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

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.