HIV evades the body’s immune defenses through multiple mutations, and the antibodies against HIV produced by the host’s immune system follow a complex and difficult-to-track evolutionary pathway. This complexity makes it difficult for scientists to develop preventive HIV vaccines that trigger effective antibodies that have evolved in some HIV-infected individuals.

Now, in a new study, researchers from the Duke Human Vaccine Institute at Duke University reported that they completed part of a roadmap for effective neutralization of HIV, identifying the steps of a critical class of HIV antibodies to produce and maintain the effective neutralization of this virus. The results of the study were published in the December 18, 2018 issue of Immunity, entitled “Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier“.

In this new study, Bonsignori, Haynes, and other colleagues focused on a special class of broadly neutralizing antibodies called VRC01 that target a conserved region of the HIV envelope called the CD4 binding site. This antibody lineage has long been recognized as a key component of protective vaccine-induced immune responses because they neutralize most HIV variants.

Bonsignori said, “These broad neutralized antibodies have undergone a long and complex process of maturation. In this field, they have been extensively studied, but until now, we have not been able to research their origins, because it is challenging to trace the order in which many mutations, deletions, and changes occur.”

These researchers inferred a common precursor of the VRC01 antibody lineage that did not mutate and reconstituted the mature pathway leading to the most broad neutralized antibodies and the mature pathways leading to antibodies that are harmful to HIV transmission.

Using this roadmap, these researchers have found that it is possible for such antibodies to be strategically bypassed along their developmental pathways to achieve broad neutralization of HIV. This strategic bypass is essentially to bypass a major obstacle that stops producing the broad neutralization of these antibodies.

Bonsignori said, “This is where everyone is trapped—we know that if we can figure out how to use these ancestral antibodies, we will be on the road. But we always encounter this obstacle. In the early stages of antibody maturation, a specific sugar on the HIV envelope prevents the production of antibodies with broad neutralization, and everything is stuck here.”

Bonsignori said the solution is to get around this sugar and bypass the obstacle instead of trying to break it. “By rebuilding different maturity paths, we find that you can go to an end in a simpler way. Now we can use these information to design immunogens that enable them to fully work with the immune system to bypass this obstacle.”