RICH2 is implicated in viraemic control of HIV-1 in black South African individuals

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 < 400 RNA copies/ml (HICs VL < 400; N = 20) and VL > 400 RNA 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.