far eluded researchers, though last week, two separate papers reported encouraging progress toward such an antigen. (See BioWorld Today, April 3, 2013.)

One reason is that it has been hard to know exactly how to keep an antibody on the straight and narrow path to broad neutralization, rather than meandering off into the much more numerous dead-end possibilities.

Up to now, charting an antibody's path from the germline to broadly neutralizing has been done after the fact.

"You took an antibody from an individual that was chronically infected and inferred the structure of the unmutated ancestor, and then inferred what antigen would bind to that ancestor," Haynes said.

That after-the-fact approach has necessitated a lot of guesswork about the evolutionary path of both the antibody and the virus. But in the April 4, 2013, issue of Nature, Haynes and his colleagues presented a roadmap that has not been reconstructed after the fact, but measured from a patient whose infection was detected so soon after it happened that there had been no time for the antibody-viral tango to start yet.

The individual in question was infected in 2005, when the official guidelines for treating HIV called for starting treatment only when T-cell counts dropped below a certain level – as they officially still do, although many doctors now start highly active antiretroviral treatment, or HAART, as soon as an infection is diagnosed.

The person in question started participating in a study that collected weekly blood samples over several years only a month after becoming infected.

By analyzing those blood samples, Haynes and his team were able to identify, rather than infer, both the original virus that first infected the patient, and the germline version of what would later become the broadly neutralizing antibody.

In a commentary published along with the paper, Michel Nussenzweig, of Rockefeller University, said the findings "present a strong and testable route to addressing the main challenges of creating an antibody-based HIV-1 vaccine." Nussenzweig published a paper in the March 28, 2013, issue of Cell showing that broadly neutralizing antibodies to HIV have mutations not just in the regions that bind antigens, but also in the surrounding areas, and that such mutations in the so-called frame are critical to increase flexibility and antibody-antigen binding.

Haynes and his colleagues said they hope that by understanding the road traveled by the broadly neutralizing antibody their subject produced, they will be able to develop a series of antigens that can be used to induce broadly neutralizing antibodies via a series of vaccinations – though Haynes' response when asked when such a vaccine might enter clinical trials was succinct: "I don't know."

What is already clear, he said, is that "this vaccine is going to be made completely differently from other successful vaccines." For one thing, it implies that a successful HIV vaccine will literally not be a one-shot deal. Instead, it is likely that multiple vaccinations will be necessary to provide guideposts to antibodies along their journey.

That differs sharply, of course, from currently used vaccines. Even where boosters are given, the booster is the same antigen as the original shot, meant to strengthen the antibody response but not fundamentally change it.

But for HIV, the roads to a broadly neutralizing antibody "are unfavored pathways," Haynes said, and a successful vaccine will depend on finding antigens that "can coax these lineages into becoming dominant."