Madlala Paradise author Gijsbers Rik author Christ Frauke author Hombrouck Anneleen author Werner Lise author Mlisana Koleka P. author An Ping author Abdool Karim Salim author Columbia University. Epidemiology Debyser Zeger author Winkler Cheryl A. author Ndung'u Thumbi author Columbia University. Epidemiology originator text Articles 2011 English OBJECTIVE: LEDGF/p75, encoded by the PSIP1 gene, interacts with HIV-1 integrase and targets HIV-1 integration into active genes. We investigated the influence of polymorphisms in PSIP1 on HIV-1 acquisition and disease progression in black South Africans. METHODS: Integrase binding domain of LEDGF/p75 was sequenced in 126 participants. Four haplotype tagging SNPs rs2277191, rs1033056, rs12339417 and rs10283923 referred to as SNP1, SNP2, SNP3 and SNP4, respectively, and one exonic SNP rs61744944 (SNP5, Q472L) were genotyped in 195 HIV-1 seronegative, 52 primary and 403 chronically infected individuals using TaqMan assays. LEDGF/p75 expression was quantified by real-time RT-PCR. The impact of Q472L mutation on the interaction with HIV_1 IN was measured by AlphaScreen. RESULTS: rs2277191 (SNP1) A was more frequent among seropositives (P = 0.06, Fisher's exact test). Among individuals followed longitudinally SNP1A trended towards association with higher likelihood of HIV-1 acquisition [relative hazard (RH) = 2.21, P = 0.08; Cox model] and it was also associated with rapid disease progression (RH = 5.98, P = 0.04; Cox model) in the recently infected (primary infection) cohort. rs12339417 (SNP3)C was associated with slower decline of CD4(+) T cells (P = 0.02) and lower messenger RNA (mRNA) levels of LEDGF/p75 (P < 0.01). Seroconverters had higher preinfection mRNA levels of LEDGF/p75 (P < 0.01) and these levels decreased after HIV-1 infection (P = 0.02). CONCLUSIONS: Genetic variants of PSIP1 may affect HIV-1 outcomes. Further studies are needed to confirm the effect of genetic variation of PSIP1 on HIV-1 pathogenesis in different cohorts. Virology Epidemiology 24 14 1711 1719 2011 http://dx.doi.org/10.1097/QAD.0b013e328349c693 http://hdl.handle.net/10022/AC:P:12511 NNC NNC 2012-02-08 11:35:45 -0500 2013-02-18 15:14:46 -0500 6512 eng