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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 cells1,2,3,4. 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.

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Figure 1: MiRNA(s) inhibit HIV-1 expression by acting on the 3′ end of the HIV-1 genome.
Figure 2: Identification of the binding sites of cellular miRNAs at the 3′ end of HIV-1 genomic RNA.
Figure 3: Combined miRNA inhibitors can facilitate HIV-1 protein expression and viral production in resting primary CD4+ T cells.
Figure 4: Effect of miRNA inhibitors upon HIV-1 production from resting CD4+ T cells isolated from HIV-1–infected patients on suppressive HAART.

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We thank K. Zhang for his technical help, J. DeSimone and D. Horn for their assistance in enrolling patients and Y. Wang for conducting X-ray irradiation. This work was supported by grants from the US National Institutes of Health (AI058798 and AI052732) to H.Z. and the National Basic Research Program of China (grant 2004CB518801) to W.H.

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Authors and Affiliations



J.H. carried out most experiments. F.W., E.A., H.T., Z.L. and W.H. participated in some of the experiments such as purification of the cells, generation of some plasmid constructs, and DNA or RNA sequencing. K.C. performed some immunoblotting. K.S. and G.V. placed HIV-1–infected individuals on HAART and H.Z. directed and supervised the experiments and interpretation of data. The manuscript was prepared by J.H. and H.Z.

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Correspondence to Hui Zhang.

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H.Z. and J.H. are going to apply for a patent for the antisense inhibitors to miR-28, miR-125b, miR-150, miR-225 and miR-382 for their possible usage in activating HIV-1 latency.

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Supplementary Figs. 1-10 and Supplementary Tables 1-4 (PDF 1270 kb)

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Huang, J., Wang, F., Argyris, E. et al. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med 13, 1241–1247 (2007).

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