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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Frontiers Media S.A.
2021
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oai:doaj.org-article:606f17dc663147008740c3e9a01e0b5c2021-12-01T15:08:03ZAn HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition1664-322410.3389/fimmu.2021.760571https://doaj.org/article/606f17dc663147008740c3e9a01e0b5c2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.760571/fullhttps://doaj.org/toc/1664-3224In 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.Joy EbonwuJoy EbonwuRia LassaunièreMaria PaximadisMaria PaximadisMark GoosenMark GoosenRenate StrehlauRenate StrehlauGlenda E. GrayGlenda E. GrayLouise KuhnLouise KuhnCaroline T. TiemessenCaroline T. TiemessenFrontiers Media S.A.articleFc gamma receptorFCGR2Cgenetic variantpolymorphismgene copy numberperinatal HIV-1 acquisitionImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
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| collection |
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| topic |
Fc gamma receptor FCGR2C genetic variant polymorphism gene copy number perinatal HIV-1 acquisition Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
Fc gamma receptor FCGR2C genetic variant polymorphism gene copy number perinatal HIV-1 acquisition Immunologic diseases. Allergy RC581-607 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 |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
hiv vaccine protective allele in fcgr2c associates with increased odds of perinatal hiv acquisition |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/606f17dc663147008740c3e9a01e0b5c |
| work_keys_str_mv |
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