The role of miRNAs in HIV infection of primary macrophages

Macrophages act as a reservoir for HIV, producing infectious progeny virus even in the context of anti-retroviral therapy. We have observed that HIV-infected human monocyte-derived macrophages (MDM) survive in culture for twice as long as uninfected MDM through an unknown mechanism. Because microRNAs (miRNAs) coordinate cell processes, such as apoptosis and cell cycle progression, we investigated the role of human and HIV-encoded miRNAs in the enhanced survival of HIV-infected MDM. Using two bioinformatic algorithms, we predicted six miRNA-like structures in the genomes of two HIV laboratory strains and in a consensus sequence derived from 525 HIV-1 viral isolates. However, no HIV-encoded miRNAs were detected experimentally. Microarray analysis of human miRNAs expressed after HIV infection of MDM identified 51 differentially regulated miRNAs; 44 were up-regulated and 7 were down-regulated at least 2-fold. Over-expression of miR-191, miR-23a or miR-22, miRNAs up-regulated 8-11-fold after infection, significantly enhanced the survival of uninfected MDM. Inhibition of each of these miRNAs reduced the survival of HIV-infected MDM to that of uninfected MDM. To identify potential genes that might be regulated by these miRNAs, we compared mRNA expression of HIV-infected and uninfected MDM. Early Growth Response-1 (EGR1), a cellular transcription factor that was down-regulated 44-fold after HIV infection, is a target of miR-191. Moreover, knocking down EGR1 extended MDM survival. Therefore miR-191 regulation of EGR1 contributes to the survival of HIV-infected macrophages.