An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition
In the Thai RV144 HIV-1 vaccine trial, a three-variant haplotype within the Fc gamma receptor 2C gene (FCGR2C) reduced the risk of HIV-1 acquisition. A follow-on trial, HVTN702, of a similar vaccine candidate found no efficacy in South Africa, where the predominant population is polymorphic for only...
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| Format: | Article |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.760571/full |
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| author | Joy Ebonwu Joy Ebonwu Ria Lassaunière Maria Paximadis Maria Paximadis Mark Goosen Mark Goosen Renate Strehlau Renate Strehlau Glenda E. Gray Glenda E. Gray Louise Kuhn Louise Kuhn Caroline T. Tiemessen Caroline T. Tiemessen |
| author_facet | Joy Ebonwu Joy Ebonwu Ria Lassaunière Maria Paximadis Maria Paximadis Mark Goosen Mark Goosen Renate Strehlau Renate Strehlau Glenda E. Gray Glenda E. Gray Louise Kuhn Louise Kuhn Caroline T. Tiemessen Caroline T. Tiemessen |
| author_sort | Joy Ebonwu |
| collection | DOAJ |
| description | In the Thai RV144 HIV-1 vaccine trial, a three-variant haplotype within the Fc gamma receptor 2C gene (FCGR2C) reduced the risk of HIV-1 acquisition. A follow-on trial, HVTN702, of a similar vaccine candidate found no efficacy in South Africa, where the predominant population is polymorphic for only a single variant in the haplotype, c.134-96C>T (rs114945036). To investigate a role for this variant in HIV-1 acquisition in South Africans, we used the model of maternal-infant HIV-1 transmission. A nested case-control study was conducted of infants born to mothers living with HIV-1, comparing children with perinatally-acquired HIV-1 (cases, n = 176) to HIV-1-exposed uninfected children (controls, n = 349). All had received nevirapine for prevention of mother-to-child transmission. The FCGR2C copy number and expression variants (c.−386G>C, c.−120A>T c.169T>C, and c.798+1A>G) were determined using a multiplex ligation-dependent probe amplification assay and the c.134-96C>T genotype with Sanger sequencing. The copy number, genotype and allele carriage were compared between groups using univariate and multivariate logistic regression. The FCGR2C c.134-96C>T genotype distribution and copy number differed significantly between HIV-1 cases and exposed-uninfected controls (P = 0.002, PBonf = 0.032 and P = 0.010, PBonf = > 0.05, respectively). The FCGR2C c.134-96T allele was overrepresented in the cases compared to the controls (58% vs 42%; P = 0.001, PBonf = 0.016). Adjusting for birthweight and FCGR2C copy number, perinatal HIV-1 acquisition was associated with the c.134-96C>T (AOR = 1.89; 95% CI 1.25-2.87; P = 0.003, PBonf = 0.048) and c.169C>T (AOR = 2.39; 95% CI 1.45-3.95; P = 0.001, PBonf = 0.016) minor alleles but not the promoter variant at position c.−386G>C. The c.134-96C>T variant was in strong linkage disequilibrium with the c.169C>T variant, but remained significantly associated with perinatal acquisition when adjusted for c.169C>T in multivariate analysis. In contrast to the protective effect observed in the Thai RV144 trial, we found the FCGR2C variant c.134-96T-allele associated with increased odds of perinatal HIV-1 acquisition in South African children. These findings, taken together with a similar deleterious association found with HIV-1 disease progression in South African adults, highlight the importance of elucidating the functional relevance of this variant in different populations and vaccination/disease contexts. |
| first_indexed | 2024-12-14T14:21:47Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T14:21:47Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-606f17dc663147008740c3e9a01e0b5c2022-12-21T22:58:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-11-011210.3389/fimmu.2021.760571760571An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV AcquisitionJoy Ebonwu0Joy Ebonwu1Ria Lassaunière2Maria Paximadis3Maria Paximadis4Mark Goosen5Mark Goosen6Renate Strehlau7Renate Strehlau8Glenda E. Gray9Glenda E. Gray10Louise Kuhn11Louise Kuhn12Caroline T. Tiemessen13Caroline T. Tiemessen14Division of Public Health Surveillance and Response, National Institute for Communicable Diseases, Johannesburg, South AfricaFaculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaVirus Research and Development Laboratory, Department of Virus and Microbiological Special Diagnostics, Statens Serum Institut, Copenhagen, DenmarkFaculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaCentre for HIV & STIs, National Institute for Communicable Diseases, Johannesburg, South AfricaFaculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaCentre for HIV & STIs, National Institute for Communicable Diseases, Johannesburg, South AfricaEmpilweni Services and Research Unit, Rahima Moosa Mother and Child Hospital, Johannesburg, South AfricaDepartment of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaPerinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaSouth African Medical Research Council, Cape Town, South AfricaGertrude H. Sergievsky Centre, College of Physicians and Surgeons, Columbia University, New York, NY, United States0Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United StatesFaculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaCentre for HIV & STIs, National Institute for Communicable Diseases, Johannesburg, South AfricaIn the Thai RV144 HIV-1 vaccine trial, a three-variant haplotype within the Fc gamma receptor 2C gene (FCGR2C) reduced the risk of HIV-1 acquisition. A follow-on trial, HVTN702, of a similar vaccine candidate found no efficacy in South Africa, where the predominant population is polymorphic for only a single variant in the haplotype, c.134-96C>T (rs114945036). To investigate a role for this variant in HIV-1 acquisition in South Africans, we used the model of maternal-infant HIV-1 transmission. A nested case-control study was conducted of infants born to mothers living with HIV-1, comparing children with perinatally-acquired HIV-1 (cases, n = 176) to HIV-1-exposed uninfected children (controls, n = 349). All had received nevirapine for prevention of mother-to-child transmission. The FCGR2C copy number and expression variants (c.−386G>C, c.−120A>T c.169T>C, and c.798+1A>G) were determined using a multiplex ligation-dependent probe amplification assay and the c.134-96C>T genotype with Sanger sequencing. The copy number, genotype and allele carriage were compared between groups using univariate and multivariate logistic regression. The FCGR2C c.134-96C>T genotype distribution and copy number differed significantly between HIV-1 cases and exposed-uninfected controls (P = 0.002, PBonf = 0.032 and P = 0.010, PBonf = > 0.05, respectively). The FCGR2C c.134-96T allele was overrepresented in the cases compared to the controls (58% vs 42%; P = 0.001, PBonf = 0.016). Adjusting for birthweight and FCGR2C copy number, perinatal HIV-1 acquisition was associated with the c.134-96C>T (AOR = 1.89; 95% CI 1.25-2.87; P = 0.003, PBonf = 0.048) and c.169C>T (AOR = 2.39; 95% CI 1.45-3.95; P = 0.001, PBonf = 0.016) minor alleles but not the promoter variant at position c.−386G>C. The c.134-96C>T variant was in strong linkage disequilibrium with the c.169C>T variant, but remained significantly associated with perinatal acquisition when adjusted for c.169C>T in multivariate analysis. In contrast to the protective effect observed in the Thai RV144 trial, we found the FCGR2C variant c.134-96T-allele associated with increased odds of perinatal HIV-1 acquisition in South African children. These findings, taken together with a similar deleterious association found with HIV-1 disease progression in South African adults, highlight the importance of elucidating the functional relevance of this variant in different populations and vaccination/disease contexts.https://www.frontiersin.org/articles/10.3389/fimmu.2021.760571/fullFc gamma receptorFCGR2Cgenetic variantpolymorphismgene copy numberperinatal HIV-1 acquisition |
| spellingShingle | Joy Ebonwu Joy Ebonwu Ria Lassaunière Maria Paximadis Maria Paximadis Mark Goosen Mark Goosen Renate Strehlau Renate Strehlau Glenda E. Gray Glenda E. Gray Louise Kuhn Louise Kuhn Caroline T. Tiemessen Caroline T. Tiemessen An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition Frontiers in Immunology Fc gamma receptor FCGR2C genetic variant polymorphism gene copy number perinatal HIV-1 acquisition |
| title | An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition |
| title_full | An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition |
| title_fullStr | An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition |
| title_full_unstemmed | An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition |
| title_short | An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition |
| title_sort | hiv vaccine protective allele in fcgr2c associates with increased odds of perinatal hiv acquisition |
| topic | Fc gamma receptor FCGR2C genetic variant polymorphism gene copy number perinatal HIV-1 acquisition |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.760571/full |
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