Identification of Near-Pan-neutralizing Antibodies against HIV-1 by Deconvolution of Plasma Humoral Responses

• Published in: Cell Vol. 173; no. 7; pp. 1783 - 1795.e14
• Main Authors: Sajadi, Mohammad Mohseni, Dashti, Amir, Rikhtegaran Tehrani, Zahra, Tolbert, William D., Seaman, Michael S., Ouyang, Xin, Gohain, Neelakshi, Pazgier, Marzena, Kim, Dongkyoon, Cavet, Guy, Yared, Jean, Redfield, Robert R., Lewis, George K., DeVico, Anthony L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.06.2018
• Subjects: Amino Acid Sequence; Antibodies, Neutralizing - blood; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; antibody; antiviral agents; Binding Sites; bone marrow; broadly neutralizing antibody; CD4 Antigens - chemistry; CD4 Antigens - metabolism; Crystallography, X-Ray; HIV Antibodies - blood; HIV Antibodies - immunology; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - immunology; HIV Envelope Protein gp120 - metabolism; HIV-1; HIV-1 - genetics; HIV-1 - metabolism; Human immunodeficiency virus 1; Humans; humoral immunity; Molecular Dynamics Simulation; monoclonal antibodies; neutralization; pan-neutralization; plasma cells; polyclonal antibodies; Protein Binding; Protein Structure, Tertiary; proteomics; Pseudovirus; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - immunology; repertoire; RNA, Viral - blood; vaccines; X-ray diffraction; HIV-1; broadly neutralizing antibody; humoral immunity; antibody; repertoire; pan-neutralization
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2018.03.061

Anti-HIV-1 envelope broadly neutralizing monoclonal antibodies (bNAbs) isolated from memory B cells may not fully represent HIV-1-neutralizing profiles measured in plasma. Accordingly, we characterized near-pan-neutralizing antibodies extracted directly from the plasma of two “elite neutralizers.” Circulating anti-gp120 polyclonal antibodies were deconvoluted using proteomics to guide lineage analysis of bone marrow plasma cells. In both subjects, a single lineage of anti-CD4-binding site (CD4bs) antibodies explained the plasma-neutralizing activity. Importantly, members of these lineages potently neutralized 89%–100% of a multi-tier 117 pseudovirus panel, closely matching the specificity and breadth of the circulating antibodies. X-ray crystallographic analysis of one monoclonal, N49P7, suggested a unique ability to bypass the CD4bs Phe43 cavity, while reaching deep into highly conserved residues of Layer 3 of the gp120 inner domain, likely explaining its extreme potency and breadth. Further direct analyses of plasma anti-HIV-1 bNAbs should provide new insights for developing antibody-based antiviral agents and vaccines. [Display omitted] •HIV neutralizing activity is understood via plasma anti-gp120 response deconvolution•Near-pan-neutralizing activity is commonly traced to one anti-CD4bs IgG lineage•Plasma bNAbs persist and function as a minor fraction of the polyclonal response•Plasma anti-CD4bs mAbs have unique features and near-pan neutralizing properties An HIV-neutralizing antibody achieves near-pan-neutralizing activity through recognition of a highly conserved, difficult-to-access region of the viral gp120 glycoprotein.