In the current study we show that the Rev protein of Human Immunodeficiency Virus type 1 (HIV-1) inhibits nuclear import and mediates nuclear export of the HIV-1 integrase (IN) protein, which catalyzes integration of the viral cDNA. Interaction between IN and Rev in virus infected cells, resulting in the formation of a Rev-IN complex, has been previously described by us. Here we show that nuclear import of the IN, is inhibited by early expressed Rev. No nuclear import of IN was observed when Rev-overexpressing cells were infected by wild-type HIV-1. Similarly, no translocation of IN into nuclei was observed in the presence of Rev-derived peptides. On the other hand, massive nuclear import was observed following infection by a ΔRev virus or in the presence of peptides that promote dissociation of the Rev-IN complex. Our results show that IN is only transiently present within the nuclei of infected cells. Treatment of infected cells with leptomycin B caused nuclear retention of the Rev-IN complex. Removal of the leptomycin from these treated cells resulted in nuclear export of both Rev and IN. On the other hand, disruption of the nuclear located Rev-IN complex resulted in export of only the Rev protein indicating Rev-mediated nuclear export of IN. Our results suggest the involvement of Rev in regulating the integration process by limiting the number of integration events per cell despite the presence of numerous copies of viral cDNA.

中文翻译：

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HIV-1整合酶的核质穿梭由病毒Rev蛋白控制


在当前的研究中，我们表明人类免疫缺陷病毒 1 型 (HIV-1) 的 Rev 蛋白抑制 HIV-1 整合酶 (IN) 蛋白的核输入并介导核输出，从而催化病毒 cDNA 的整合。我们之前已经描述过病毒感染细胞中 IN 和 Rev 之间的相互作用，导致 Rev-IN 复合物的形成。在这里，我们表明早期表达的 Rev 抑制了 IN 的核输入。当 Rev 过表达细胞被野生型 HIV-1 感染时，没有观察到 IN 的核输入。类似地，在 Rev 衍生肽存在的情况下，没有观察到 IN 易位到细胞核中。另一方面，在 ΔRev 病毒感染后或在存在促进 Rev-IN 复合物解离的肽的情况下，观察到大量的核输入。我们的结果表明，IN 仅短暂存在于受感染细胞的细胞核内。用瘦霉素 B 处理受感染的细胞导致 Rev-IN 复合物在核内滞留。从这些处理的细胞中去除瘦霉素导致 Rev 和 IN 均输出核。另一方面，核定位的 Rev-IN 复合物的破坏导致仅 Rev 蛋白的输出，表明 Rev 介导的 IN 核输出。我们的结果表明，尽管存在大量病毒 cDNA 拷贝，但 Rev 通过限制每个细胞的整合事件数量来参与调节整合过程。