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; 254^e), 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 254^e 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 254^e major allele homozygosity and 255ⁱ heterozygosity (254^eAA/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 254^eAA/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 254^e-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.