Journal Article

Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies

Ernandes, Michael J., Cupo, Albert, Soto, Cinque, Morris, Lynn, Roark, Ryan S., Georgiou, George, Louder, Mark K., Kim, Helen J., Kong, Rui, Yang, Yongping, Abdool Karim, Salim S., Kwong, Peter D., Pancera, Marie, Zhang, Zhenhai, Sheward, Daniel J., Bhiman, Jinal N., Garrett, Nigel J., McKee, Krisha, Druz, Aliaksandr, Schmidt, Stephen D., Georgiev, Ivelin S., Gorman, Jason, Staupe, Ryan P., Nonyane, Molati, Rudicell, Rebecca S., Wilson, Ian A., O’Dell, Sijy, Sanders, Rogier W., Schramm, Chaim A., Crooks, Ema T., Binley, James M., Wibmer, Constantinos Kurt, Mascola, John R., Doria-Rose, Nicole A., DeKosky, Brandon J., Altae-Tran, Han R., Williamson, Carolyn, Longo, Nancy S., Mullikin, James C., Moore, John P., Moore, Penny L., Bailer, Robert T., Ward, Andrew B., Shapiro, Lawrence, Hoi, Kam H.

2014

Overview

Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01–12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30–38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development. A longitudinal study of an individual patient developing neutralizing antibodies against HIV-1 (targeting the V1V2 region of gp120) reveals how such neutralizing antibodies develop and evolve over time, providing important insights relevant to vaccine development. HIV-neutralizing antibody formation examined A better understanding of how HIV-1-neutralizing antibodies are generated could be a useful contribution to the design of improved AIDS vaccines. John Mascola and colleagues have now elucidated the immunological pathway of an important category of HIV-1-neutralizing antibody — those that target the variable V1V2 region of the viral envelope. These antibodies are more frequently elicited than CD4-binding site antibodies in the early stages of HIV infection and feature modest affinity maturation, a process that favours mutations in antibody variable domains that enhance antigen binding.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/31 / 14/28 / 45/23 / 45/47 / 45/77 / 631/1647/48 / 631/250 / 631/326/596 / 692/699/255/1901 / AIDS (Disease) / AIDS research / AIDS vaccines / AIDS Vaccines - chemistry / AIDS Vaccines - immunology / Amino Acid Sequence / Amino acids / Analysis / Antibodies / Antibodies, Neutralizing - chemistry / Antibodies, Neutralizing - genetics / Antibodies, Neutralizing - immunology / Antibodies, Neutralizing - isolation & purification / Antibody Affinity - genetics / Antibody Affinity - immunology / Antigen-antibody reactions / B-Lymphocytes - cytology / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Binding Sites - immunology / Biological products industry / CD4 Antigens - immunology / CD4 Antigens - metabolism / Cell culture / Cell Lineage / Complementarity Determining Regions - chemistry / Complementarity Determining Regions - genetics / Complementarity Determining Regions - immunology / Epitope Mapping / Epitopes, B-Lymphocyte - chemistry / Epitopes, B-Lymphocyte - immunology / Evolution, Molecular / Genes / Genomes / HIV / HIV antibodies / HIV Antibodies - chemistry / HIV Antibodies - genetics / HIV Antibodies - immunology / HIV Antibodies - isolation & purification / HIV Envelope Protein gp160 - chemistry / HIV Envelope Protein gp160 - immunology / HIV Infections - immunology / HIV-1 - chemistry / HIV-1 - immunology / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Infections / Models, Molecular / Molecular Sequence Data / multidisciplinary / Mutation / Neutralization / Neutralization (Chemistry) / Neutralization Tests / Phylogenetics / Physiological aspects / Product development / Protein Structure, Tertiary / Science / Somatic Hypermutation, Immunoglobulin - genetics / Structure / Viral antibodies / Viral envelopes