Abstract
Broadly neutralizing antibodies are not commonly produced in HIV-1 infected individuals nor by experimental HIV-1 vaccines. When these antibodies do occur, it is important to be able to isolate and characterize them to provide clues for vaccine design. CAP206 is a South African subtype C HIV-1-infected individual previously shown to have broadly neutralizing plasma antibodies targeting the envelope gp41 distal membrane proximal external region (MPER). We have now used a fluoresceinated peptide tetramer antigen with specific cell sorting to isolate a human neutralizing monoclonal antibody (mAb) against the HIV-1 envelope gp41 MPER. The isolated recombinant mAb, CAP206-CH12, utilized a portion of the distal MPER (HXB2 amino acid residues, 673–680) and neutralized a subset of HIV-1 pseudoviruses sensitive to CAP206 plasma antibodies. Interestingly, this mAb was polyreactive and used the same germ-line variable heavy (VH1-69) and variable kappa light chain (VK3-20) gene families as the prototype broadly neutralizing anti-MPER mAb, 4E10 (residues 672–680). These data indicate that there are multiple immunogenic targets in the C-terminus of the MPER of HIV-1 gp41 envelope and suggests that gp41 neutralizing epitopes may interact with a restricted set of naive B cells during HIV-1 infection.
Highlights
The isolation of new anti-HIV-1 envelope neutralizing human monoclonal antibodies is a high priority since they may identify potential targets for vaccine design
In this study we demonstrate the power of prior epitope mapping of plasma neutralizing antibodies that allowed for the rationale design of an antigen-specific memory B cell receptor ligand
We saw utilization of the same VH and VL families by this new membrane proximal external region (MPER) neutralizing monoclonal antibody (mAb), CAP206-CH12, as that used by the prototype MPER mAb 4E10
Summary
The isolation of new anti-HIV-1 envelope neutralizing human monoclonal antibodies (mAbs) is a high priority since they may identify potential targets for vaccine design. The membrane proximal external region (MPER) in gp represents an important target for anti-HIV-1 neutralizing antibodies [8] This highly conserved stretch of ,23 amino acids in gp proximal to the viral membrane is required for viral infectivity. MPER mAb 4E10 shows greater breadth and binds residues within the C-terminus with amino acids W672, F673 and W680 critical for binding [9]. Both antibodies have long CDRH3 regions with hydrophobic CDRH3 loops that confer lipid polyreactivity [10]. The neutralizing capacity of antibodies targeting other epitopes within the MPER is largely unknown
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