14th Conference on Retroviruses and Opportunistic Infections Los Angeles, California - February 25-28, 2007

Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 17)

Corinne Loeuillet¹, S Deutsch², P Taffé³, M Rotger¹, J Beckmann⁴, S Antonarakis², and A Telenti^1
1Univ Hosp, Univ of Lausanne, Switzerland; ²Univ of Geneva Med Sch and Univ Hosp Geneva, Switzerland; ³Swiss HIV Cohort Study Data Ctr, Lausanne; and ⁴Univ Hosp and Univ of Lausanne, Switzerland

BACKGROUND: Advances in large-scale analysis of human genomic variability provide unprecedented opportunities to study the genetic basis of susceptibility to HIV-1. We report on the use of an in vitro system for the identification of susceptibility loci using whole genome linkage and association analyses.

METHODS: B lymphoblastoid cell lines (LBL) from 198 individuals (15 CEPH multigeneration pedigrees) were transduced with vesicular stomatitis virus (VSV)-lentivirus-green fluorescent protein (GFP). Trait data (percentage of GFP-positive cells and mean fluorescence intensity [MFI]) were used for genome scan linkage analysis (2600 single nucleotide polymorphism [SNP] markers). Linkage was confirmed by transduction of LBL from 56 independent HapMap individuals in a genome association analysis using 521 tag SNP on a 3-Mb region centered around the initial linkage assignment. Candidate markers were assessed for association with CD4 T-cell permissiveness in cells from 128 healthy blood donors. Association of a candidate marker with disease progression in vivo was investigated in a HIV-1-infected human cohort of 805 individuals.

RESULTS: The heritability of susceptibility to VSV-lentivirus-GFP in vitro was 0.53 and 0.43 for percentage of GFP+ cells and MFI, respectively. Linkage analysis identified a locus on chromosome 8q24.3 (logarithm of odds [LOD]=2.89, p=2E-04). Association analysis using LBL from unrelated individuals identified SNP rs2572886G>A to be associated with the percentage of GFP trait (p=1.8 E-5). Allele A of marker rs2572886 is associated with 40% increase in susceptibility to the VSV-lentivirus-GFP in LBL cells (p=0.001), and 57% increase in susceptibility to HIV 1 in CD4 T cells (p=0.019). Allele A was associated with greater viral load, and faster progression of immunosuppression in the HIV-1-infected cohort.

CONCLUSIONS: We identified, using a multistep procedure involving unbiased whole-genome linkage scan followed by association studies, a novel locus on chromosome 8 that influences human susceptibility to HIV-1. This is the first time a quantitative trait locus initially mapped by in vitro approaches, has also been shown to be relevant in a clinical setting.

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2007-02-25
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