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Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages

Bol, SM and Moerland, PD and Limou, S and van Remmerden, Y and Coulonges, C and van Manen, D and Herbeck, JT and Fellay, J and Sieberer, M and Sietzema, JG and van 't Slot, R and Martinson, J and Zagury, JF and Schuitemaker, H and van 't Wout, AB (2011) Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages. PLoS ONE, 6 (2).

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Abstract

Background: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages. Methodology/Principal Findings: Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16×10 ). While the association was not genome-wide significant (p<1×10 ), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.84×10 ). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048). Conclusions/Significance: These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo. © 2011 Bol et al. -5 -7 -6


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bol, SM
Moerland, PD
Limou, S
van Remmerden, Y
Coulonges, C
van Manen, D
Herbeck, JT
Fellay, J
Sieberer, M
Sietzema, JG
van 't Slot, R
Martinson, Jjmartins@pitt.eduJMARTINS
Zagury, JF
Schuitemaker, H
van 't Wout, AB
Date: 8 March 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0017190
Schools and Programs: Graduate School of Public Health > Human Genetics
Refereed: Yes
MeSH Headings: Adult; Cells, Cultured; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; HIV Infections--genetics; HIV Infections--immunology; HIV Infections--virology; HIV-1--physiology; Humans; Linkage Disequilibrium; Macrophages--metabolism; Macrophages--pathology; Macrophages--virology; 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
Other ID: NLM PMC3045405
PubMed Central ID: PMC3045405
PubMed ID: 21364930
Date Deposited: 07 Aug 2012 15:47
Last Modified: 30 Mar 2021 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/13423

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