Polymorphism in HIV-1 dependency factor PDE8A affects mRNA level and HIV-1 replication in primary macrophages

Sebastiaan M. Bol; Thijs Booiman; Evelien M. Bunnik; Perry D. Moerland; Karel van Dort; Jerome F. Strauss; Margit Sieberer; Hanneke Schuitemaker; Neeltje A. Kootstra; Angélique B. van't Wout

doi:10.1016/j.virol.2011.08.013

Polymorphism in HIV-1 dependency factor PDE8A affects mRNA level and HIV-1 replication in primary macrophages

Sebastiaan M. Bol, Thijs Booiman, Evelien M. Bunnik, Perry D. Moerland, Karel van Dort, Jerome F. Strauss, Margit Sieberer, Hanneke Schuitemaker, Neeltje A. Kootstra, Angélique B. van't Wout

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Four genome-wide RNAi screens have recently identified hundreds of HIV-1 dependency factors (HDFs). Previously, we reported a large variation in the ability of HIV-1 to replicate in monocyte-derived macrophages (MDM) derived from >400 healthy seronegative blood donors. Here we determined whether SNPs in genes encoding newly identified HDFs were associated with this variation in HIV-1 replication. We found a significant association between the minor allele of SNP rs2304418 in phosphodiesterase 8A (PDE8A) and lower HIV-1 replication (p=2.4×10^-6). The minor allele of SNP rs2304418 was also significantly associated with lower PDE8A mRNA levels in MDM (p=8.3×10^-5). In accordance with this, overexpression of PDE8A in HEK293T cells resulted in increased HIV-1 replication, while subsequent knock-down of PDE8A decreased replication. This study links host genetic variation in a newly identified HDF to variation in HIV-1 replication in a relevant primary target cell for HIV-1 and may provide new leads for treatment of this infection.

Original language	English (US)
Pages (from-to)	32-42
Number of pages	11
Journal	Virology
Volume	420
Issue number	1
DOIs	https://doi.org/10.1016/j.virol.2011.08.013
State	Published - Nov 10 2011
Externally published	Yes

Keywords

HIV-1
HIV-1 dependency factor
Macrophage
PDE8A
RNAi
SNP

ASJC Scopus subject areas

Virology

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10.1016/j.virol.2011.08.013

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title = "Polymorphism in HIV-1 dependency factor PDE8A affects mRNA level and HIV-1 replication in primary macrophages",

abstract = "Four genome-wide RNAi screens have recently identified hundreds of HIV-1 dependency factors (HDFs). Previously, we reported a large variation in the ability of HIV-1 to replicate in monocyte-derived macrophages (MDM) derived from >400 healthy seronegative blood donors. Here we determined whether SNPs in genes encoding newly identified HDFs were associated with this variation in HIV-1 replication. We found a significant association between the minor allele of SNP rs2304418 in phosphodiesterase 8A (PDE8A) and lower HIV-1 replication (p=2.4×10-6). The minor allele of SNP rs2304418 was also significantly associated with lower PDE8A mRNA levels in MDM (p=8.3×10-5). In accordance with this, overexpression of PDE8A in HEK293T cells resulted in increased HIV-1 replication, while subsequent knock-down of PDE8A decreased replication. This study links host genetic variation in a newly identified HDF to variation in HIV-1 replication in a relevant primary target cell for HIV-1 and may provide new leads for treatment of this infection.",

keywords = "HIV-1, HIV-1 dependency factor, Macrophage, PDE8A, RNAi, SNP",

author = "Bol, {Sebastiaan M.} and Thijs Booiman and Bunnik, {Evelien M.} and Moerland, {Perry D.} and {van Dort}, Karel and Strauss, {Jerome F.} and Margit Sieberer and Hanneke Schuitemaker and Kootstra, {Neeltje A.} and {van't Wout}, {Ang{\'e}lique B.}",

note = "Funding Information: We acknowledge funding from the Landsteiner Foundation Blood Research (registration number 0526 ) and the European Union (Marie Curie International Reintegration Grant 029167 ). ",

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doi = "10.1016/j.virol.2011.08.013",

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T1 - Polymorphism in HIV-1 dependency factor PDE8A affects mRNA level and HIV-1 replication in primary macrophages

AU - Bol, Sebastiaan M.

AU - Booiman, Thijs

AU - Bunnik, Evelien M.

AU - Moerland, Perry D.

AU - van Dort, Karel

AU - Strauss, Jerome F.

AU - Sieberer, Margit

AU - Schuitemaker, Hanneke

AU - Kootstra, Neeltje A.

AU - van't Wout, Angélique B.

N1 - Funding Information: We acknowledge funding from the Landsteiner Foundation Blood Research (registration number 0526 ) and the European Union (Marie Curie International Reintegration Grant 029167 ).

PY - 2011/11/10

Y1 - 2011/11/10

N2 - Four genome-wide RNAi screens have recently identified hundreds of HIV-1 dependency factors (HDFs). Previously, we reported a large variation in the ability of HIV-1 to replicate in monocyte-derived macrophages (MDM) derived from >400 healthy seronegative blood donors. Here we determined whether SNPs in genes encoding newly identified HDFs were associated with this variation in HIV-1 replication. We found a significant association between the minor allele of SNP rs2304418 in phosphodiesterase 8A (PDE8A) and lower HIV-1 replication (p=2.4×10-6). The minor allele of SNP rs2304418 was also significantly associated with lower PDE8A mRNA levels in MDM (p=8.3×10-5). In accordance with this, overexpression of PDE8A in HEK293T cells resulted in increased HIV-1 replication, while subsequent knock-down of PDE8A decreased replication. This study links host genetic variation in a newly identified HDF to variation in HIV-1 replication in a relevant primary target cell for HIV-1 and may provide new leads for treatment of this infection.

AB - Four genome-wide RNAi screens have recently identified hundreds of HIV-1 dependency factors (HDFs). Previously, we reported a large variation in the ability of HIV-1 to replicate in monocyte-derived macrophages (MDM) derived from >400 healthy seronegative blood donors. Here we determined whether SNPs in genes encoding newly identified HDFs were associated with this variation in HIV-1 replication. We found a significant association between the minor allele of SNP rs2304418 in phosphodiesterase 8A (PDE8A) and lower HIV-1 replication (p=2.4×10-6). The minor allele of SNP rs2304418 was also significantly associated with lower PDE8A mRNA levels in MDM (p=8.3×10-5). In accordance with this, overexpression of PDE8A in HEK293T cells resulted in increased HIV-1 replication, while subsequent knock-down of PDE8A decreased replication. This study links host genetic variation in a newly identified HDF to variation in HIV-1 replication in a relevant primary target cell for HIV-1 and may provide new leads for treatment of this infection.

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KW - PDE8A

KW - RNAi

KW - SNP

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Polymorphism in HIV-1 dependency factor PDE8A affects mRNA level and HIV-1 replication in primary macrophages

Abstract

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