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Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope.

ABSTRACT: Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448gp120 glycan. Effective bNAbs can therefore be raised against HIV-1 Env's silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development.

SUBMITTER: Schoofs T

PROVIDER: S-EPMC6591006 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope.

Schoofs Till T Barnes Christopher O CO Suh-Toma Nina N Golijanin Jovana J Schommers Philipp P Gruell Henning H West Anthony P AP Bach Franziska F Lee Yu Erica YE Nogueira Lilian L Georgiev Ivelin S IS Bailer Robert T RT Czartoski Julie J Mascola John R JR Seaman Michael S MS McElrath M Juliana MJ Doria-Rose Nicole A NA Klein Florian F Nussenzweig Michel C MC Bjorkman Pamela J PJ

Immunity 20190521 6

Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env's silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compa ...[more]

PMID: 31126879

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Project description:UnlabelledThe potency and breadth of the recently isolated neutralizing human monoclonal antibodies to HIV-1 have stimulated interest in their use to prevent or to treat HIV-1 infection. Due to the antigenically diverse nature of the HIV-1 envelope (Env), no single antibody is highly active against all viral strains. While the physical combination of two broadly neutralizing antibodies (bNAbs) can improve coverage against the majority of viruses, the clinical-grade manufacturing and testing of two independent antibody products are time and resource intensive. In this study, we constructed bispecific immunoglobulins (IgGs) composed of independent antigen-binding fragments with a common Fc region. We developed four different bispecific IgG variants that included antibodies targeting four major sites of HIV-1 neutralization. We show that these bispecific IgGs display features of both antibody specificities and, in some cases, display improved coverage over the individual parental antibodies. All four bispecific IgGs neutralized 94% to 97% of antigenically diverse viruses in a panel of 206 HIV-1 strains. Among the bispecific IgGs tested, VRC07 × PG9-16 displayed the most favorable neutralization profile. It was superior in breadth to either of the individual antibodies, neutralizing 97% of viruses with a median 50% inhibitory concentration (IC50) of 0.055 μg/ml. This bispecific IgG also demonstrated in vivo pharmacokinetic parameters comparable to those of the parental bNAbs when administered to rhesus macaques. These results suggest that IgG-based bispecific antibodies are promising candidates for the prevention and treatment of HIV-1 infection in humans.ImportanceTo prevent or treat HIV-1 infection, antibodies must potently neutralize nearly all strains of HIV-1. Thus, the physical combination of two or more antibodies may be needed to broaden neutralization coverage and diminish the possibility of viral resistance. A bispecific antibody that has two different antibody binding arms could potentially display neutralization characteristics better than those of any single parental antibody. Here we show that bispecific antibodies contain the binding specificities of the two parental antibodies and that a single bispecific antibody can neutralize 97% of viral strains with a high overall potency. These findings support the use of bispecific antibodies for the prevention or treatment of HIV-1 infection.

Project description:The development of HIV broadly neutralizing antibodies (bNAbs) has previously been shown to be associated with viral evolution and high levels of genetic diversity in the HIV envelope (Env) glycoprotein. However, few studies have examined Env evolution in those who fail to develop neutralization breadth in order to assess whether bNAbs result from distinct evolutionary pathways. We compared Env evolution in eight HIV-1-infected participants who developed bNAbs to six donors with similar viral loads who did not develop bNAbs over three years of infection. We focused on Env V1V2 and C3V4, as these are major targets for both strain-specific neutralizing antibodies (nAbs) and bNAbs. Overall evolutionary rates (ranging from 9.92 × 10-3 to 4.1 × 10-2 substitutions/site/year) and viral diversity (from 1.1% to 6.5%) across Env, and within targeted epitopes, did not distinguish bNAb donors from non-bNAb donors. However, bNAb participants had more positively selected residues within epitopes than those without bNAbs, and several of these were common among bNAb donors. A comparison of the kinetics of strain-specific nAbs and bNAbs indicated that selection pressure at these residues increased with the onset of breadth. These data suggest that highly targeted viral evolution rather than overall envelope diversity is associated with neutralization breadth. The association of shared positively selected sites with the onset of breadth highlights the importance of diversity at specific positions in these epitopes for bNAb development, with implications for the development of sequential and cocktail immunization strategies.IMPORTANCE Millions of people are still being infected with HIV decades after the first recognition of the virus. Currently, no vaccine is able to elicit bNAbs that will prevent infection by global HIV strains. Several studies have implicated HIV Env diversity in the development of breadth. However, Env evolution in individuals who fail to develop breadth despite mounting potent strain-specific neutralizing responses has not been well defined. Using longitudinal neutralization, epitope mapping, and sequence data from 14 participants, we found that overall measures of viral diversity were similar in all donors. However, the number of positively selected sites within Env epitopes was higher in bNAb participants than in strain-specific donors. We further identified common sites that were positively selected as bNAbs developed. These data indicate that while viral diversity is required for breadth, this should be highly targeted to specific residues to shape the elicitation of bNAbs by vaccination.

Dataset Information

Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope.

Publications

Broad and Potent Neutralizing Antibodies Recognize the Silent Face of the HIV Envelope.

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