title: Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability of Transmitted/Founder Envelope Glycosylation Favor the Development of Heterologous Neutralization Breadth.
abstract: A recent study of plasma neutralization breadth in HIV-1 infected individuals at nine International AIDS Vaccine Initiative (IAVI) sites reported that viral load, HLA-A*03 genotype, and subtype C infection were strongly associated with the development of neutralization breadth. Here, we refine the findings of that study by analyzing the impact of the transmitted/founder (T/F) envelope (Env), early Env diversification, and autologous neutralization on the development of plasma neutralization breadth in 21 participants identified during recent infection at two of those sites: Kigali, Rwanda (n = 9) and Lusaka, Zambia (n = 12). Single-genome analysis of full-length T/F Env sequences revealed that all 21 individuals were infected with a highly homogeneous population of viral variants, which were categorized as subtype C (n = 12), A1 (n = 7), or recombinant AC (n = 2). An extensive amino acid sequence-based analysis of variable loop lengths and glycosylation patterns in the T/F Envs revealed that a lower ratio of NXS to NXT-encoded glycan motifs correlated with neutralization breadth. Further analysis comparing amino acid sequence changes, insertions/deletions, and glycan motif alterations between the T/F Env and autologous early Env variants revealed that extensive diversification focused in the V2, V4, and V5 regions of gp120, accompanied by contemporaneous viral escape, significantly favored the development of breadth. These results suggest that more efficient glycosylation of subtype A and C T/F Envs through fewer NXS-encoded glycan sites is more likely to elicit antibodies that can transition from autologous to heterologous neutralizing activity following exposure to gp120 diversification. This initiates an Env-antibody co-evolution cycle that increases neutralization breadth, and is further augmented over time by additional viral and host factors. These findings suggest that understanding how variation in the efficiency of site-specific glycosylation influences neutralizing antibody elicitation and targeting could advance the design of immunogens aimed at inducing antibodies that can transition from autologous to heterologous neutralizing activity.
authors.affiliation: Yerkes National Primate Research Center, Emory University Atlanta, Georgia, United States of America.|Emory Vaccine Center, Emory University Atlanta, Georgia, United States of America.
authors.forename: S Abigail
authors.initials: SA
authors.lastname: Smith
authors.affiliation: Yerkes National Primate Research Center, Emory University Atlanta, Georgia, United States of America.|Emory Vaccine Center, Emory University Atlanta, Georgia, United States of America.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Burton
authors.affiliation: Zambia Emory HIV Research Project, Lusaka, Ndola and Kitwe, Zambia.
authors.forename: William
authors.initials: W
authors.lastname: Kilembe
authors.affiliation: Zambia Emory HIV Research Project, Lusaka, Ndola and Kitwe, Zambia.
authors.forename: Shabir
authors.initials: S
authors.lastname: Lakhi
authors.affiliation: Projet San Francisco, Kigali, Rwanda.
authors.forename: Etienne
authors.initials: E
authors.lastname: Karita
authors.affiliation: International AIDS Vaccine Initiative (IAVI), New York, New York, United States of America.|UCSF Department of Epidemiology and Biostatistics, San Francisco, California, United States of America.
authors.forename: Matt
authors.identifier: http://orcid.org/0000-0002-2918-1373
authors.initials: M
authors.lastname: Price
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University Atlanta, Georgia, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.affiliation: Yerkes National Primate Research Center, Emory University Atlanta, Georgia, United States of America.|Emory Vaccine Center, Emory University Atlanta, Georgia, United States of America.|Department of Pathology and Laboratory Medicine, Emory University Atlanta, Georgia, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.affiliation: Yerkes National Primate Research Center, Emory University Atlanta, Georgia, United States of America.|Emory Vaccine Center, Emory University Atlanta, Georgia, United States of America.|Department of Pathology and Laboratory Medicine, Emory University Atlanta, Georgia, United States of America.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D006031:Glycosylation; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D009500:Neutralization Tests; D016133:Polymerase Chain Reaction; D012432:Rwanda; D015024:Zambia; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus