In Vitro Whole-Genome Analysis Identifies a Susceptibility Locus for HIV-1

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Abstract
Advances in large-scale analysis of human genomic variability provide unprecedented opportunities to study the genetic basis of susceptibility to infectious agents. We report here the use of an in vitro system for the identification of a locus on HSA8q24.3 associated with cellular susceptibility to HIV-1. This locus was mapped through quantitative linkage analysis using cell lines from multigeneration families, validated in vitro, and followed up by two independent association studies in HIV-positive individuals. Single nucleotide polymorphism rs2572886, which is associated with cellular susceptibility to HIV-1 in lymphoblastoid B cells and in primary T cells, was also associated with accelerated disease progression in one of two cohorts of HIV-1–infected patients. Biological analysis suggests a role of the rs2572886 region in the regulation of the LY6 family of glycosyl-phosphatidyl-inositol (GPI)–anchored proteins. Genetic analysis of in vitro cellular phenotypes provides an attractive approach for the discovery of susceptibility loci to infectious agents. Individuals differ in their susceptibility to the HIV-1 virus, and the determinants of susceptibility are encoded in the human genome. Genetic variants influencing this trait have been identified by investigating candidate genes thought likely to be involved in HIV-1 pathogenesis or by whole-genome association studies, which type more than 500,000 genetic variants per individual (genome-wide association studies) to see which ones associate with susceptibility. We have addressed the issue of identification of new genetic variants influencing susceptibility to HIV-1 by a novel strategy based on the in vitro infection of cells. For this, immortalized B lymphocytes from 15 families (198 cell lines) were infected by a HIV-based vector. Differences in cellular susceptibility to infection—a genetic trait—could be mapped to a precise region on Chromosome 8, suggesting a role of the LY6 family of GPI-anchored proteins in HIV-1 infection. Genetic analysis of in vitro standardized cellular phenotypes provides a new approach to the discovery of the basis of genetic susceptibility to infectious agents.