D-112 Structure of a natively-glycosylated HIV-1 Env reveals a new mode for VH1-2 antibody recognition of the CD4 binding site relevant to vaccine

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HIV-1 vaccine design is informed by structural studies that elucidate mechanisms by which broadly neutralizing antibodies (bNAbs) recognize/accommodate N-glycans on the trimeric envelope glycoprotein (Env). However, variability in high-mannose and complex-type Env glycoforms leads to heterogeneity that usually precludes crystallization. We will present 3.5 Å and 3.9 Å crystal structures of a native-like Env trimer with fully-processed/native glycosylation, revealing heterogeneous glycan shields of untrimmed high-mannose and complex-type N-glycans that we used to define complete epitopes of 2 bNAbs and potential antibody-vulnerable glycan holes. The Env trimer was complexed with 10–1074 (against the V3-loop) and IOMA, a new CD4-binding site (CD4bs) antibody. Although IOMA is derived from VH1-2*02, the germline gene of CD4bs-targeting VRC01-class bNAbs, its light chain lacks the short CDRL3 loop that defines VRC01-class bNAbs and thus it resembles 8ANC131-class/VH1-46–derived CD4bs bNAbs, which have normal-length CDRL3s. The existence of bNAbs that combine features of VRC01-class and 8ANC131-class antibodies has implications for immunization strategies targeting VRC01-like bNAbs.

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