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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, 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 J, Zagury JF, Schuitemaker H, van 't Wout AB - PLoS ONE (2011)

Bottom Line: We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16 × 10(-5)).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).These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo.

View Article: PubMed Central - PubMed

Affiliation: Landsteiner Laboratory, Sanquin Research, Department of Experimental Immunology, and Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands.

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(-5)). While the association was not genome-wide significant (p<1 × 10(-7)), 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(-6)). 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.

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Related in: MedlinePlus

Significant association between rs12483205 and in vitro replication of HIV-1 in macrophages derived from an independent group of 31 healthy blood donors.The negative association between the rs12483205 minor allele and Gag p24 levels in MDM culture supernatant 14 days after inoculation with HIV-1, was found to match with the results from the genome-wide association study. Open circles represent results from donors with the CCR5 Δ32 wild-type genotype, filled circles from donors with the CCR5 wt/Δ32 heterozygous genotype. MAJ, homozygous for the major allele; HZ, heterozygote; MIN, homozygous for the minor allele.
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pone-0017190-g002: Significant association between rs12483205 and in vitro replication of HIV-1 in macrophages derived from an independent group of 31 healthy blood donors.The negative association between the rs12483205 minor allele and Gag p24 levels in MDM culture supernatant 14 days after inoculation with HIV-1, was found to match with the results from the genome-wide association study. Open circles represent results from donors with the CCR5 Δ32 wild-type genotype, filled circles from donors with the CCR5 wt/Δ32 heterozygous genotype. MAJ, homozygous for the major allele; HZ, heterozygote; MIN, homozygous for the minor allele.

Mentions: The empirical p values for linear regression using 107 permutations of the genotype for each SNP in Table 2 were in close agreement with the asymptotic p values (Table 2). However, none of these SNPs remained statistically significant after a conservative correction for multiple testing (Bonferroni threshold of p<1×10−7; Figure S1). We next investigated the association between the SNPs in the five most promising genes (rs2304418 in PDE8A, rs2905 in UBR7, rs1046099 and rs1270629 in MOAP1, rs12483205 in DYRK1A and rs17519417 in SPOCK3) in a second group of blood donors (replication cohort). MDM from an independent group of 32 healthy blood donors were infected with HIV-1 and Gag p24 levels were measured 14 days after infection. One donor was found to be homozygous for the 32 base pair deletion in CCR5, rendering the cells completely resistant to infection with CCR5-using HIV-1, and results obtained with macrophages from this donor were excluded from further analysis. The associations for the SNPs in PDE8A, UBR7, MOAP1 and SPOCK3 with Gag p24 production by MDM could not be replicated in this small group of 31 donors (data not shown). However, in this replication cohort we again found a strong association between SNP rs12483205 in DYRK1A and in vitro HIV-1 replication in macrophages (p = 0.0034) (Figure 2, Table S2), also after correction for cell number and normalization (p = 0.0081; n = 28, information on cell number was missing for 3 donors) (data not shown, Table S2). This association remained significant after correction for multiple testing (Bonferroni corrected p = 0.020 (0.0034×6 SNPs for which we tried to replicate the association)) and when calculating the empirical p value for linear regression using 105 permutations of the genotypes (p = 0.004) (Table S1).


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

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 J, Zagury JF, Schuitemaker H, van 't Wout AB - PLoS ONE (2011)

Significant association between rs12483205 and in vitro replication of HIV-1 in macrophages derived from an independent group of 31 healthy blood donors.The negative association between the rs12483205 minor allele and Gag p24 levels in MDM culture supernatant 14 days after inoculation with HIV-1, was found to match with the results from the genome-wide association study. Open circles represent results from donors with the CCR5 Δ32 wild-type genotype, filled circles from donors with the CCR5 wt/Δ32 heterozygous genotype. MAJ, homozygous for the major allele; HZ, heterozygote; MIN, homozygous for the minor allele.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045405&req=5

pone-0017190-g002: Significant association between rs12483205 and in vitro replication of HIV-1 in macrophages derived from an independent group of 31 healthy blood donors.The negative association between the rs12483205 minor allele and Gag p24 levels in MDM culture supernatant 14 days after inoculation with HIV-1, was found to match with the results from the genome-wide association study. Open circles represent results from donors with the CCR5 Δ32 wild-type genotype, filled circles from donors with the CCR5 wt/Δ32 heterozygous genotype. MAJ, homozygous for the major allele; HZ, heterozygote; MIN, homozygous for the minor allele.
Mentions: The empirical p values for linear regression using 107 permutations of the genotype for each SNP in Table 2 were in close agreement with the asymptotic p values (Table 2). However, none of these SNPs remained statistically significant after a conservative correction for multiple testing (Bonferroni threshold of p<1×10−7; Figure S1). We next investigated the association between the SNPs in the five most promising genes (rs2304418 in PDE8A, rs2905 in UBR7, rs1046099 and rs1270629 in MOAP1, rs12483205 in DYRK1A and rs17519417 in SPOCK3) in a second group of blood donors (replication cohort). MDM from an independent group of 32 healthy blood donors were infected with HIV-1 and Gag p24 levels were measured 14 days after infection. One donor was found to be homozygous for the 32 base pair deletion in CCR5, rendering the cells completely resistant to infection with CCR5-using HIV-1, and results obtained with macrophages from this donor were excluded from further analysis. The associations for the SNPs in PDE8A, UBR7, MOAP1 and SPOCK3 with Gag p24 production by MDM could not be replicated in this small group of 31 donors (data not shown). However, in this replication cohort we again found a strong association between SNP rs12483205 in DYRK1A and in vitro HIV-1 replication in macrophages (p = 0.0034) (Figure 2, Table S2), also after correction for cell number and normalization (p = 0.0081; n = 28, information on cell number was missing for 3 donors) (data not shown, Table S2). This association remained significant after correction for multiple testing (Bonferroni corrected p = 0.020 (0.0034×6 SNPs for which we tried to replicate the association)) and when calculating the empirical p value for linear regression using 105 permutations of the genotypes (p = 0.004) (Table S1).

Bottom Line: We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16 × 10(-5)).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).These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo.

View Article: PubMed Central - PubMed

Affiliation: Landsteiner Laboratory, Sanquin Research, Department of Experimental Immunology, and Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands.

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(-5)). While the association was not genome-wide significant (p<1 × 10(-7)), 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(-6)). 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.

Show MeSH
Related in: MedlinePlus