We propose unconventional, unique and exceptionally novel methods to uncover the structure of broadly neutralizeable epitopes in the variable loops of gp120. This work challenges the standard paradigm that the variable loops of gp120 are too dynamic and variable to have conserved epitopes useful in a vaccine. We were able to devise a novel computational de-noising approach to the sequence and structural variability in these loops and have a high likelihood of identifying the first broadly neutralizing antibodies targeting epitopes in V1, V2 V4 and/or V5. We are confident of attaining this significant outcome based on our preliminary results with the V3 loop. The research group and the proposed research is uniquely suited to the stated goals of the HIT-IT initiative, rather than a conventional research grant (R01) application. This is because we have a proven track record of this kind of innovation targeting the V3 loop, and because the research addresses a problem that is both crucial to an HIV vaccine and simultaneously thought currently to be too challenging to address.
All prior failed HIV vaccines have targeted sequence conserved and non-gp120 determinants in the virus. This is primarily because the dynamic, sequence variable surface loops of gp120 are considered too challenging to dissect for hidden broadly neutralizing antibody epitopes. This research proposes a highly innovative tactic to meet this challenge and produce the first structure-based design of immunogens mimicking broadly neutralizing epitopes in the variable loops V1, V2, V4 and V5.
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