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Cooperativity among rev-associated nuclear export signals regulates HIV-1 Gene expression and is a determinant of virus species tropism

Cooperativity among rev-associated nuclear export signals regulates HIV-1 Gene expression and is a determinant of virus species tropism

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ALIGETI, Mounavya, Ryan T. BEHERENS, Ginger M. POCOCK, Johannes SCHINDELIN, Christian DIETZ, Kevin W. ELICEIRI, Chad M. SWANSON, Michael H. MALIM, Paul AHLQUIST, Nathan M. SHERER, 2014. Cooperativity among rev-associated nuclear export signals regulates HIV-1 Gene expression and is a determinant of virus species tropism. In: Journal of Virology. 88(24), pp. 14207-14221. ISSN 0022-538X. eISSN 1098-5514

@article{Aligeti2014Coope-30092, title={Cooperativity among rev-associated nuclear export signals regulates HIV-1 Gene expression and is a determinant of virus species tropism}, year={2014}, doi={10.1128/JVI.01897-14}, number={24}, volume={88}, issn={0022-538X}, journal={Journal of Virology}, pages={14207--14221}, author={Aligeti, Mounavya and Beherens, Ryan T. and Pocock, Ginger M. and Schindelin, Johannes and Dietz, Christian and Eliceiri, Kevin W. and Swanson, Chad M. and Malim, Michael H. and Ahlquist, Paul and Sherer, Nathan M.} }

2015-02-26T14:29:38Z Beherens, Ryan T. Aligeti, Mounavya Malim, Michael H. Murine cells exhibit a profound block to HIV-1 virion production that was recently mapped to a species-specific structural attribute of the murine version of the CRM1 (mCRM1) nuclear export receptor, and rescued by expression of human CRM1 (hCRM1). In human cells, the HIV-1 Rev protein recruits hCRM1 to intron-containing viral mRNAs encoding the Rev response element (RRE), thereby facilitating viral late gene expression. Here we exploited murine 3T3 fibroblasts as a gain-of-function system to study hCRM1's species-specific role in regulating Rev's effector functions. We show that Rev is rapidly exported from the nucleus by mCRM1 despite only weak contributions to HIV-1's post-transcriptional stages. Indeed, Rev preferentially accumulates in the cytoplasm of murine 3T3 cells with or without hCRM1 expression, in contrast to human HeLa cells where Rev exhibits striking en masse transitions between the nuclear and cytoplasmic compartments. Efforts to bias Rev's trafficking either into or out of the nucleus revealed that Rev encoding a second CRM1 binding domain (Rev-2xNES), or Rev-dependent viral gag-pol mRNAs bearing tandem RREs (GP-2xRRE), rescue virus particle production in murine cells even in the absence of hCRM1. Combined, these results suggest a model wherein Rev-associated nuclear export signals cooperate to regulate the number or quality of CRM1's interactions with viral Rev/RRE ribonucleoprotein complexes in the nucleus. This mechanism regulates CRM1-dependent viral gene expression and is a determinant of HIV-1's capacity to produce virions in non-human cell types.<br />Importance Cells derived from mice and other non-human species exhibit profound blocks to HIV-1 replication. Here we elucidate a block to HIV-1 gene expression attributable to the murine version of the CRM1 (mCRM1) nuclear export receptor. In human cells, hCRM1 regulates the nuclear export of viral intron-containing mRNAs through the activity of the viral Rev adapter protein that forms a multimeric complex on these mRNAs prior to recruiting hCRM1. We demonstrate that Rev-dependent gene expression is poor in murine cells despite the finding that, surprisingly, the bulk of Rev interacts efficiently with mCRM1 and is rapidly exported from the nucleus. Instead, we map the mCRM1 defect to the apparent inability of this factor to engage Rev multimers in the context of large viral Rev/RNA ribonucleoprotein complexes. These findings shed new light on HIV-1 gene regulation and could inform the development of novel antiviral strategies that target viral gene expression. Cooperativity among rev-associated nuclear export signals regulates HIV-1 Gene expression and is a determinant of virus species tropism Ahlquist, Paul Schindelin, Johannes Pocock, Ginger M. Dietz, Christian Malim, Michael H. eng Sherer, Nathan M. Aligeti, Mounavya Sherer, Nathan M. Ahlquist, Paul Schindelin, Johannes 2015-02-26T14:29:38Z Swanson, Chad M. Eliceiri, Kevin W. 2014 Dietz, Christian Pocock, Ginger M. Swanson, Chad M. Eliceiri, Kevin W. Beherens, Ryan T.

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