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

PLoS Pathogens

Shabir Lakhi¹  Samantha L. Burton¹  Eric Hunter²  Susan Allen³  Cynthia A. Derdeyn⁴  William Kilembe⁵  S. Abigail Smith⁵  Matt Price⁶  Etienne Karita⁶ 

[1] Emory Vaccine Center, Emory University Atlanta, Georgia, United States of America;International AIDS Vaccine Initiative (IAVI), New York, New York, United States of America;Projet San Francisco, Kigali, Rwanda;UCSF Department of Epidemiology and Biostatistics, San Francisco, California, United States of America;Yerkes National Primate Research Center, Emory University Atlanta, Georgia, United States of America;Zambia Emory HIV Research Project, Lusaka, Ndola and Kitwe, Zambia

关键词: HIV-1;    Antibodies;    Sequence motif analysis;    Glycosylation;    Amino acid sequence analysis;    Sequence alignment;    Sequence analysis;    Antigens;   

DOI  :  10.1371/journal.ppat.1005989

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY