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

7 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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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 - HIV-1 dependency factor

KW - Macrophage

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

Keywords

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