HOWE LLAMAS UNUSUAL ANTIBODIES MIGHT HELP IN THE FIGHT AGAINST HIV/AIDS
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
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