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

• Published in: Nature medicine Vol. 13; no. 10; pp. 1241 - 1247
• Main Authors: Zhang, Hui, Huang, Jialing, Wang, Fengxiang, Argyris, Elias, Chen, Keyang, Liang, Zhihui, Tian, Heng, Huang, Wenlin, Squires, Kathleen, Verlinghieri, Gwen
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.10.2007
• Subjects: Antiretroviral agents; Binding Sites; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - virology; Cells, Cultured; HIV; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immunology; Inhibitors; Life cycles; Lymphocytes; Medical research; MicroRNAs - metabolism; Plasmids; Ribonucleic acid; RNA; Transfection; Virology; Virus Latency - drug effects
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1639

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. 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.