Probing the HIV-1 genomic RNA trafficking pathway and dimerization by genetic recombination and single virion analyses.
Probing the HIV-1 genomic RNA trafficking pathway and dimerization by genetic recombination and single virion analyses.
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DOI：
10.1371/journal.ppat.1000627
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发表时间：
2009-10
期刊：
影响因子：
6.7
通讯作者：
Hu WS
中科院分区：
文献类型：
--
作者：
Moore MD;Nikolaitchik OA;Chen J;Hammarskjöld ML;Rekosh D;Hu WS
Once transcribed, the nascent full-length RNA of HIV-1 must travel to the appropriate host cell sites to be translated or to find a partner RNA for copackaging to form newly generated viruses. In this report, we sought to delineate the location where HIV-1 RNA initiates dimerization and the influence of the RNA transport pathway used by the virus on downstream events essential to viral replication. Using a cell-fusion-dependent recombination assay, we demonstrate that the two RNAs destined for copackaging into the same virion select each other mostly within the cytoplasm. Moreover, by manipulating the RNA export element in the viral genome, we show that the export pathway taken is important for the ability of RNA molecules derived from two viruses to interact and be copackaged. These results further illustrate that at the point of dimerization the two main cellular export pathways are partially distinct. Lastly, by providing Gag in trans, we have demonstrated that Gag is able to package RNA from either export pathway, irrespective of the transport pathway used by the gag mRNA. These findings provide unique insights into the process of RNA export in general, and more specifically, of HIV-1 genomic RNA trafficking. High genetic diversity of HIV-1 presents a difficult barrier for drug treatment and vaccine development. HIV-1 efficiently reassorts mutations in its genome by packaging two copies of RNA into one virion and using portions of each RNA as the template for DNA synthesis. Thus, a key to HIV-1's genetic diversity is how it packages two RNAs into one virion. We have previously shown that HIV-1 packages RNA as a dimer, rather than two monomers. In this report, we determined that HIV-1 RNA finds its copackaged dimer partner mostly in the cytoplasm, not the nucleus, of the infected cells. We also found that the host cell machinery used to transport the HIV-1 RNA out of the nucleus affects the ability of two RNAs to copackage into one virion: HIV-1 RNAs transported using the CRM-1 pathway does not copackage efficiently with RNA transported by the NXF1 pathway. This is also the first demonstration that RNAs transported by the two major cellular pathways, CRM-1 and NXF1, are partially segregated at some point in the cytoplasm. Therefore, this work provides novel insights to both HIV replication mechanisms and cellular RNA transport pathways.
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