A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies

Bibollet-Ruche, Frédéric; Russell, Ronnie M.; Ding, Wenge; Liu, Weimin; Li, Yingying; Wagh, Kshitij; Wrapp, Daniel; Habib, Rumi; Skelly, Ashwin N.; Roark, Ryan S.; Sherrill-Mix, Scott; Wang, Shuyi; Rando, Juliette; Lindemuth, Emily; Cruickshank, Kendra; Park, Young-Hoon; Baum, Rachel; Carey, John W; Connell, Andrew Jesse; Li, Hui; Giorgi, Elena E.; Ge, Song; Ding, Shilei; Finzi, Andrés; Newman, Amanda; Hernandéz, Giovanna; Machiele, Emily; Cain, Derek W.; Mansouri, Katayoun; Lewis, Mark G.; Montefiori, David C.; Wiehe, Kevin; Alam, S. Munir; Teng, I-Ting; Kwong, Peter D.; Andrabi, Raiees; Verkoczy, Laurent; Burton, Dennis R.; Korber, Bette T.; Saunders, Kevin O.; Haynes, Barton F.; Edwards, Robert J.; Shaw, George M.; Hahn, Beatrice H.

doi:10.1128/mbio.03370-22

Cited by 7 publications

(6 citation statements)

References 99 publications

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“…A number of other V2 apex-targeting strategies have also been designed and tested for eliciting Ab responses targeted to the V2 apex. These strategies were exemplified by clade C-based UFO designs with structure-guided mutations at the V2 apex that elicited autologous neutralization in rabbits ( 46 ), germline targeting immunogens that activated the human V2-apex bNAb heavy-chain precursor-expressing B cells in knock-in mice ( 26 ), V2-apex bNAb inferred precursor-binding SOSIPs that improved exposure of the V2-apex region ( 49 ), and signature-based epitope targeted vaccines that broadened neutralizing Ab responses in immunized guinea pigs ( 50 ). Nonetheless, vaccines capable of generating the prototypic V2-apex bNAbs in wild-type animals remain elusive.…”

Section: Discussionmentioning

confidence: 99%

“…These V2-apex bNAbs preferentially bind Env as trimers, recognize N -glycans on the V1V2 apical surface as part of their epitopes, and require that the V2C-strand assumes a beta-sheet conformation ( 21 – 25 ). The V2w class mAbs from rhesus macaques infected with chimeric simian-chimpanzee immunodeficiency viruses were recently reported and shown to target the V2 apex, but these mAbs neutralize weakly because the V2w epitopes are occluded in the native closed Env conformation ( 26 ). The fourth class of mAbs, V2i, targets epitopes near the integrin α4β7-binding motif at the underbelly of V1V2 ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

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Vaccination with immune complexes modulates the elicitation of functional antibodies against HIV-1

Hioe,

Liu,

Banin

et al. 2023

Front. Immunol.

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IntroductionNeutralizing antibodies (Abs) are one of the immune components required to protect against viral infections. However, developing vaccines capable of eliciting neutralizing Abs effective against a broad array of HIV-1 isolates has been an arduous challenge.ObjectiveThis study sought to test vaccines aimed to induce Abs against neutralizing epitopes at the V1V2 apex of HIV-1 envelope (Env).MethodsFour groups of rabbits received a DNA vaccine expressing the V1V2 domain of the CRF01_AE A244 strain on a trimeric 2J9C scaffold (V1V2-2J9C) along with a protein vaccine consisting of an uncleaved prefusion-optimized A244 Env trimer with V3 truncation (UFO-BG.ΔV3) or a V1V2-2J9C protein and their respective immune complexes (ICs). These IC vaccines were made using 2158, a V1V2-specific monoclonal Ab (mAb), which binds the V2i epitope in the underbelly region of V1V2 while allosterically promoting the binding of broadly neutralizing mAb PG9 to its V2 apex epitope in vitro.ResultsRabbit groups immunized with the DNA vaccine and uncomplexed or complexed UFO-BG.ΔV3 proteins (DNA/UFO-UC or IC) displayed similar profiles of Env- and V1V2-binding Abs but differed from the rabbits receiving the DNA vaccine and uncomplexed or complexed V1V2-2J9C proteins (DNA/V1V2-UC or IC), which generated more cross-reactive V1V2 Abs without detectable binding to gp120 or gp140 Env. Notably, the DNA/UFO-UC vaccine elicited neutralizing Abs against some heterologous tier 1 and tier 2 viruses from different clades, albeit at low titers and only in a fraction of animals, whereas the DNA/V1V2-UC or IC vaccines did not. In comparison with the DNA/UFO-UC group, the DNA/UFO-IC group showed a trend of higher neutralization against TH023.6 and a greater potency of V1V2-specific Ab-dependent cellular phagocytosis (ADCP) but failed to neutralize heterologous viruses.ConclusionThese data demonstrate the capacity of V1V2-2J9C-encoding DNA vaccine in combination with UFO-BG.ΔV3, but not V1V2-2J9C, protein vaccines, to elicit homologous and heterologous neutralizing activities in rabbits. The elicitation of neutralizing and ADCP activities was modulated by delivery of UFO-BG.ΔV3 complexed with V2i mAb 2158.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vaccination with immune complexes modulates the elicitation of functional antibodies against HIV-1

Hioe,

Liu,

Banin

et al. 2023

Front. Immunol.

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Section: Progress In Duke the Consortia For Hiv/aids Vaccine Developm...mentioning

confidence: 99%

“…To overcome the dearth of V2-glycan bnAb precursors, Hahn et al have used neutralization signature analysis [ 65 ] to define Envs that can bind and trigger multiple V2 glycan UCAs [ 66 ]. They have begun to use such Envs to explore the types of V2-directed antibodies they induce [ 66 ]. Hahn and team have also defined simian immunodeficiency viruses that induce Env V2 targeted responses that may be used as boosts for V2 UCAs expanded by HIV Envs [ 67 , 68 ].…”

Section: Progress In Duke the Consortia For Hiv/aids Vaccine Developm...mentioning

confidence: 99%

Progress with induction of HIV broadly neutralizing antibodies in the Duke Consortia for HIV/AIDS Vaccine Development

Haynes,

Wiehe,

Alam

et al. 2023

Current Opinion in HIV and AIDS

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Purpose of review Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather HIV bnAbs are disfavored by a number of virus and host factors. The purpose of the review is to discuss recent progress made in the design and use of immunogens capable of inducing HIV bnAbs in the Duke Consortia for HIV/AIDS Vaccine Development. Recent findings New immunogens capable of binding with high affinity to unmutated common ancestors (UCAs) of bnAb B cell lineages have been designed and strategies for stabilization of HIV Env in its prefusion state are being developed. Success is starting to be translated from preclinical studies of UCA-targeting immunogens in animals, to success of initiating bnAb lineages in humans. Summary Recent progress has been made in both immunogen design and in achieving bnAb B cell lineage induction in animal models and now in human clinical trials. With continued progress, a practical HIV/AIDS vaccine may be possible. However, host constraints on full bnAb maturation remain as potential roadblocks for full maturation of some types of bnAbs.

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“…All three SCIVs encoded the wildtype His at position 375 of the envelope glycoprotein. Plasma viral loads were determined as previously described 40,53 . All animals received an intravenous infusion of 25 mg/kg of the anti-CD8b mAb CD8beta255R1 at the time of SCIV inoculation.…”

Section: Experimental Model and Subject Detailsmentioning

confidence: 99%

Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model

Musharrafieh,

Safonova,

Song

et al. 2023

Preprint

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Eliciting broadly neutralizing antibodies-(bnAbs) remains a major goal of HIV-1 vaccine research. Previously, we showed that a soluble chimpanzee SIV Envelope-(Env) trimer, MT145K, bound several human V2-apex bnAb-precursors and stimulated an appropriate response in V2-apex bnAb precursor-expressing knock-in mice. Here, we tested the immunogenicity of three MT145 variants (MT145, MT145K, MT145K.dV5) expressed as chimeric simian-chimpanzee-immunodeficiency-viruses-(SCIVs) in rhesus macaques-(RMs). All three viruses established productive infections with high setpoint vRNA titers. RMs infected with the germline-targeting SCIV_MT145K and SCIV_MT145K.dV5 exhibited larger and more clonally expanded B cell lineages featuring long anionic heavy chain complementary-determining-regions-(HCDR3s) compared with wildtype SCIV_MT145. Moreover, antigen-specific B cell analysis revealed enrichment for long-CDHR3-bearing antibodies in SCIV_MT145K.dV5 infected animals with paratope features resembling prototypic V2-apex bnAbs and their precursors. Although none of the animals developed bnAbs, these results show that germline-targeting SCIVs can activate and preferentially expand B cells expressing V2-apex bnAb-like precursors, the first step in bnAb elicitation.

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A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies

Cited by 7 publications

References 99 publications

Vaccination with immune complexes modulates the elicitation of functional antibodies against HIV-1

Vaccination with immune complexes modulates the elicitation of functional antibodies against HIV-1

Progress with induction of HIV broadly neutralizing antibodies in the Duke Consortia for HIV/AIDS Vaccine Development

Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model

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