Identification of a mimotope of a complex gp41 human immunodeficiency virus epitope related to a non-structural protein of Hepacivirus previously implicated in Kawasaki disease

Current HIV vaccine strategies are hampered by difficulty with recapitulating heavily mutated broadly neutralizing antibodies. We have previously isolated a highly mutated antibody termed “group C 76-Q13-6F5” (6F5) that uses immunoglobulin heavy chain variable region (VH)1-02. 6F5 targets a conformational epitope on HIV gp41 and mediates Ab-dependent cell cytotoxicity (ADCC). Reverting the group C 76 antibodies’ variable chain to VH1-02 germline in antibody 76Canc showed retained ADCC activity. A vaccine targeting an epitope functionally recognized by germline antibodies offers a distinct advantage. Due to the 76Canc germline antibody ability to retain anti-HIV function, we sought to identify a protein target that could form the basis of a vaccine. 76Canc specifically recognized a number of acidic peptides on a microarray containing 29,127 linear peptides. Meme analysis identified a peptide sequence similar to a non-structural protein of Hepacivirus previously implicated in Kawasaki disease (KD). Binding was confirmed to significant peptides, including the Hepacivirus-related and KD-related peptide. On serum competition studies using samples from children with KD compared to controls, targeting of this epitope showed no specific correlation to the clinical syndrome of KD. Yeast-displayed human protein microarray autoantigen screening was also reassuring. This study identifies a peptide that can mimic the gp41 epitope targeted by 76C group antibodies (i.e., a mimotope). We show little risk of autoimmune targeting inclusive of inflammation similar to KD, implying non-specific humoral immunity targeting of similar peptides during KD. Development of an HIV vaccine based on such peptides should proceed, but with continued caution.