Most vaccines work by inducing an immune response characterized by neutralizing antibodies against the respective pathogen. An effective HIV vaccine has remained elusive so far, but researchers have continued to make progress, often employing innovative methods. A study published on December 18th in PLOS Pathogens reports that a combination of antibodies from llamas can neutralize (destroy) a wide range of circulating HIV viruses.
After initial disappointment that HIV vaccine candidates were unable to elicit neutralizing antibodies, researchers found that some HIV-infected individuals did produce such antibodies. The current challenge is therefore to find safe and effective vaccine formulations (as opposed to HIV infection) that trigger the development of neutralizing antibodies that can recognize and prevent infection with all or most circulating HIV subtypes.
Many known neutralizing antibodies are directed against a specific part of the virus that binds to the CD4 receptor on the human target cells, and structural biology studies indicated that the site is a narrow groove. Antibodies in most mammals are relatively large proteins made up of two copies of two different individual parts (or chains), and bulkiness might be one reason why neutralizing antibodies are rare. Llamas are a notable exception: besides the common four-chain antibodies they also produce smaller ones made up of only two of the four chains. Robin Weiss, an HIV expert, and Theo Verrips, a llama antibody expert, therefore started working with this unconventional research animal.
Laura McCoy (working with Weiss at University College London, UK) led an international group of researchers to test immunization protocols and the resulting immune response in llamas. Having previously identified one particular HIV neutralizing llama antibody, for this study the researchers immunized two additional llamas and identified a total of three new neutralizing antibodies. The four HIV neutralizing llama antibodies target different parts of the CD4-binding site of the virus, and the researchers could show that when used in combination, rather than interfering with each other, they are more potent and can neutralize all of the 60 different HIV strains tested.
To understand how the llama immunization--which included two sets of four sequential vaccine injections per animal--worked, the researchers sequenced many copies of antibody-coding genes from blood cells collected after the first set of immunizations and after a further four rounds of vaccination. They also looked at the "naïve" antibody repertoire from seven llamas that had not been vaccinated. The results suggest that the neutralizing antibodies were not part of the pre-immunization repertoire, nor were they detectable after the first vaccination round. Rather, they were generated as immune cells repeatedly encountered the vaccine and responded by maturing specific antibodies that can recognize it.
While it is encouraging that broadly neutralizing antibodies were found in all of the immunized llamas, they are present only at low concentrations in the blood, and so fail to meet the goal for a protective HIV vaccine. Nonetheless, the researchers conclude that the llama model has allowed them to examine the generation of four broadly neutralizing antibodies induced by vaccination, which has not been possible in any other species. Their results, they say, "show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies, and provide a framework to analyze the effectiveness of immunization protocols."
Laura McCoy (now at the Scripps Research Institute, La Jolla, USA)
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Authors and Affiliations
Laura E. McCoy, University College London, UK
Lucy Rutten, QVQ B.V., The Netherlands
Dan Frampton, University College London, UK
Ian Anderson, University College London, UK
Luke Granger, King's College London School of Medicine, Guy's Hospital, UK
Rachael Bashford-Rogers, Wellcome Trust Sanger Institute, UK
Gillian Dekkers, University College London, UK
Nika M. Strokappe, QVQ B.V., The Netherlands
Michael S. Seaman, Beth Israel Deaconess Medical Center, Harvard Medical School, USA
Willie Koh, University College London, UK
Vanina Grippo, Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Argentina
Alexander Kliche, University of Regensburg, Germany
Theo Verrips, QVQ B.V., The Netherlands
Paul Kellam, Wellcome Trust Sanger Institute, UK
Ariberto Fassati, University College London, UK
Robin A. Weiss, University College London, UK
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Funding: This work was supported by the European Commission sixth Frame Work Programme as part of the European Vaccines and Microbicides Enterprise (EUROPRISE), the European Commission seventh Frame Work Programme as part of the Combined Highly Active Anti-retroviral Microbicides project (CHAARM) [to RAW], the Bill and Melinda Gates Foundation as part of the Collaboration for AIDS Vaccine Discovery (CAVD grant 38637 [to RAW] and grant 1032144 [to MSS]), and the UK Medical Research Council [RAW and AF]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: LR and TV are employed by a commercial company, QVQ B.V. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials.
Citation: McCoy LE, Rutten L, Frampton D, Anderson I, Granger L, et al. (2014) Molecular Evolution of Broadly Neutralizing Llama Antibodies to the CD4-Binding Site of HIV-1. PLoS Pathog 10(12): e1004552. doi:10.1371/journal.ppat.1004552