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Translational Regulation of HIV-1 Replication by HIV-1 Rev Cellular Cofactors Sam68, eIF5A, hRIP, and DDX3

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Abstract

Nuclear export and translation of HIV-1 RNA are two important posttranscriptional events for HIV-1 gene expression and replication. HIV-1 Rev functions to export unspliced and incompletely spliced HIV-1 RNA from the nucleus to the cytoplasm; it requires interaction with several cellular cofactors such as Sam68, eIF5A, hRIP, and DDX3. Meanwhile, some studies have also implicated Rev and some of its cofactors such as Sam68 in HIV-1 RNA translation. Thus, in this study, we aimed to characterize the potential function of all these four Rev cofactors in HIV-1 RNA translation. Ectopic expression, siRNA knockdown, and trans-complementation assays confirmed that all these cofactors were very important for HIV-1 gene expression and production through Rev and, accordingly, Rev-dependent reporter gene expression. Importantly, these studies revealed for the first time that each of these cofactors also regulated Rev-independent reporter gene expression. To directly determine the roles of these cofactors in HIV-1 RNA translation, we designed and synthesized a full-length capped HIV-1 RNA in vitro, transfected it into cells to bypass the RNA nuclear export step, and determined HIV-1 Gag expression from the cytoplasmic RNA in the cells that had ectopically expressed or siRNA knocked down cofactors. Gag expression was found to closely correlate with the expression levels of all these cofactors. Furthermore, we took advantage of a HIV-1 internal ribosomal entry site (IRES)-based bicistronic reporter gene assay and determined the effects of these cofactors on cap-independent IRES-mediated HIV-1 translation. The results showed that DDX3, eIF5A, and hRIP enhanced HIV-1 IRES-mediated translation, whereas Sam68 did not. Taken together, these results show that HIV-1 Rev cofactors Sam68, eIF5A, hRIP, and DDX3 also function in the translation of HIV-1 RNA and suggest that the regulatory mechanisms of HIV-1 RNA translation are likely different among these cofactors.

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Acknowledgments

This work was supported by the grant R01NS065785 from the National Institutes of Health.

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The authors declare that they have no competing interests or conflicts of interest.

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  1. Jorge Henao-Mejia

    Present address: Department of Immunobiology, Yale University School of Medicine, 300 Cedar St., New Haven, CT, 06520, USA

Authors and Affiliations

  1. The First Affiliated Hospital, Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, 710061, People’s Republic of China

    Jinfeng Liu, Hao Liu & Yingren Zhao

  2. Department of Microbiology and Immunology, Indiana University School of Medicine, R2 302, 950 W. Walnut St., Indianapolis, IN, 46202, USA

    Jinfeng Liu, Jorge Henao-Mejia & Johnny J. He

  3. Center for AIDS Research, Indiana University School of Medicine, R2 302, 950 W. Walnut St., Indianapolis, IN, 46202, USA

    Johnny J. He

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Liu, J., Henao-Mejia, J., Liu, H. et al. Translational Regulation of HIV-1 Replication by HIV-1 Rev Cellular Cofactors Sam68, eIF5A, hRIP, and DDX3. J Neuroimmune Pharmacol 6, 308–321 (2011). https://doi.org/10.1007/s11481-011-9265-8

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