title: RICH2 is implicated in viraemic control of HIV-1 in black South African individuals.
abstract: 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 254eminor allele was always present with a 255iminor allele but not vice versa. The SNPs did not show significant over- or underrepresentation in any particular group, however the combination of 254emajor allele homozygosity and 255iheterozygosity (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.
authors.affiliation: National Institute for Communicable Diseases, Centre for HIV and STIs, Cell Biology, Johannesburg, South Africa; School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Electronic address: paxim@nicd.ac.za.
authors.forename: Maria
authors.initials: M
authors.lastname: Paximadis
authors.affiliation: National Institute for Communicable Diseases, Centre for HIV and STIs, Cell Biology, Johannesburg, South Africa.
authors.forename: Refilwe N
authors.initials: RN
authors.lastname: Ngqobe
authors.affiliation: Johns Hopkins University Center for AIDS Research, Baltimore, MD, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Chaisson
authors.affiliation: Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Johannesburg, South Africa; MRC Soweto Matlosana Centre for HIV/AIDS and TB Research, South Africa.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Martinson
authors.affiliation: National Institute for Communicable Diseases, Centre for HIV and STIs, Cell Biology, Johannesburg, South Africa; School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Caroline T
authors.initials: CT
authors.lastname: Tiemessen
mesh_terms: D000328:Adult; D000483:Alleles; D017398:Alternative Splicing; D044383:Black People; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D016022:Case-Control Studies; D018450:Disease Progression; D060467:Disease Resistance / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000208:ethnology / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000235:genetics*; D013019:South Africa; D019562:Viral Load; D014766:Viremia / Q000208:ethnology / Q000235:genetics* / Q000276:immunology / Q000821:virology
chemical_list: C539906:ARHGAP44 protein, human; D020690:GTPase-Activating Proteins; D016328:NF-kappa B; D012367:RNA, Viral
keywords: HIV-1; Host genes; Natural control; RICH2; Tetherin