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The impact of bone marrow stromal antigen-2 (BST2) gene variants on HIV-1 control in black South African individuals.

ABSTRACT: Bone marrow stromal cell antigen 2 (BST2 or tetherin) is a host-encoded, interferon-inducible antiviral restriction factor which blocks the release of enveloped viruses. Few studies have assessed the role of BST2 polymorphisms on HIV-1 acquisition or disease progression in sub-Saharan Africa. This study investigated the frequency of four HIV-1-associated BST2 variants rs3217318, rs12609479, rs10415893 and rs113189798 in uninfected and HIV-1 infected black South Africans. Homozygosity for the rs12609479-A minor allele, previously associated with decreased HIV-1 acquisition risk, was underrepresented in HIV-1 uninfected black South Africans (2%) compared to reference African (9%) and in particular European populations (61%) (p = .047 and p < .0001, respectively). To determine if any of these gene variants influenced HIV-1 control in the absence of antiretroviral treatment (ART), we compared HIV-1 infected ART-naïve progressors [n = 72] and controllers [n = 71], the latter includes elite controllers [EC: n = 23; VL < 50 RNA copies/ml]. Heterozygosity for the rs12609479 SNP (G/A) was enriched in progressors compared to ECs (47.2% vs 21.7%, OR = 3.50 [1.16-10.59], p = .03), while rs113189798 heterozygosity (A/G) showed a strong trend of overrepresentation in ECs compared to progressors (47.8% vs 26.4%, OR = 0.39 [0.14-1.04], p = .07). Heterozygosity for the promoter indel rs3217318 (i19/Δ19) was associated with a faster rate of CD4⁺ T-cell decline in progressors (p = .0134). Carriage of the rs3217318 (i19/Δ19), rs12609479 (G/G), rs10415893(G/A) and rs113189798 (A/G) combined genotype, denoted as i19Δ19 GG GA AG, was associated with significantly higher CD4⁺ T-cell counts in progressors (p = .03), a finding predominantly driven by the _GG_AG combination. Our data suggest that the possession of select BST2 genotype combinations may be implicated in HIV-1 disease progression and natural spontaneous control.

SUBMITTER: Dias BDC

PROVIDER: S-EPMC8752124 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An intronic single nucleotide polymorphism (SNP) in RICH2 (rs2072255; 255i), in complete linkage disequilibrium (LD) with an exonic SNP (rs2072254; 254e), has been identified in a genome wide association study to be associated with progression to AIDS in Caucasian individuals. RICH2 links tetherin to the cortical actin network and the RICH2/tetherin interaction has been shown to be important for the downstream activation of NF-κβ and the consequential promotion of proinflammatory responses. We investigated the role of these two SNPs in natural control of HIV-1 in black South Africans including healthy controls (HCs; N=102) and antiretroviral-naive HIV-1-infected controllers (HICs; N=52) and progressors (N=74). HICs were stratified as elite controllers (ECs; N=11), viraemic controllers (VCs; N=30), high viral load (VL) long term non-progressors (HVL LTNPs; N=11) and also according to VL<400RNA copies/ml (HICs VL<400; N=20) and VL>400RNA copies/ml (HICs VL>400; N=32). Results showed that in contrast to Caucasians who had very strong LD between these SNPs (r2=0.97), black populations exhibited low LD (r2=0.11-0.27), however a 254e minor allele was always present with a 255i minor allele but not vice versa. The SNPs did not show significant over- or underrepresentation in any particular group, however the combination of 254e major allele homozygosity and 255i heterozygosity (254eAA/255iGA) was underrepresented in HICs (OR=3.26; P=0.04) and VCs (OR=7.77; P=0.02) compared to HCs, and in HICs VL>400 compared to both HCs (P=0.002) and progressors (P=0.02). A lower CD4+ T-cell count was associated with 254eAA/255iGA and 255i (GA+AA) in the total HIV-1-infected group (P=0.043) and progressors (P=0.017), respectively. In silico analysis predicted loss of an exonic splice enhancer site with the 254e-G allele. We postulate that altered splicing of RICH2 will affect levels of RICH2 expression and consequently NF-κβ activation. These findings point to a role for RICH2 and tetherin in viraemic natural control of HIV-1.

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The impact of bone marrow stromal antigen-2 (BST2) gene variants on HIV-1 control in black South African individuals.

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