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.