HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design

Abstract

BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4.1 Å and 3.4 Å single-particle cryo-EM structures of two inferred germline (iGL) BG24 precursors complexed with engineered Env-based immunogens lacking CD4bs N-glycans. Structures reveal critical Env contacts by BG24iGL and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24iGL variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276gp120 glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.

Injection Drug Use Alters Plasma Regulation of the B Cell Response

“…IgM was significantly elevated in PWID, while IgD and kappa light chain were significantly decreased (Figure 1D). A significant decrease in immunoglobulin utilizing the VH1-2 heavy chain variable region was also evident in PWID, which is notable as it has previously been reported as enriched in a subset of HIV-specific broadly neutralizing antibodies targeting the conserved CD4 binding site [42].…”

High throughput analysis of B cell dynamics and neutralizing antibody development during immunization with a novel clade C HIV-1 envelope

“…However, knowledge about the specific B cells that produce neutralizing antibodies in response to vaccination remains limited. Envelope (Env) specific B cells are abundantly elicited by vaccination, but the capability of a single B cell to produce a neutralizing antibody is likely influenced by myriad factors, including the germline features and pairing of the VH and VL chain variable domains [4][5][6][7], the lymphoid environment [2], the form of antigen [8] , adjuvant [8][9][10], and clonal expansion [11,12]. Many studies support that a protective B cell response against HIV-1 will require a vaccine to elicit neutralizing antibodies of high potency, durability, and breadth.…”