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The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity

Abstract

Primate lentiviruses such as human immunodeficiency type 1 (HIV-1) have the capacity to infect non-dividing cells such as tissue macrophages1. In the process, viral complementary DNA traverses the nuclear envelope to integrate within chromatin2. Given the intimate association between chromatin and the nuclear envelope3, we examined whether HIV-1 appropriates nuclear envelope components during infection. Here we show that emerin, an integral inner-nuclear-envelope protein, is necessary for HIV-1 infection. Infection of primary macrophages lacking emerin was abortive in that viral cDNA localized to the nucleus but integration into chromatin was inefficient, and conversion of viral cDNA to non-functional episomal cDNA increased. HIV-1 cDNA associated with emerin in vivo, and the interaction of viral cDNA with chromatin was dependent on emerin. Barrier-to-autointegration factor (BAF), the LEM (LAP, emerin, MAN) binding partner of emerin, was required for the association of viral cDNA with emerin and for the ability of emerin to support virus infection. Therefore emerin, which bridges the interface between the inner nuclear envelope and chromatin, may be necessary for chromatin engagement by viral cDNA before integration.

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Figure 1: siRNA-mediated silencing of nuclear envelope proteins inhibits HIV-1 infection of primary macrophages.
Figure 2: Emerin and BAF silencing promotes abortive infection of macrophages by preventing viral cDNA integration.
Figure 3: Association of HIV-1 cDNA with chromatin requires BAF and emerin.
Figure 4: HIV-1 cDNA association with emerin in vivo is dependent on BAF and requires the viral integrase.

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Acknowledgements

We thank A. Dauphin and J. Zhou for research support, B. Mellor for preparation of the figures, K. Departie and L. Smith for manuscript preparation, and A. Engelman for providing HIV-1 integrase mutants. The University of Massachusetts Center for AIDS Research and the AIDS Research Reference Reagent Program, Division of AIDS, NIAID, National Institutes of Health (NIH), provided assay support and reagents. This study was supported by grants from the NIH to M.S.

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Correspondence to Mario Stevenson.

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Supplementary Figures

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Supplementary Methods

This file contains additional information on the methods used in this study, including Cells and siRNA transfections, PCR analysis and Western blotting. This file also contains additional references. (DOC 54 kb)

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Jacque, JM., Stevenson, M. The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity. Nature 441, 641–645 (2006). https://doi.org/10.1038/nature04682

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