Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes

The latency of human immunodeficiency virus type 1 ( HIV- 1) in resting primary CD4(+) T cells is the major barrier for the eradication of the virus in patients on suppressive highly active antiretroviral therapy ( HAART). Even with optimal HAART treatment, replication- competent HIV- 1 still exists in resting primary CD4(+) T cells(1-4). Multiple restriction factors that act upon various steps of the viral life cycle could contribute to viral latency. Here we show that cellular microRNAs ( miRNAs) potently inhibit HIV- 1 production in resting primary CD4(+) T cells. We have found that the 3' ends of HIV-1 messenger RNAs are targeted by a cluster of cellular miRNAs including miR- 28, miR-125b, miR- 150, miR- 223 and miR- 382, which are enriched in resting CD4(+) T cells as compared to activated CD4(+) T cells. Specific inhibitors of these miRNAs substantially counteracted their effects on the target mRNAs, measured either as HIV- 1 protein translation in resting CD4(+) T cells transfected with HIV- 1 infectious clones, or as HIV- 1 virus production from resting CD4(+) T cells isolated from HIV-1 infected individuals on suppressive HAART. Our data indicate that cellular miRNAs are pivotal in HIV-1 latency and suggest that manipulation of cellular miRNAs could be a novel approach for purging the HIV-1 reservoir.