Antiviral neutralizing antibodies: from in vitro to in vivo activity

Burton, Dennis R.

doi:10.1038/s41577-023-00858-w

Cited by 30 publications

(21 citation statements)

References 225 publications

(301 reference statements)

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“…To conclude, the multiple possibilities above notwithstanding, we favor the following causalities: differences in glycans between BG505 and B41 Env, and within the latter trimer population, stably confer distinct conformational propensities; B41 Env is thus more prone than BG505 Env to adopt a partially open conformation; the opening reduces the stoichiometry, because steric clashes would prevent PGT151 from binding; and the reduced stoichiometry, in turn, yields sub-neutralizing bNAb occupancy on Env and causes the PF (Fig. 8 ) [ 3 , 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…Neutralizing antibodies (NAbs), whether induced by infection or vaccination, are the best correlate of protection against viral infections in general [ 1 – 3 ]. Neutralization is defined as interrupting the viral replicative cycle before the first virally encoded transcriptional event by the binding of the neutralizing agent to the virion surface [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Conformational antigenic heterogeneity as a cause of the persistent fraction in HIV-1 neutralization

et al. 2023

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Background Neutralizing antibodies (NAbs) protect against HIV-1 acquisition in animal models and show promise in treatment of infection. They act by binding to the viral envelope glycoprotein (Env), thereby blocking its receptor interactions and fusogenic function. The potency of neutralization is largely determined by affinity. Less well explained is the persistent fraction, the plateau of remaining infectivity at the highest antibody concentrations. Results We observed different persistent fractions for neutralization of pseudovirus derived from two Tier-2 isolates of HIV-1, BG505 (Clade A) and B41 (Clade B): it was pronounced for B41 but not BG505 neutralization by NAb PGT151, directed to the interface between the outer and transmembrane subunits of Env, and negligible for either virus by NAb PGT145 to an apical epitope. Autologous neutralization by poly- and monoclonal NAbs from rabbits immunized with soluble native-like B41 trimer also left substantial persistent fractions. These NAbs largely target a cluster of epitopes lining a hole in the dense glycan shield of Env around residue 289. We partially depleted B41-virion populations by incubating them with PGT145- or PGT151-conjugated beads. Each depletion reduced the sensitivity to the depleting NAb and enhanced it to the other. Autologous neutralization by the rabbit NAbs was decreased for PGT145-depleted and enhanced for PGT151-depleted B41 pseudovirus. Those changes in sensitivity encompassed both potency and the persistent fraction. We then compared soluble native-like BG505 and B41 Env trimers affinity-purified by each of three NAbs: 2G12, PGT145, or PGT151. Surface plasmon resonance showed differences among the fractions in antigenicity, including kinetics and stoichiometry, congruently with the differential neutralization. The large persistent fraction after PGT151 neutralization of B41 was attributable to low stoichiometry, which we explained structurally by clashes that the conformational plasticity of B41 Env causes. Conclusion Distinct antigenic forms even of clonal HIV-1 Env, detectable among soluble native-like trimer molecules, are distributed over virions and may profoundly mold neutralization of certain isolates by certain NAbs. Affinity purifications with some antibodies may yield immunogens that preferentially expose epitopes for broadly active NAbs, shielding less cross-reactive ones. NAbs reactive with multiple conformers will together reduce the persistent fraction after passive and active immunization.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conformational antigenic heterogeneity as a cause of the persistent fraction in HIV-1 neutralization

et al. 2023

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“…Such combined net effects would increase or decrease the stoichiometry of binding. Ultimately, as a result, the stoichiometry falls above or below a minimum threshold of paratopes bound per virion required for neutralization [1,7,24,79,84,[114][115][116].…”

Section: Plos Pathogensmentioning

confidence: 99%

“…Neutralizing antibodies (NAbs) are the best correlate of protection against several viral infections [1][2][3][4][5][6][7]. Broadly active NAbs (bNAbs) protect against HIV-1 acquisition in animal models, but eliciting them through active immunization with their sole target, the viral envelope glycoprotein (Env), has proved elusive [8][9][10][11][12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Glycan heterogeneity as a cause of the persistent fraction in HIV-1 neutralization

Ringe,

Colin,

Ozorowski

et al. 2023

PLoS Pathog

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Neutralizing antibodies (NAbs) to multiple epitopes on the HIV-1-envelope glycoprotein (Env) have been isolated from infected persons. The potency of NAbs is measured more often than the size of the persistent fraction of infectivity at maximum neutralization, which may also influence preventive efficacy of active or passive immunization and the therapeutic outcome of the latter. Many NAbs neutralize HIV-1 CZA97.012, a clone of a Clade-C isolate, to ~100%. But here NAb PGT151, directed to a fusion-peptide epitope, left a persistent fraction of 15%. NAb PGT145, ligating the Env-trimer apex, left no detectable persistent fraction. The divergence in persistent fractions was further analyzed by depletion of pseudoviral populations of the most PGT151- and PGT145-reactive virions. Thereby, neutralization by the non-depleting NAb increased, whereas neutralization by the depleting NAb decreased. Furthermore, depletion by PGT151 increased sensitivity to autologous neutralization by sera from rabbits immunized with soluble native-like CZA97.012 trimer: substantial persistent fractions were reduced. NAbs in these sera target epitopes comprising residue D411 at the V4-β19 transition in a defect of the glycan shield on CZA97.012 Env. NAb binding to affinity-fractionated soluble native-like CZA97.012 trimer differed commensurately with neutralization in analyses by ELISA and surface plasmon resonance. Glycan differences between PGT151- and PGT145-purified trimer fractions were then demonstrated by mass spectrometry, providing one explanation for the differential antigenicity. These differences were interpreted in relation to a new structure at 3.4-Å resolution of the soluble CZA97.012 trimer determined by cryo-electron microscopy. The trimer adopted a closed conformation, refuting apex opening as the cause of reduced PGT145 binding to the PGT151-purified form. The evidence suggests that differences in binding and neutralization after trimer purification or pseudovirus depletion with PGT145 or PGT151 are caused by variation in glycosylation, and that some glycan variants affect antigenicity through direct effects on antibody contacts, whereas others act allosterically.

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“…While neutralizing antibodies are likely the most effective way to block viral infection, nonneutralizing antibody and cellular immune responses that control virus replication post entry are also thought to be important (reviewed by [5] and [6]). These responses were evaluated in two recent vaccine efficacy trials, the Imbokodo (HVTN705/HPX2008) and Mosaico (HVTN706/HPX3002) trials.…”

Section: Introductionmentioning

confidence: 99%

Anticipating HIV viral escape – resistance to active and passive immunization

Williamson,

Lynch,

Moore

2023

Current Opinion in HIV and AIDS

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Purpose Active and passive immunization strategies are challenged by the extraordinary diversity of HIV, and the need for high titers of neutralizing antibodies to confer protective immunity. This review summarises recent studies and the barrier that these interventions will need to overcome to prevent viral resistance. Recent findings Studies from the antibody mediated prevention trial identified a measure of protective titers, finding that higher titers than anticipated will be needed to prevent infection. This benchmark has advanced our ability to predict combinations of broadly neutralizing antibodies (bNAbs) that will provide optimal coverage. To limit escape, these combinations should ensure that the majority of viruses are bound by a minimum of two antibodies. The characterization of currently circulating viruses has revealed increased resistance to some bNAbs over time, highlighting the need for continued surveillance, especially in under-studied populations and subtypes. Active vaccination will face similar challenges in combating diversity, although despite successes in germline targeting, this approach is not yet able to elicit bNAbs. Summary Cumulatively these studies highlight the need to target multiple antibody epitopes for maximum coverage, but also to restrict escape pathways. Successful immunization strategies should anticipate viral escape and devise strategies to counteract this.

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Antiviral neutralizing antibodies: from in vitro to in vivo activity

Cited by 30 publications

References 225 publications

Conformational antigenic heterogeneity as a cause of the persistent fraction in HIV-1 neutralization

Conformational antigenic heterogeneity as a cause of the persistent fraction in HIV-1 neutralization

Glycan heterogeneity as a cause of the persistent fraction in HIV-1 neutralization

Anticipating HIV viral escape – resistance to active and passive immunization

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