Article: article from journal or magazin.
Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages.
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: epublish
Background: HIV-1 infected macrophages play an important role inrendering resting T cells permissive for infection, in spreading HIV-1to T cells, and in the pathogenesis of AIDS dementia. During highlyactive anti-retroviral treatment (HAART), macrophages keep producingvirus because tissue penetration of antiretrovirals is suboptimal andthe efficacy of some is reduced. Thus, to cure HIV-1 infection withantiretrovirals we will also need to efficiently inhibit viralreplication in macrophages. The majority of the current drugs block theaction of viral enzymes, whereas there is an abundance of yetunidentified host factors that could be targeted. We here presentresults from a genome-wide association study identifying novel geneticpolymorphisms that affect in vitro HIV-1 replication in macrophages.Methodology/Principal Findings: Monocyte-derived macrophages from 393blood donors were infected with HIV-1 and viral replication wasdetermined using Gag p24 antigen levels. Genomic DNA from individualswith macrophages that had relatively low (n = 96) or high (n = 96) p24production was used for SNP genotyping with the Illumina 610 Quadbeadchip. A total of 494,656 SNPs that passed quality control weretested for association with HIV-1 replication in macrophages, usinglinear regression. We found a strong association between in vitro HIV-1replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A(p = 2.16 x 10(-5)). While the association was not genome-widesignificant (p < 1 x 10(-7)), we could replicate this association usingmonocyte-derived macrophages from an independent group of 31 individuals(p = 0.0034). Combined analysis of the initial and replication cohortincreased the strength of the association (p = 4.84 x 10(-6)). Inaddition, we found this SNP to be associated with HIV-1 diseaseprogression in vivo in two independent cohort studies (p = 0.035 and p =0.0048).Conclusions/Significance: These findings suggest that the kinase DYRK1Ais involved in the replication of HIV-1, in vitro in macrophages as wellas in vivo.
Adult, Cells, Cultured, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HIV Infections/genetics, HIV Infections/immunology, HIV-1/physiology, Humans, Linkage Disequilibrium, Macrophages/metabolism, Macrophages/pathology, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases/genetics, Protein-Serine-Threonine Kinases/physiology, Protein-Tyrosine Kinases/genetics, Protein-Tyrosine Kinases/physiology, Virus Replication/genetics
Web of science
Last modification date