Nucleocytoplasmic shuttling of HIV-1 integrase is controlled by the viral Rev protein

Levin, Aviad; Hayouka, Zvi; Friedler, Assaf; Loyter, Abraham

doi:10.4161/nucl.11300

Cited by 11 publications

(14 citation statements)

References 55 publications

(83 reference statements)

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“…As shown in Figure 1B and C, these two peptides failed to promote dissociation of the IN-TNPO3 complex, indicating that different domains mediate the interaction of IN with these two nuclearimport receptors. The results in Figure 1 also show that neither peptide had any effect on the interaction between Rev and IN, shown by us previously to occur in virus-infected cells [40][41][42][43][44] and indicating specificity of function.…”

Section: Introductionmentioning

confidence: 49%

“…7A). Interestingly, the Rev protein which, similar to the Rev-derived peptides, has been shown to block nuclear import of IN, 42 prevented interaction of IN with both receptors. The disruption of the IN-TNPO3 complex by the Rev derived and IN-1 peptides is not necessarily due to direct masking of the TNPO3 binding sites.…”

Section: Discussionmentioning

confidence: 99%

“…The co-IP experiments depicted in Figure 1A show that in virus-infected cells, expected to lead to cytoplasmic retention of IN as well. Although the Rev-IN complex can be observed in the PICs of the infected cells, 40,44 a large portion of it is localized within the cytoplasm 42 and is not necessarily associated with the PIC. This is probably due to the fact that Rev promotes dissociation of the IN from the PIC localized viral cDNA.…”

Section: In Interacts With Both Importin α and Tnpo3mentioning

confidence: 99%

“…3, Table 1 and reviewed in ref. 42), most likely due to their ability to disrupt the IN-TNPO3 complex. The same three peptides were also found to inhibit nuclear import of the viral cDNA (Fig.…”

Section: In Interacts With Both Importin α and Tnpo3mentioning

confidence: 99%

“…3 and Table 1) despite its inability to disrupt the interaction between IN and its nuclear receptors (Fig. 2C) full-length Rev protein blocks IN nuclear import, 42 it was essential to study the effect of Rev itself on the interactions between IN and the nuclear-import receptors. When Rev-expressing cells were infected with HIV-1, IN failed to interact with either importin α or TNPO3 (Fig.…”

Section: In Interacts With Both Importin α and Tnpo3mentioning

confidence: 99%

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Transportin 3 and importin α are required for effective nuclear import of HIV-1 integrase in virus-infected cells

Levin

Hayouka

Friedler

et al. 2010

Nucleus

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Section: Introductionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: In Interacts With Both Importin α and Tnpo3mentioning

confidence: 99%

Section: In Interacts With Both Importin α and Tnpo3mentioning

confidence: 99%

Section: In Interacts With Both Importin α and Tnpo3mentioning

confidence: 99%

See 3 more Smart Citations

Transportin 3 and importin α are required for effective nuclear import of HIV-1 integrase in virus-infected cells

Levin

Hayouka

Friedler

et al. 2010

Nucleus

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Structure‐Based Design of an RNA‐Binding p‐Terphenylene Scaffold that Inhibits HIV‐1 Rev Protein Function

et al. 2013

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Structure‐Based Design of an RNA‐Binding p‐Terphenylene Scaffold that Inhibits HIV‐1 Rev Protein Function

et al. 2013

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Numerous antibiotics bind to ribosomal RNA, and many functional RNA motifs have considerable therapeutic potential. However, the development of small RNA-binding agents has been hampered by the difficulties posed by these structures, which have limited physicochemical diversity and are often flexible.[1] In order for this approach to be successful, it is essential to identify new chemical scaffolds recognizing RNA.The Rev response element (RRE) is a strongly conserved 350-nucleotide structure located in the env gene of human immunodeficiency virus type-1 (HIV-1) RNA. Within subdomain IIB of the RRE, the unusually widened major groove of a 4:6 internal loop forms a high-affinity complex [2] with the arginine-rich a-helix of Rev, a virally encoded 116 amino acid protein that adopts a helix-turn-helix conformation [3] ( Figure 1). This interaction between internal loop IIB and the RNA-binding a-helix of Rev (Rev 34-50 ) is essential for virus viability because it triggers a cascade of events that allow the transport of unspliced or incompletely spliced viral RNA molecules into the cytoplasm of the infected cell in the late phase of the viral infectious cycle. These events include the cooperative incorporation of additional Rev molecules into the complex through interactions with further sites on the RRE and protein-protein contacts, [4] and the tethering of the RRE-Rev ribonucleoprotein to the Crm1 host export factor. In addition to RNA nuclear export, Rev has been shown to enhance translation and packaging [5] and to control the nucleocytoplasmic shuttling of the HIV-1 integrase.[6] Clearly, this protein represents a pivotal target for HIV-1 therapy, but to date, the development of Rev-based inhibitors has remained an elusive goal. Herein we report the structurebased design of new RNA-binding p-terphenyl Rev mimics that inhibit RRE-Rev function and HIV-1 replication.We aimed to generate organic ligands that mimic the three-dimensional distribution of the side chains of Rev 34-50 complexed with internal loop IIB of the RRE [2] (Figure 1 a). Some reports had shown that tris-3,2',2''-substituted p-ter- Figure 1. Structure-based design of RNA-binding p-terphenyls. a) View of the complex formed by internal loop IIB of the RRE and Rev 34-50 . The a-helix (red) is deeply embedded in its RNA receptor (gray). b) Representation of a bilaterally substituted p-terphenyl molecule (green) superposed on an a-helix (red). c) Chemical structure and synthesis strategy of a 3,5,2',6',2'',6''-substituted p-terphenyl molecule. d) Secondary structures of the RNA oligonucleotides utilized in this study:

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Nucleocytoplasmic shuttling of HIV-1 integrase is controlled by the viral Rev protein

Cited by 11 publications

References 55 publications

Transportin 3 and importin α are required for effective nuclear import of HIV-1 integrase in virus-infected cells

Transportin 3 and importin α are required for effective nuclear import of HIV-1 integrase in virus-infected cells

Structure‐Based Design of an RNA‐Binding p‐Terphenylene Scaffold that Inhibits HIV‐1 Rev Protein Function

Structure‐Based Design of an RNA‐Binding p‐Terphenylene Scaffold that Inhibits HIV‐1 Rev Protein Function

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