Rapid selection of HIV envelopes that bind to neutralizing antibody B cell lineage members with functional improbable mutations

Swanson, Olivia; Rhodes, Brianna; Wang, Avivah; Xia, Shi-Mao; Parks, Robert; Chen, Haiyan; Sanzone, Aja; Cooper, Melissa; Louder, Mark K.; Lin, Bob C.; Doria‐Rose, Nicole A.; Bonsignori, Mattia; Saunders, Kevin O.; Wiehe, Kevin; Haynes, Barton F.; Azoitei, Mihai L.

doi:10.1016/j.celrep.2021.109561

Cited by 11 publications

(22 citation statements)

References 62 publications

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“…HIV-1 bNAbs obtain a large number of somatic mutations, but not all mutations are functionally important. B cells evolve by positive selection to identify boosting candidate immunogens ( Swanson et al., 2021 ). In line with previous observations from viremic controllers or elite controllers ( Freund et al., 2017 ; Kumar et al., 2019 ), we observed that autologous plasmas can potently neutralize viruses not only from earlier time points but also from concurrent and later time points.…”

Section: Discussionmentioning

confidence: 99%

Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time

Wang

Liang

Huang

et al. 2022

Front. Cell. Infect. Microbiol.

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The diversity of HIV-1 envelope (Env) glycoproteins affects the potency and breadth of broadly neutralizing antibodies (bNAbs), a promising alternative to antiretroviral drugs for the prevention and treatment of HIV-1 infection. To facilitate immunogen design and development of therapeutic neutralizing antibodies, we characterized viral evolution and monitored the changes in neutralizing activity/sensitivity of a long-term non-progressor patient with HIV-1 CRF07_BC infection. Fifty-nine full-length Env gene fragments were derived from four plasma samples sequentially harvested from the patient between 2016 and 2020. Sequencing of patient-derived Env genes revealed that potential N-linked glycosylation sites (PNGS) in V1 and V5 significantly increased over time. Further, 24 functional Env-pseudotyped viruses were generated based on Env gene sequences. While all 24 Env-pseudotyped viruses remained sensitive to concurrent and subsequent autologous plasma, as well as bNAbs, including 10E8, VRC01, and 12A21, Env-pseudotyped viruses corresponding to later sampling time were increasingly more resistant to autologous plasma and bNAbs. All 24 Env-pseudotyped viruses were resistant to bNAbs 2G12, PGT121, and PGT135. The neutralization breadth of plasma from all four sequential samples was 100% against the global HIV-1 reference panel. Immune escape mutants resulted in increased resistance to bNAb targeting of different epitopes. Our study identified known mutations F277W in gp41 and previously uncharacterized mutation S465T in V5 which may be associated with increased viral resistance to bNAbs.

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Section: Discussionmentioning

confidence: 99%

Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time

Wang

Liang

Huang

et al. 2022

Front. Cell. Infect. Microbiol.

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“…For vaccine types that do not rely on viral replication, Env immunogens would need to contain a shorter V1V2 loop and lack the N413 glycan to expand the desired DH270-like bnAb precursors. Then, Envs that could elicit improbable mutations in DH270-lineage members, as described elsewhere, would be used ( 16 , 17 , 29 ). This regimen would be analogous to the prime-boost regimens previously used for the CH103 and CH235 cooperating bnAb lineages, for which structural investigations guided the development of immunogens that elicited long-lasting antibody responses in macaques ( 12 – 14 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of two cooperating antibodies unveils immune pressure imposed on HIV Env to elicit a V3-glycan supersite broadly neutralizing antibody lineage

Finkelstein

Miller²,

Erdman³

et al. 2022

Front. Immunol.

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Elicitation of broadly neutralizing antibodies (bnAbs) is a goal of vaccine design as a strategy for targeting highly divergent strains of HIV-1. Current HIV-1 vaccine design efforts seek to elicit bnAbs by first eliciting their precursors through prime-boost regimens. This requires an understanding of the co-evolution between viruses and antibodies. Towards this goal, we have analyzed two cooperating antibodies, DH475 and DH272, which exerted pressure on the HIV population in an infected donor, called CH848, to evolve in such a way that it became sensitive to the V3-glycan supersite DH270 bnAb lineage. We obtained a 2.90Å crystal structure of DH475 in complex with the Man9 glycan and a negative stain EM model of DH272 in complex with the HIV-1 spike trimer, Env. Coupled with additional modeling studies and biochemical data, our studies reveal that DH475 contacts a V3- and V4-glycan dependent epitope accessible on an open or shed Env and that DH272 makes critical contacts with the V1V2 and V3 loops on HIV-1 Env. Using these data, we suggest a prime-boost regimen that may facilitate the initiation of DH270-like bnAb precursors.

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“…Similar mutations occur in the I2 intermediate, most notably an F101C mutation spatially adjacent to the LCDR3 base that results in the formation of an additional disulfide bond in the antibody between residues 91 and 101 (Supplemental Figure 9D). This mutation is among the previously described minimal set of mutations needed to reach ~90% of DH270.6 breadth 29 . A considerable number of mutations in and affecting LDCR3 were also a part of the minDH270 construct and have distinct effects on epitope interaction in the I2 intermediate bound structure.…”

Section: Maturation After I3: a Complex Series Of Mutations In I2 Res...mentioning

confidence: 99%

“…Particles were picked automatically using a Gaussian disk of 80 Å in radius as the search template. All the picked particles were extracted with box size of 384 pixels and down scaled to 192 pixels (binning 2) and subjected to 8 rounds of refinement in cisTEM 29 , using an ab-initio model generated with cryoSPARC 26 . The distribution of scores assigned to each particle by cisTEM showed a clear bi-modal distribution and only particles in the group containing the higher scores were selected for further processing.…”

Section: Data Processingmentioning

confidence: 99%

“…HIV-1 bnAbs, including those in the DH270 clone, are enriched for key, low probability mutations 17 . Second, of the forty-two mutations in the most broad and potent member in this clone, only twelve are needed to reach ninety percent of its breadth, allowing us to pinpoint the most critical regions of the antibody that need to be optimized 29 . Finally, key for considering affinity maturation in the context of vaccine development, we have shown that rationally designed immunogens can expand DH270 bnAb V3-glycan precursors 22 .…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for breadth development in a HIV-1 neutralizing antibody

Henderson

Zhou

Stalls

et al. 2022

Preprint

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Antibody affinity maturation enables adaptive immune responses to a wide range of pathogens. In some individuals broadly neutralizing antibodies develop to recognize rapidly mutating pathogens with extensive sequence diversity. Vaccine design for pathogens such as HIV-1 and influenza have therefore focused on recapitulating the natural affinity maturation process. Here, we determined structures of antibodies in complex with HIV-1 Envelope for all observed members and ancestral states of a broadly neutralizing HIV-1 antibody clonal B cell lineage. These structures track the development of neutralization breadth from the unmutated common ancestor and define affinity maturation at high spatial resolution. By elucidating contacts mediated by key mutations at different stages of antibody development we have identified sites on the epitope-paratope interface that are the focus of affinity optimization. Thus, our results identify bottlenecks on the path to natural affinity maturation and reveal solutions for these that will inform immunogen design aimed at eliciting a broadly neutralizing immune response by vaccination.

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Rapid selection of HIV envelopes that bind to neutralizing antibody B cell lineage members with functional improbable mutations

Cited by 11 publications

References 62 publications

Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time

Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time

Analysis of two cooperating antibodies unveils immune pressure imposed on HIV Env to elicit a V3-glycan supersite broadly neutralizing antibody lineage

Structural basis for breadth development in a HIV-1 neutralizing antibody

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