Rapid and Focused Maturation of a VRC01-Class HIV Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan

• Published in: Immunity (Cambridge, Mass.) Mass.), 2019-07, Vol.51 (1), p.141-154.e6
• Main Authors: Umotoy, Jeffrey, Bagaya, Bernard S., Joyce, Collin, Schiffner, Torben, Menis, Sergey, Saye-Francisco, Karen L., Biddle, Trevor, Mohan, Sanjay, Vollbrecht, Thomas, Kalyuzhniy, Oleksander, Madzorera, Sharon, Kitchin, Dale, Lambson, Bronwen, Nonyane, Molati, Kilembe, William, Poignard, Pascal, Schief, William R., Burton, Dennis R., Murrell, Ben, Moore, Penny L., Briney, Bryan, Sok, Devin, Landais, Elise
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; AIDS Vaccines - genetics; AIDS Vaccines - immunology; Amino Acid Sequence; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - metabolism; Antibodies, Neutralizing - genetics; Antibodies, Neutralizing - metabolism; Antibody Affinity; B-Lymphocytes - immunology; Binding sites; Broadly Neutralizing Antibodies - genetics; Broadly Neutralizing Antibodies - metabolism; CD4 antigen; CD4 Antigens - metabolism; Complementarity Determining Regions - genetics; Correlation analysis; Glycan; HIV; HIV Antibodies - genetics; HIV Antibodies - metabolism; HIV Envelope Protein gp120 - immunology; HIV Envelope Protein gp120 - metabolism; HIV Infections - immunology; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immunoglobulins; Infections; Infectious diseases; Maturation; Medicin och hälsovetenskap; Monoclonal antibodies; Mutation; Neutralization; Neutralizing; Plasma; Polysaccharides - metabolism; Protein Binding; Vaccines
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2019.06.004

The VH1-2 restricted VRC01-class of antibodies targeting the HIV envelope CD4 binding site are a major focus of HIV vaccine strategies. However, a detailed analysis of VRC01-class antibody development has been limited by the rare nature of these responses during natural infection and the lack of longitudinal sampling of such responses. To inform vaccine strategies, we mapped the development of a VRC01-class antibody lineage (PCIN63) in the subtype C infected IAVI Protocol C neutralizer PC063. PCIN63 monoclonal antibodies had the hallmark VRC01-class features and demonstrated neutralization breadth similar to the prototype VRC01 antibody, but were 2- to 3-fold less mutated. Maturation occurred rapidly within ∼24 months of emergence of the lineage and somatic hypermutations accumulated at key contact residues. This longitudinal study of broadly neutralizing VRC01-class antibody lineage reveals early binding to the N276-glycan during affinity maturation, which may have implications for vaccine design. [Display omitted] •Isolation of PCIN63, a VRC01-class CD4-binding site Ab lineage with only 12% SHM•PCIN63 lineage emerged at 40 months post infection and achieved breadth in 2 years•Identification of a putative PCIN63 UCA reveals the importance of the CDRL3•PCIN63 bnAbs segregate in N276 glycan- dependent and -independent sub-families Understanding the molecular basis of HIV Env-specific broadly neutralizing antibodies (bnAbs) development especially, at early stages, is key for germline-targeting vaccine design strategies. Umotoy et al. mapped the development of a VRC01-class bnAb lineage that achieved breadth in 2 years, revealing early binding to the N276-glycan during affinity maturation, which may have implications for vaccine design.