title: Association of polymorphisms in the LEDGF/p75 gene (PSIP1) with susceptibility to HIV-1 infection and disease progression.
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.
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Paradise
authors.initials: P
authors.lastname: Madlala
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Anneleen
authors.initials: A
authors.lastname: Hombrouck
authors.forename: Lise
authors.initials: L
authors.lastname: Werner
authors.forename: Koleka
authors.initials: K
authors.lastname: Mlisana
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019426:Integrases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C504649:PSIP1 protein, human; D014157:Transcription Factors; D019426:Integrases