Broadly neutralizing HIV antibodies: from the beginning

“There is a crack in everything, that’s how the light gets in”. Leonard Cohen, 1992.
Broadly neutralizing HIV antibodies: from the beginning

HIV is highly variable and an antibody-based HIV vaccine should elicit broadly neutralizing antibodies (bnAbs), capable of neutralizing the great majority of strains to which a vaccinee might be exposed. Our lab and that of Hermann Katinger in Vienna isolated and described the first human bnAbs in the early 1990s. These antibodies were not tremendously potent and although broad against the subtype of HIV prevalent in the US and Europe, they were less effective against global isolates, including those circulating in Africa. Nevertheless, we learned a lot about what bnAbs could do against HIV in the next few years of research and the bnAbs established that, in principle, an antibody-based HIV was possible. I was personally bolstered in this view when I received a handwritten letter of support from the great vaccinologist Maurice Hilleman.

Despite early successes, we thought we could do better. So with the International AIDS Vaccine Initiative (IAVI), we began a program in 2006 to identify HIV-infected individuals from across the globe with high serum titers of bnAbs, reasoning that they would be the best source of monoclonal bnAbs that could help guide us in HIV vaccine design in a process that has become known as Reverse Vaccinology 2.0 (“reverse” because one is using antibodies to generate a vaccine rather than the other way round and “2.0” because “1.0” describes Rino Rappuoli’s elegant genetic approach to vaccine development). In order to screen large numbers of sera (about 2,000) against multiple HIV isolates, we teamed up with Monogram to do the first high-throughput screening for antibody neutralization. This allowed us to identify to find a few special individuals with outstanding breadth of serum neutralization-we termed them “elite neutralizers”. How to isolate likely quite rare monoclonal bnAbs from these individuals?

By chance, I had been asked to advise on a company, Spaltudaq (later Theraclone), that was developing isolation of mAbs by single B cell technology that had been first described in the 1990s and was applying it to the study of tumor infiltrates. We saw the opportunity combine this approach with Monogram high-throughput neutralization screening to find monoclonal bnAbs. It worked! In 2008, we isolated two mAbs, PG9 and PG16, that showed promise in the initial screen.

We quickly showed that the antibodies were more than an order of magnitude more potent than anything described to date with a breadth covering about 80% of global isolates. Laura Walker, a graduate student in the lab, set about characterizing the antibodies and quickly showed they recognized a brand-new epitope at the apex of the HIV Envelope trimer and were strongly trimer preferring. The antibodies used a trick to penetrate the glycan shield that protects the protein surface of the trimer from antibody recognition; namely, a long H3 loop that also interacts with glycans. This motif has now been seen in many bnAbs.

We published our findings in Science in September 2009 and that kicked off the so-called “second generation” of HIV bnAbs. Many novel bnAbs have been isolated since to define several new epitopes on the HIV envelope and to reveal that a surprising amount of the surface of this heavily protected protein can be recognized by antibodies. I believe that our view of what antibodies can do has changed significantly in recent years led by some of the studies on HIV bnAbs. Thus, I now think that that antibodies can recognize virtually every nook and cranny on a protein, although one may have to search widely to find them all, both in terms of looking through many donor responses and very deeply in to each response. Modern technologies make this feasible. We have referred to antiviral antibodies generally with remarkable properties in terms of potency and/or cross reactivity with other viruses or strains of the same virus as “super antibodies”. For HIV, a number of super antibodies are being explored as potential prophylactic and therapeutic agents and we are working in that area with IAVI and the NIH Vaccine Research Center.

Our aspiration has long been an HIV vaccine. BnAbs are just the beginning and for the last few years we have been working within large consortia funded by the National Institutes of Allergy and Infectious Diseases (NIAID) and the Bill and Melinda Gates Foundation (BMGF) to that end. We feel that real progress has been made, especially very recently, and we are looking forward to exciting clinical results in the near future as novel immunogens and concepts are evaluated in humans.

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