Titre
Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages.
Type
article
Institution
Externe
Périodique
Auteur(s)
Bol, S.M.
Auteure/Auteur
Moerland, P.D.
Auteure/Auteur
Limou, S.
Auteure/Auteur
van Remmerden, Y.
Auteure/Auteur
Coulonges, C.
Auteure/Auteur
van Manen, D.
Auteure/Auteur
Herbeck, J.T.
Auteure/Auteur
Fellay, J.
Auteure/Auteur
Sieberer, M.
Auteure/Auteur
Sietzema, J.G.
Auteure/Auteur
van 't Slot, R.
Auteure/Auteur
Martinson, J.
Auteure/Auteur
Zagury, J.F.
Auteure/Auteur
Schuitemaker, H.
Auteure/Auteur
van 't Wout, A.B.
Auteure/Auteur
Liens vers les personnes
ISSN
1932-6203
Statut éditorial
Publié
Date de publication
2011
Volume
6
Numéro
2
Première page
e17190
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: epublish
Résumé
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.
Sujets
PID Serval
serval:BIB_D2509C0439AB
PMID
Open Access
Oui
Date de création
2012-03-01T14:14:25.037Z
Date de création dans IRIS
2025-05-21T03:59:33Z