Within you, without you: HIV-1 Rev and RNA export

Center for Biologics Evaluation and Research, Food and Drug Administration, USA.
Retrovirology (Impact Factor: 4.19). 02/2004; 1(1):35. DOI: 10.1186/1742-4690-1-35
Source: PubMed

ABSTRACT Nucleo-cytoplasmic transport of RNA is one of many cellular pathways whose illumination has progressed hand in hand with understanding of retroviral mechanisms. A recent paper in Cell reports the involvement of an RNA helicase in the pathway by which HIV exports partially spliced and unspliced RNA out of the nucleus. This suggests the ubiquity of RNA helicases in RNA export from the nucleus, and has novel mechanistic implications.

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    • "The unspliced and the partially spliced viral mRNA which encode structural and the accessory proteins, are exported to the cytoplasm with the help of early protein Rev. Rev (Regulator of virion expression) has a nuclear localization signal (NLS) as well as a nuclear export signal (NES). Inside the nucleus, Rev binds to Rev Response Element (RRE) on viral mRNAs and transports them across the nuclear membrane for the expression of other HIV-1 proteins [1], [2], [3]. The Rev deficient virus cannot form new virion particles due to inefficient molecular export of unspliced viral mRNA to the cytoplasm, signifying the role of Rev in the viral life cycle [1]. "
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    ABSTRACT: CNS associated cells are permissive to HIV-1 infection, but poor in virus production due to attenuated Rev activity. The temporal and the spatial distribution of Rev in human astrocyte 1321N1 and glioblastoma GO-G-CCM were monitored for explaining the reduced Rev activity and low viral production during HIV-1 infection. Rev remained localized to the nuclei of these cells upon infection, attenuating its export activity, as manifested by low copy number of RRE-containing viral-mRNA in the cytoplasm of these cells. In contrast to infection, when Rev alone was transiently expressed, it localized in the cytoplasm of 1321N1. The localization changed to the nucleus when Rev was expressed in the presence of other viral proteins through pro-viral DNA pNL4-3. This study, for the first time, revealed the impact of other HIV-1 proteins apart from host factors in regulating the subcellular localization of Rev in astrocytes and hence the fate of HIV-1 infection in these cells.
    PLoS ONE 09/2013; 8(9):e72905. DOI:10.1371/journal.pone.0072905 · 3.23 Impact Factor
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    • "Rev protein of HIV-1 plays a key role in viral replication by regulating the nuclear export of unspliced viral mRNAs [37]. Both D17 and D24 contained a Rev open reading frame encoding 126 amino acid residues as a result of amino acid-substitution for two of the natural stop codons (Figure 4B). "
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    ABSTRACT: The pathogenic significance of coreceptor switch in the viral infection of HIV-1 is not completely understood. This situation is more complex in subtype C infection where coreceptor switch is either absent or extremely rare. To gain insights into the mechanisms that underlie coreceptor requirement of subtype C, we screened several primary viral isolates and identified a clinical sample that demonstrated a potential to grow on standard T-cell lines with no detectable CCR5 expression. The subject was diagnosed with HIV-1 associated dementia in the absence of opportunistic infections of the brain. To isolate molecular clones from this virus, we devised a novel strategy based on anchor primers that target a sequence in the reverse transcriptase, highly conserved among diverse subtypes of HIV-1. Using this strategy, we isolated 8 full-length molecular clones from the donor. Two of the eight molecular clones, 03In94_D17 and 03In94_D24, (D17 and D24) generated replication-competent viruses. Phylogenetic analysis of the full-length viral sequences revealed that both clones were non-recombinant subtype C viruses. They contain intact open reading frames in all the viral proteins. Both the viral clones are endowed with several unique molecular and biological properties. The viral promoter of the clones is characterized by the presence of four NF-kB binding elements, a feature rarely seen in the subtype C HIV-1 LTR. Interestingly, we identified the coexistence of two different forms of Rev, a truncated form common to subtype C and a full-length form less common for this subtype, in both proviral and plasma virus compartments. An exceptional property of the viruses, atypical of subtype C, is their ability to use a wide range of coreceptors including CCR5, CXCR4, and several others tested. Sequence analysis of Env of D17 and D24 clones identified differences within the variable loops providing important clues for the expanded coreceptor use. The V1, V2 and V4 loops in both of the molecular clones are longer due to the insertion of several amino acid residues that generated potential N-linked glycosylation sites. The exceptional biological and molecular properties of these clones make them invaluable tools to understand the unique pathogenic characteristics of subtype C.
    Retrovirology 02/2008; 5(1):25. DOI:10.1186/1742-4690-5-25 · 4.19 Impact Factor
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    • "The Rev:RRE:Crm1 complex is translocated through the nuclear pore complex to the cytoplasm. This translocation is dependant on the RNA helicase activity of DDX3, which binds to the Rev:RRE:Crm1 complex on the nuclear side of the Nuclear Pore Complex and accompanies it through to the cytoplasmic side [11,12]. After dissociation, the viral transcripts are recognized by the translation machinery for synthesis of viral structural proteins [2]. "
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    ABSTRACT: The HIV Rev protein is known to facilitate export of incompletely spliced and unspliced viral transcripts to the cytoplasm, a necessary step in virus life cycle. The Rev-mediated nucleo-cytoplasmic transport of nascent viral transcripts, dependents on interaction of Rev with the RRE RNA structural element present in the target RNAs. The C-terminal variant of dsRNA-binding nuclear protein 90 (NF90ctv) has been shown to markedly attenuate viral replication in stably transduced HIV-1 target cell line. Here we examined a mechanism of interference of viral life cycle involving Rev-NF90ctv interaction. Since Rev:RRE complex formations depend on protein:RNA and protein:protein interactions, we investigated whether the expression of NF90ctv might interfere with Rev-mediated export of RRE-containing transcripts. When HeLa cells expressed both NF90ctv and Rev protein, we observed that NF90ctv inhibited the Rev-mediated RNA transport. In particular, three regions of NF90ctv protein are involved in blocking Rev function. Moreover, interaction of NF90ctv with the RRE RNA resulted in the expression of a reporter protein coding sequences linked to the RRE structure. Moreover, Rev influenced the subcellular localization of NF90ctv, and this process is leptomycin B sensitive. The dsRNA binding protein, NF90ctv competes with HIV Rev function at two levels, by competitive protein:protein interaction involving Rev binding to specific domains of NF90ctv, as well as by its binding to the RRE-RNA structure. Our results are consistent with a model of Rev-mediated HIV-1 RNA export that envisions Rev-multimerization, a process interrupted by NF90ctv.
    Retrovirology 02/2006; 3(1):83. DOI:10.1186/1742-4690-3-83 · 4.19 Impact Factor
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