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The FCGR2C allele that modulated the risk of HIV-1 infection in the Thai RV144 vaccine trial is implicated in HIV-1 disease progression.

ABSTRACT: In the HIV-1 Thai RV144 vaccine trial-the only trial to demonstrate any vaccine efficacy to date-a three-variant haplotype within the Fc gamma receptor 2C gene (FCGR2C) modified the risk of HIV-1 acquisition. A similar vaccine regimen is currently being evaluated in South Africa in the HVTN702 trial, where the predominant population is polymorphic for only a single variant in the haplotype, c.134-96C>T. To investigate the significance of c.134-96C>T in HIV-specific immunity in South Africans, this study assessed its role in HIV-1 disease progression. In a cohort of HIV-1-infected South African controllers (n?=?71) and progressors (n?=?73), the c.134-96C>T minor allele significantly associated with increased odds of HIV-1 disease progression (odds ratio 3.80, 95% confidence interval 1.90-7.62; P?=?2.0?×?10-4, PBonf?=?2.4?×?10-3). It is unlikely that the underlying mechanism involves wild-type Fc?RIIc function, since only a single study participant was predicted to express wild-type Fc?RIIc as determined by the FCGR2C c.798+1A>G splice-site variant. Conversely, in silico analysis revealed a potential role for c.134-96C>?T in modulating mRNA transcription. In conclusion, these data provide additional evidence towards a role for FCGR2C c.134-96C>T in the context of HIV-1 and underscore the need to investigate its significance in the HVTN702 efficacy trial in South Africa.

SUBMITTER: Lassauniere R

PROVIDER: S-EPMC6881233 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The FCGR2C allele that modulated the risk of HIV-1 infection in the Thai RV144 vaccine trial is implicated in HIV-1 disease progression.

Lassaunière Ria R Paximadis Maria M Ebrahim Osman O Chaisson Richard E RE Martinson Neil A NA Tiemessen Caroline T CT

Genes and immunity 20181219 8

In the HIV-1 Thai RV144 vaccine trial-the only trial to demonstrate any vaccine efficacy to date-a three-variant haplotype within the Fc gamma receptor 2C gene (FCGR2C) modified the risk of HIV-1 acquisition. A similar vaccine regimen is currently being evaluated in South Africa in the HVTN702 trial, where the predominant population is polymorphic for only a single variant in the haplotype, c.134-96C>T. To investigate the significance of c.134-96C>T in HIV-specific immunity in South Africans, th ...[more]

PMID: 30563969

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Project 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, P Bonf = 0.032 and P = 0.010, P Bonf = > 0.05, respectively). The FCGR2C c.134-96T allele was overrepresented in the cases compared to the controls (58% vs 42%; P = 0.001, P Bonf = 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, P Bonf = 0.048) and c.169C>T (AOR = 2.39; 95% CI 1.45-3.95; P = 0.001, P Bonf = 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.

Dataset Information

The FCGR2C allele that modulated the risk of HIV-1 infection in the Thai RV144 vaccine trial is implicated in HIV-1 disease progression.

Publications

The FCGR2C allele that modulated the risk of HIV-1 infection in the Thai RV144 vaccine trial is implicated in HIV-1 disease progression.

Similar Datasets

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