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Induction of cross-reactive HIV-1 specific antibody responses by engineered V1V2 immunogens with reduced conformational plasticity

•K155M stabilizes V1V2 β-strand conformation relevant to broad antibody recognition.•β-strand stabilized V1V2 immunogens elicit antibody responses with greater cross-reactivity.•Fine-tuning immunogen conformation modulates immunogenicity. Antibodies against the HIV-1 V1V2 loops were the only correla... Full description

Journal Title: Vaccine 2020, Vol.38 (18), p.3436-3446
Main Author: Lai, Jennifer I
Other Authors: Eszterhas, Susan K , Brooks, Seth A , Guo, Chengzi , Zolla-Pazner, Susan , Seaman, Michael S , Bailey-Kellogg, Chris , Griswold, Karl E , Ackerman, Margaret E
Format: Electronic Article Electronic Article
Language: English
Subjects:
HIV
Quelle: Alma/SFX Local Collection
Publisher: Netherlands: Elsevier Ltd
ID: ISSN: 0264-410X
Link: https://www.ncbi.nlm.nih.gov/pubmed/32192810
Zum Text:
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title: Induction of cross-reactive HIV-1 specific antibody responses by engineered V1V2 immunogens with reduced conformational plasticity
format: Article
creator:
  • Lai, Jennifer I
  • Eszterhas, Susan K
  • Brooks, Seth A
  • Guo, Chengzi
  • Zolla-Pazner, Susan
  • Seaman, Michael S
  • Bailey-Kellogg, Chris
  • Griswold, Karl E
  • Ackerman, Margaret E
subjects:
  • 1 vaccines
  • AIDS Vaccines
  • Animal models
  • Animals
  • Antibodies
  • Antibodies, Neutralizing
  • Antibody Formation
  • Antibody response
  • Antigenicity
  • Antigens
  • Article
  • based immunogen design
  • Binding sites
  • Coils
  • Conformation
  • Context
  • Glycoprotein gp120
  • Glycoproteins
  • Health risks
  • HIV
  • HIV Antibodies
  • HIV Envelope Protein gp120 - genetics
  • HIV Infections
  • HIV-1 - genetics
  • HIV-1 vaccines
  • Human immunodeficiency virus
  • Immunization
  • Immunogenicity
  • Infections
  • Mice
  • Peptides
  • Plastic properties
  • Plasticity
  • Structure
  • Structure-based immunogen design
  • V1V2 loops
  • Vaccines
  • Viruses
ispartof: Vaccine, 2020, Vol.38 (18), p.3436-3446
description: •K155M stabilizes V1V2 β-strand conformation relevant to broad antibody recognition.•β-strand stabilized V1V2 immunogens elicit antibody responses with greater cross-reactivity.•Fine-tuning immunogen conformation modulates immunogenicity. Antibodies against the HIV-1 V1V2 loops were the only correlate of reduced infection risk in the RV144 vaccine trial, highlighting the V1V2 loops as promising targets for vaccine design. The V1V2 loops are structurally plastic, exhibiting either an α-helix-coil or β-strand conformation. V1V2-specific antibodies may thus recognize distinct conformations, and an antibody’s conformational specificity can be an important determinant of breadth and function. Restricting V1V2 conformational plasticity in an immunogen may thus provide control over the conformational specificity and quality of a vaccine-elicited antibody response. Previously, we identified a V1V2 sequence variant (K155M) that results in enhanced recognition by cross-reactive antibodies recognizing the β-strand conformation. Here, we relate V1V2 antigenicity to immunogenicity by comparing the immunogenicity profiles of wildtype and K155M immunogens in two mouse models. In one model, immunization with gp70 V1V2 K155M but not wildtype elicited antibody responses that were cross-reactive to a panel of heterologous gp120 and gp140 antigens. In a second model, we compared the effect of K155M on immunogenicity in the context of gp70 V1V2, gD V1V2 and gp120, examining the effects of scaffold, epitope-focusing and immunization regimen. K155M variants, especially in the context of a gp120 immunogen, resulted in more robust, durable and cross-reactive antibody responses than wildtype immunogens. Restriction of the β-stranded V1V2 conformation in K155M immunogens may thus be associated with the induction of cross-reactive antibody responses thought to be required of a protective HIV-1 vaccine.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0264-410X
fulltext: fulltext
issn:
  • 0264-410X
  • 1873-2518
url: Link


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titleInduction of cross-reactive HIV-1 specific antibody responses by engineered V1V2 immunogens with reduced conformational plasticity
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creatorLai, Jennifer I ; Eszterhas, Susan K ; Brooks, Seth A ; Guo, Chengzi ; Zolla-Pazner, Susan ; Seaman, Michael S ; Bailey-Kellogg, Chris ; Griswold, Karl E ; Ackerman, Margaret E
creatorcontribLai, Jennifer I ; Eszterhas, Susan K ; Brooks, Seth A ; Guo, Chengzi ; Zolla-Pazner, Susan ; Seaman, Michael S ; Bailey-Kellogg, Chris ; Griswold, Karl E ; Ackerman, Margaret E
description•K155M stabilizes V1V2 β-strand conformation relevant to broad antibody recognition.•β-strand stabilized V1V2 immunogens elicit antibody responses with greater cross-reactivity.•Fine-tuning immunogen conformation modulates immunogenicity. Antibodies against the HIV-1 V1V2 loops were the only correlate of reduced infection risk in the RV144 vaccine trial, highlighting the V1V2 loops as promising targets for vaccine design. The V1V2 loops are structurally plastic, exhibiting either an α-helix-coil or β-strand conformation. V1V2-specific antibodies may thus recognize distinct conformations, and an antibody’s conformational specificity can be an important determinant of breadth and function. Restricting V1V2 conformational plasticity in an immunogen may thus provide control over the conformational specificity and quality of a vaccine-elicited antibody response. Previously, we identified a V1V2 sequence variant (K155M) that results in enhanced recognition by cross-reactive antibodies recognizing the β-strand conformation. Here, we relate V1V2 antigenicity to immunogenicity by comparing the immunogenicity profiles of wildtype and K155M immunogens in two mouse models. In one model, immunization with gp70 V1V2 K155M but not wildtype elicited antibody responses that were cross-reactive to a panel of heterologous gp120 and gp140 antigens. In a second model, we compared the effect of K155M on immunogenicity in the context of gp70 V1V2, gD V1V2 and gp120, examining the effects of scaffold, epitope-focusing and immunization regimen. K155M variants, especially in the context of a gp120 immunogen, resulted in more robust, durable and cross-reactive antibody responses than wildtype immunogens. Restriction of the β-stranded V1V2 conformation in K155M immunogens may thus be associated with the induction of cross-reactive antibody responses thought to be required of a protective HIV-1 vaccine.
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subject1 vaccines ; AIDS Vaccines ; Animal models ; Animals ; Antibodies ; Antibodies, Neutralizing ; Antibody Formation ; Antibody response ; Antigenicity ; Antigens ; Article ; based immunogen design ; Binding sites ; Coils ; Conformation ; Context ; Glycoprotein gp120 ; Glycoproteins ; Health risks ; HIV ; HIV Antibodies ; HIV Envelope Protein gp120 - genetics ; HIV Infections ; HIV-1 - genetics ; HIV-1 vaccines ; Human immunodeficiency virus ; Immunization ; Immunogenicity ; Infections ; Mice ; Peptides ; Plastic properties ; Plasticity ; Structure ; Structure-based immunogen design ; V1V2 loops ; Vaccines ; Viruses
ispartofVaccine, 2020, Vol.38 (18), p.3436-3446
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description•K155M stabilizes V1V2 β-strand conformation relevant to broad antibody recognition.•β-strand stabilized V1V2 immunogens elicit antibody responses with greater cross-reactivity.•Fine-tuning immunogen conformation modulates immunogenicity. Antibodies against the HIV-1 V1V2 loops were the only correlate of reduced infection risk in the RV144 vaccine trial, highlighting the V1V2 loops as promising targets for vaccine design. The V1V2 loops are structurally plastic, exhibiting either an α-helix-coil or β-strand conformation. V1V2-specific antibodies may thus recognize distinct conformations, and an antibody’s conformational specificity can be an important determinant of breadth and function. Restricting V1V2 conformational plasticity in an immunogen may thus provide control over the conformational specificity and quality of a vaccine-elicited antibody response. Previously, we identified a V1V2 sequence variant (K155M) that results in enhanced recognition by cross-reactive antibodies recognizing the β-strand conformation. Here, we relate V1V2 antigenicity to immunogenicity by comparing the immunogenicity profiles of wildtype and K155M immunogens in two mouse models. In one model, immunization with gp70 V1V2 K155M but not wildtype elicited antibody responses that were cross-reactive to a panel of heterologous gp120 and gp140 antigens. In a second model, we compared the effect of K155M on immunogenicity in the context of gp70 V1V2, gD V1V2 and gp120, examining the effects of scaffold, epitope-focusing and immunization regimen. K155M variants, especially in the context of a gp120 immunogen, resulted in more robust, durable and cross-reactive antibody responses than wildtype immunogens. Restriction of the β-stranded V1V2 conformation in K155M immunogens may thus be associated with the induction of cross-reactive antibody responses thought to be required of a protective HIV-1 vaccine.
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28Infections
29Mice
30Peptides
31Plastic properties
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33Structure
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36Vaccines
37Viruses
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titleInduction of cross-reactive HIV-1 specific antibody responses by engineered V1V2 immunogens with reduced conformational plasticity
authorLai, Jennifer I ; Eszterhas, Susan K ; Brooks, Seth A ; Guo, Chengzi ; Zolla-Pazner, Susan ; Seaman, Michael S ; Bailey-Kellogg, Chris ; Griswold, Karl E ; Ackerman, Margaret E
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01 vaccines
1AIDS Vaccines
2Animal models
3Animals
4Antibodies
5Antibodies, Neutralizing
6Antibody Formation
7Antibody response
8Antigenicity
9Antigens
10Article
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12Binding sites
13Coils
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15Context
16Glycoprotein gp120
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18Health risks
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20HIV Antibodies
21HIV Envelope Protein gp120 - genetics
22HIV Infections
23HIV-1 - genetics
24HIV-1 vaccines
25Human immunodeficiency virus
26Immunization
27Immunogenicity
28Infections
29Mice
30Peptides
31Plastic properties
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33Structure
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abstract•K155M stabilizes V1V2 β-strand conformation relevant to broad antibody recognition.•β-strand stabilized V1V2 immunogens elicit antibody responses with greater cross-reactivity.•Fine-tuning immunogen conformation modulates immunogenicity. Antibodies against the HIV-1 V1V2 loops were the only correlate of reduced infection risk in the RV144 vaccine trial, highlighting the V1V2 loops as promising targets for vaccine design. The V1V2 loops are structurally plastic, exhibiting either an α-helix-coil or β-strand conformation. V1V2-specific antibodies may thus recognize distinct conformations, and an antibody’s conformational specificity can be an important determinant of breadth and function. Restricting V1V2 conformational plasticity in an immunogen may thus provide control over the conformational specificity and quality of a vaccine-elicited antibody response. Previously, we identified a V1V2 sequence variant (K155M) that results in enhanced recognition by cross-reactive antibodies recognizing the β-strand conformation. Here, we relate V1V2 antigenicity to immunogenicity by comparing the immunogenicity profiles of wildtype and K155M immunogens in two mouse models. In one model, immunization with gp70 V1V2 K155M but not wildtype elicited antibody responses that were cross-reactive to a panel of heterologous gp120 and gp140 antigens. In a second model, we compared the effect of K155M on immunogenicity in the context of gp70 V1V2, gD V1V2 and gp120, examining the effects of scaffold, epitope-focusing and immunization regimen. K155M variants, especially in the context of a gp120 immunogen, resulted in more robust, durable and cross-reactive antibody responses than wildtype immunogens. Restriction of the β-stranded V1V2 conformation in K155M immunogens may thus be associated with the induction of cross-reactive antibody responses thought to be required of a protective HIV-1 vaccine.
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