Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection
ABSTRACT A prophylactic HIV vaccine would ideally induce protective immunity prior to sexual debut. Children develop broadly neutralizing antibody (bnAb) responses faster and at higher frequencies than adults, but little is known about the underlying mechanisms or the potential role of Fc-mediated e...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2020-12-01
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| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSphere.00880-20 |
| _version_ | 1818427830783967232 |
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| author | M. Muenchhoff A. W. Chung J. Roider Anne-Sophie Dugast Simone Richardson Henrik Kløverpris Alasdair Leslie Thumbi Ndung’u Penny Moore Galit Alter Philip J. R. Goulder |
| author_facet | M. Muenchhoff A. W. Chung J. Roider Anne-Sophie Dugast Simone Richardson Henrik Kløverpris Alasdair Leslie Thumbi Ndung’u Penny Moore Galit Alter Philip J. R. Goulder |
| author_sort | M. Muenchhoff |
| collection | DOAJ |
| description | ABSTRACT A prophylactic HIV vaccine would ideally induce protective immunity prior to sexual debut. Children develop broadly neutralizing antibody (bnAb) responses faster and at higher frequencies than adults, but little is known about the underlying mechanisms or the potential role of Fc-mediated effector functions in disease progression. We therefore performed systems immunology, with immunoglobulin profiling, on HIV-infected children with progressive and nonprogressive disease. Pediatric nonprogressors (PNPs) showed distinct immunoglobulin profiles with an increased ability to elicit potent Fc-mediated natural killer (NK)-cell effector functions. In contrast to previous reports in adults, both groups of children showed high levels of gp120-specific IgG Fc glycan sialylation compared to bulk IgG. Importantly, higher levels of Fc glycan sialylation were associated with increased bnAb breadth, providing the first evidence that Fc sialylation may drive affinity maturation of HIV-specific antibodies in children, a mechanism that could be exploited for vaccination strategies. IMPORTANCE To protect future generations against HIV, a vaccine will need to induce immunity by the time of sexual debut and hence requires immunization during childhood. Current strategies for a prophylactic HIV vaccine include the induction of a broadly neutralizing antibody response and the recruitment of potent effector functions of immune cells via the constant antibody Fc region. In this study, we show that nonprogressing HIV-infected children mounted antibody responses against HIV that were able to mediate potent Fc effector functions, which may contribute to the control of HIV replication. Children who had specific glycan structures on the Fc portion of antibodies against HIV were able to neutralize a broader range of HIV variants, providing evidence of a potential role of Fc glycovariation in the development of bnAbs against HIV. These findings complement our knowledge of the distinct immune landscape in early life that could be exploited in the development of vaccine strategies. |
| first_indexed | 2024-12-14T14:51:58Z |
| format | Article |
| id | doaj.art-f66d862dd1194fa4867e6134d3109279 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-12-14T14:51:58Z |
| publishDate | 2020-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-f66d862dd1194fa4867e6134d31092792022-12-21T22:57:06ZengAmerican Society for MicrobiologymSphere2379-50422020-12-015610.1128/mSphere.00880-20Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV InfectionM. Muenchhoff0A. W. Chung1J. Roider2Anne-Sophie Dugast3Simone Richardson4Henrik Kløverpris5Alasdair Leslie6Thumbi Ndung’u7Penny Moore8Galit Alter9Philip J. R. Goulder10Department of Paediatrics, University of Oxford, Oxford, United KingdomDepartment of Immunology and Microbiology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, AustraliaDepartment of Paediatrics, University of Oxford, Oxford, United KingdomRubius Diagnostics, Cambridge, Massachusetts, USACentre for HIV and STI’s, National Institute for Communicable Diseases, Johannesburg, South AfricaAfrica Health Research Institute (AHRI), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaAfrica Health Research Institute (AHRI), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaCentre for HIV and STI’s, National Institute for Communicable Diseases, Johannesburg, South AfricaThe Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USADepartment of Paediatrics, University of Oxford, Oxford, United KingdomABSTRACT A prophylactic HIV vaccine would ideally induce protective immunity prior to sexual debut. Children develop broadly neutralizing antibody (bnAb) responses faster and at higher frequencies than adults, but little is known about the underlying mechanisms or the potential role of Fc-mediated effector functions in disease progression. We therefore performed systems immunology, with immunoglobulin profiling, on HIV-infected children with progressive and nonprogressive disease. Pediatric nonprogressors (PNPs) showed distinct immunoglobulin profiles with an increased ability to elicit potent Fc-mediated natural killer (NK)-cell effector functions. In contrast to previous reports in adults, both groups of children showed high levels of gp120-specific IgG Fc glycan sialylation compared to bulk IgG. Importantly, higher levels of Fc glycan sialylation were associated with increased bnAb breadth, providing the first evidence that Fc sialylation may drive affinity maturation of HIV-specific antibodies in children, a mechanism that could be exploited for vaccination strategies. IMPORTANCE To protect future generations against HIV, a vaccine will need to induce immunity by the time of sexual debut and hence requires immunization during childhood. Current strategies for a prophylactic HIV vaccine include the induction of a broadly neutralizing antibody response and the recruitment of potent effector functions of immune cells via the constant antibody Fc region. In this study, we show that nonprogressing HIV-infected children mounted antibody responses against HIV that were able to mediate potent Fc effector functions, which may contribute to the control of HIV replication. Children who had specific glycan structures on the Fc portion of antibodies against HIV were able to neutralize a broader range of HIV variants, providing evidence of a potential role of Fc glycovariation in the development of bnAbs against HIV. These findings complement our knowledge of the distinct immune landscape in early life that could be exploited in the development of vaccine strategies.https://journals.asm.org/doi/10.1128/mSphere.00880-20Fc effector functionsFc glycosylationHIVbroadly neutralizing antibodies (bnAbs)nonneutralizing antibodiespediatric |
| spellingShingle | M. Muenchhoff A. W. Chung J. Roider Anne-Sophie Dugast Simone Richardson Henrik Kløverpris Alasdair Leslie Thumbi Ndung’u Penny Moore Galit Alter Philip J. R. Goulder Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection mSphere Fc effector functions Fc glycosylation HIV broadly neutralizing antibodies (bnAbs) nonneutralizing antibodies pediatric |
| title | Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection |
| title_full | Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection |
| title_fullStr | Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection |
| title_full_unstemmed | Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection |
| title_short | Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection |
| title_sort | distinct immunoglobulin fc glycosylation patterns are associated with disease nonprogression and broadly neutralizing antibody responses in children with hiv infection |
| topic | Fc effector functions Fc glycosylation HIV broadly neutralizing antibodies (bnAbs) nonneutralizing antibodies pediatric |
| url | https://journals.asm.org/doi/10.1128/mSphere.00880-20 |
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