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How llamas’ unusual antibodies might help in the fight
against HIV/AIDS
EMBARGO: December 18, 2014, 11am Pacific / 2pm Eastern
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 HIVinfected
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 preimmunization 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.”
Contact:
Laura McCoy (now at the Scripps Research Institute, La Jolla, USA)
e-mail: [email protected]
phone: +1.424.209.1914 (before Dec. 17)
+44.771.324.2340 (Dec. 17-30)
Robin Weiss
e-mail: [email protected]
phone: +44.780.684.7394
Please use this URL to provide readers access to the paper (Link goes live
upon article publication):
http://dx.plos.org/10.1371/journal.ppat.1004552
Press-Only Preview Of The Article:
http://www.plos.org/wp-content/uploads/2013/05/PLOS_Pathogens_McCoy_December_18.pdf
Related Image for Press Use:
http://www.plos.org/wp-content/uploads/2013/05/Llama-AIDS-band-Ppt.jpg
Caption: Llamas contribute to the fight against AIDS
Image Credit: Nika Stropakke, CC-BY
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
Please contact [email protected] if you would like more information.
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
Image 1:
Caption: Llamas contribute to the fight against AIDS.
Credit: Nika Stropakke, CC-BY
Usage Restrictions: None
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