Home

Association of polymorphisms in the LEDGF/p75 gene (PSIP1) with susceptibility to HIV-1 infection and disease progression

Paradise Madlala; Rik Gijsbers; Frauke Christ; Anneleen Hombrouck; Lise Werner; Koleka P. Mlisana; Ping An; Salim Abdool Karim; Zeger Debyser; Cheryl A. Winkler; Thumbi Ndung'u

Title:
Association of polymorphisms in the LEDGF/p75 gene (PSIP1) with susceptibility to HIV-1 infection and disease progression
Author(s):
Madlala, Paradise
Gijsbers, Rik
Christ, Frauke
Hombrouck, Anneleen
Werner, Lise
Mlisana, Koleka P.
An, Ping
Abdool Karim, Salim
Debyser, Zeger
Winkler, Cheryl A.
Ndung'u, Thumbi
Date:
Type:
Articles
Department:
Epidemiology
Volume:
24
Permanent URL:
Book/Journal Title:
AIDS
Abstract:
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.
Subject(s):
Virology
Epidemiology
Publisher DOI:
http://dx.doi.org/10.1097/QAD.0b013e328349c693
Item views:
118
Metadata:
View

In Partnership with the Center for Digital Research and Scholarship at Columbia University Libraries/Information Services.