HIV continues to cause significant morbidity and mortality around the world, emphasizing the need for an effective preventive HIV vaccine. Most existing viral vaccines, usually developed empirically, protect by inducing potent humoral immunity. However, vaccines against HIV have not been able to induce such protective responses. Potent neutralizing antibody responses in natural HIV-1 infection offer new clues about the mechanisms of their development in humans. However, only a subset of naturally infected individuals makes broadly neutralizing antibodies (bnAbs), and none of the individuals immunized with experimental HIV vaccines do. The native HIV envelope glycoprotein (Env) trimer is the major target for neutralizing antibodies, and it appears that binding to the Env trimer is required for neutralization. However, the high degree of variability in Env as well as the restricted accessibility for antibodies due to the glycan shield and other structural features such as the variable loops are among the reasons to explain why eliciting protective antibodies has been so difficult.
The nature of neutralizing antibody responses in natural HIV-1 infection should offer new clues for the design of an optimal Env immunogen. Especially individuals identified as elite neutralizers, with exceptionally potent neutralizing antibodies, represent a new resource to unravel the mechanisms behind the development of these very potent and broad neutralizing antibodies in humans. Therefore, we isolated monoclonal antibodies from an elite neutralizer from the Amsterdam Cohort Studies and found an antibody with very potent neutralising properties (http://go.nature.com/2eZx46C). Using negative stain electron microscopy and other techniques, we found that this antibody bound to a novel target epitope, showing the fusion peptide on the envelope glycoprotein, needed to infect target cells, as a site of vulnarability. In addition, we also constructed soluble native like envelope glycoproteins from early virus variants of the same elite neutralizer. The availability of a native-like Env trimer and a bNAb from the same elite neutralizer opens new avenues for HIV vaccine design aimed at generating similar bNAbs against a key functional site on HIV.
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