Authors: Kimberley Ndungu, Future Science Group
A team of researchers from the Duke Human Vaccine Institute (DHVI; NC, USA) and Boston Children’s Hospital (MA, USA) have discovered that short-lasting antibodies can be coaxed into multiplying as a fighter forces against HIV.
The researchers used animal models to overcome the enduring challenge of developing a HIV vaccine. The team built on previous research that identified when and how neutralizing antibodies, bnAbs, arise in individuals with HIV infections and what prevents the antibodies from proliferating to target the virus.
“The reason we don’t have a HIV vaccine is because the immune system doesn’t want to make the kind of antibodies that are needed to neutralize the virus,” explained co-senior author Barton F. Haynes (DHVI). “This study is proof of concept that we can engineer the immune system to create an environment where the right antibodies can be made.”
A limitation of the immune system is that it identifies some bnAbs as a danger and actively shuts down their production. Further, these antibodies require rare gene changes that are infrequently made during a crucial B-cell diversification process.
In order to trace those relevant mutations, the researchers engineered a HIV protein – targeting the V3 glycan region on the virus envelope – that preferentially binds to the antibodies with the rare mutations.
The team also used mouse models that express human neutralizing antibody precursors and discovered that their immunogen could influence a lineage of B cells to undergo the unlikely mutations resulting in broadly neutralizing antibodies.
“Our ability to make mouse models that express human broadly neutralizing antibodies has provided powerful new model systems in which we can iteratively test experimental HIV vaccines,” commented co-senior author, Frederick Alt, who directs Boston Children’s Program in Cellular and Molecular Medicine.
A second lineage of bnAbs, which bind to a different region of the virus, also went through the rare mutations. Following this, the researchers reconstructed the antibodies history to develop a second immunogen, which they tested in non-human primates. The team discovered that this also selected for the necessary mutations and led to the development of potent neutralizing antibodies.
“We have identified the mutations we need, which the immune system won’t easily make and can select for them in a vaccine that targets that mutation,” commented co-lead author Kevin Saunders (DHVI). “We have shown that we can overcome this major roadblock and can select for the right mutational changes in these bnAb precursors when they are starting to get better and better at neutralizing activity.”
Future studies are required to identify additional antibodies that could be targeted as they build immunogens to constitute the HIV vaccine.
“Without proper antigen selection it will take multiple decades of vaccination to elicit effective antibodies,” commented co-lead author, Kevin Wiehe (DHVI). “We can accelerate this timeline by designing sequential immunogens that select for the required combination of functional antibody mutations.”
The findings from the current study demonstrate the intricacies of obtaining broadly neutralizing antibodies for HIV, however, the research also has broader applications. The knowledge gained from this HIV research has direct implications for cancer immunotherapies and treatments for autoimmune disorders.
“We have learned much about the rules of how the B cell arm of the immune system is controlled and how to manipulate the immune system in a way that it makes the desired type of antibodies,” concluded Haynes.
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