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.
authors.affiliation: Department of Experimental Immunology, Sanquin Research, Landsteiner Laboratory and Center for Infection and Immunity at the Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sebastiaan M
authors.initials: SM
authors.lastname: Bol
authors.forename: Thijs
authors.initials: T
authors.lastname: Booiman
authors.forename: Evelien M
authors.initials: EM
authors.lastname: Bunnik
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.forename: Karel
authors.initials: K
authors.lastname: van Dort
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
authors.forename: Margit
authors.initials: M
authors.lastname: Sieberer
authors.forename: Hanneke
authors.initials: H
authors.lastname: Schuitemaker
authors.forename: Neeltje A
authors.initials: NA
authors.lastname: Kootstra
authors.forename: Angélique B
authors.initials: AB
authors.lastname: van 't Wout
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D014644:Genetic Variation; D015658:HIV Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D012333:RNA, Messenger; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C112770:PDE8A protein, human