TY - JOUR
T1 - RICH2 is implicated in viraemic control of HIV-1 in black South African individuals
AU - Paximadis, Maria
AU - Ngqobe, Refilwe N.
AU - Chaisson, Richard E.
AU - Martinson, Neil A.
AU - Tiemessen, Caroline T.
N1 - Funding Information:
This work is based on the research supported by grants awards from the Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council (a grantee of the Bill & Melinda Gates Foundation), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa and the National Institutes of Health, USA (R01HL090312 and P30AI094189: R. E. Chaisson).
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - HIV-1
KW - Host genes
KW - Natural control
KW - RICH2
KW - Tetherin
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U2 - 10.1016/j.meegid.2017.01.007
DO - 10.1016/j.meegid.2017.01.007
M3 - Article
C2 - 28069446
AN - SCOPUS:85009288374
SN - 1567-1348
VL - 49
SP - 78
EP - 87
JO - Infection, Genetics and Evolution
JF - Infection, Genetics and Evolution
ER -