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Neutralizing antibody escape during HIV-1 mother-to-child transmission involves conformational masking of distal epitopes in envelope.

ABSTRACT: HIV-1 variants transmitted to infants are often resistant to maternal neutralizing antibodies (NAbs), suggesting that they have escaped maternal NAb pressure. To define the molecular basis of NAb escape that contributes to selection of transmitted variants, we analyzed 5 viruses from 2 mother-to-child transmission pairs, in which the infant virus, but not the maternal virus, was resistant to neutralization by maternal plasma near transmission. We generated chimeric viruses between maternal and infant envelope clones obtained near transmission and examined neutralization by maternal plasma. The molecular determinants of NAb escape were distinct, even when comparing two maternal variants to the transmitted infant virus within one pair, in which insertions in V4 of gp120 and substitutions in HR2 of gp41 conferred neutralization resistance. In another pair, deletions and substitutions in V1 to V3 conferred resistance, but neither V1/V2 nor V3 alone was sufficient. Although the sequence determinants of escape were distinct, all of them involved modifications of potential N-linked glycosylation sites. None of the regions that mediated escape were major linear targets of maternal NAbs because corresponding peptides failed to compete for neutralization. Instead, these regions disrupted multiple distal epitopes targeted by HIV-1-specific monoclonal antibodies, suggesting that escape from maternal NAbs occurred through conformational masking of distal epitopes. This strategy likely allows HIV-1 to utilize relatively limited changes in the envelope to preserve the ability to infect a new host while simultaneously evading multiple NAb specificities present in maternal plasma.

SUBMITTER: Goo L

PROVIDER: S-EPMC3446598 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Neutralizing antibody escape during HIV-1 mother-to-child transmission involves conformational masking of distal epitopes in envelope.

Goo Leslie L Milligan Caitlin C Simonich Cassandra A CA Nduati Ruth R Overbaugh Julie J

Journal of virology 20120627 18

HIV-1 variants transmitted to infants are often resistant to maternal neutralizing antibodies (NAbs), suggesting that they have escaped maternal NAb pressure. To define the molecular basis of NAb escape that contributes to selection of transmitted variants, we analyzed 5 viruses from 2 mother-to-child transmission pairs, in which the infant virus, but not the maternal virus, was resistant to neutralization by maternal plasma near transmission. We generated chimeric viruses between maternal and i ...[more]

PMID: 22740394

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Project description:Respiratory syncytial virus (RSV) is a top cause of severe lower respiratory tract disease and mortality in infants and the elderly. Currently, no vaccine or effective treatment exists for RSV. The RSV G glycoprotein mediates viral attachment to cells and contributes to pathogenesis by modulating host immunity through interactions with the human chemokine receptor CX3CR1. Antibodies targeting the RSV G central conserved domain are protective in both prophylactic and postinfection animal models. Here, we describe the crystal structure of the broadly neutralizing human monoclonal antibody 3G12 bound to the RSV G central conserved domain. Antibody 3G12 binds to a conformational epitope composed of highly conserved residues, explaining its broad neutralization activity. Surprisingly, RSV G complexed with 3G12 adopts a distinct conformation not observed in previously described RSV G-antibody structures. Comparison to other structures reveals that the RSV G central conserved domain is flexible and can adopt multiple conformations in the regions flanking the cysteine noose. We also show that restriction of RSV G flexibility with a proline mutation abolishes binding to antibody 3G12 but not antibody 3D3, which recognizes a different conformation of RSV G. Our studies provide new insights for rational vaccine design, indicating the importance of preserving both the global structural integrity of antigens and local conformational flexibility at antigenic sites, which may elicit a more diverse antibody response and broader protection against infection and disease.IMPORTANCE Respiratory syncytial virus (RSV) causes severe respiratory infections in infants, young children, and the elderly, and currently, no licensed vaccine exists. In this study, we describe the crystal structure of the RSV surface glycoprotein G in complex with a broadly neutralizing human monoclonal antibody. The antibody binds to RSV G at a highly conserved region stabilized by two disulfide bonds, but it captures RSV G in a conformation not previously observed, revealing that this region is both structured and flexible. Importantly, our findings provide insight for the design of vaccines that elicit diverse antibodies, which may provide broad protection from infection and disease.

Project description:The trimeric envelope spikes on the HIV-1 virus surface initiate infection and comprise key targets for antiviral humoral responses. Circulating virions variably present intact envelope spikes, which react with neutralizing antibodies; and altered envelope structures, which bind non-neutralizing antibodies. Once bound, either type of antibody can enable humoral effector mechanisms with the potential to control HIV-1 infection in vivo. However, it is not clear how the presentation of neutralizing vs. non-neutralizing epitopes defines distinct virus populations and/or envelope structures on single particles. Here we used single-virion fluorescence correlation spectroscopy (FCS), fluorescence resonance energy transfer (FRET), and two-color coincidence FCS approaches to examine whether neutralizing and non-neutralizing antibodies are presented by the same envelope structure. Given the spatial requirements for donor-acceptor energy transfer (≤10 nm), FRET signals generated by paired neutralizing and non-neutralizing fluorescent Fabs should occur via proximal binding to the same target antigen. Fluorescent-labeled Fabs of the neutralizing anti-gp120 antibodies 2G12 and b12 were combined with Fabs of the non-neutralizing anti-gp41 antibody F240, previously thought to mainly bind gp41 "stumps." We find that both 2G12-F240 and/or b12-F240 Fab combinations generate FRET signals on multiple types of virions in solution. FRET efficiencies position the neutralizing and non-neutralizing epitopes between 7.1 and 7.8 nm apart; potentially fitting within the spatial dimensions of a single trimer-derived structure. Further, the frequency of FRET detection suggests that at least one of such structures occurs on the majority of particles in a virus population. Thus, there is frequent, overlapping presentation of non-neutralizing and neutralizing epitope on freely circulating HIV-1 surfaces. Such information provides a broader perspective of how anti-HIV humoral immunity interfaces with circulating virions.

Dataset Information

Neutralizing antibody escape during HIV-1 mother-to-child transmission involves conformational masking of distal epitopes in envelope.

Publications

Neutralizing antibody escape during HIV-1 mother-to-child transmission involves conformational masking of distal epitopes in envelope.

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