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.
aHIV Pathogenesis Programme, University of KwaZulu-Natal, Durban
bDepartment of Genetics, University of KwaZulu-Natal, Pietermaritzburg, South Africa
cMolecular Medicine, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium
dCentre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa
eBasic Research Laboratory, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, Frederick, Maryland, USA.
Correspondence to Thumbi Ndung’u, PhD, Private Bag 7, Congella 4013, DDMRI Level 1, Room 117, 719 Umbilo Road, Durban 4001, South Africa. Tel: +27 31 260 4727; fax: +27 31 260 4036; e-mail: firstname.lastname@example.org
Received 1 March, 2011
Revised 2 June, 2011
Accepted 10 June, 2011