Vif Counteracts a Cyclophilin A-Imposed Inhibition of Simian Immunodeficiency Viruses in Human Cells

Takeuchi, Hiroaki; Buckler-White, Alicia; Goila-Gaur, Ritu; Miyagi, Eri; Khan, Muhammad Haroon; Opi, Sandrine; Kao, Sandra; Sokolskaja, Elena; Pertel, Thomas; Luban, Jeremy; Strebel, Klaus

doi:10.1128/jvi.02727-06

Cited by 16 publications

(15 citation statements)

References 59 publications

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“…Also, the observation that proteasome inhibitors partially rescue reverse transcription of Vpx-deficient viruses in DCs is consistent with the idea that SIVmac virions may be targeted by a TRIM5α-like restriction, or by another E3 ubiquitin ligase in monocyte-derived cells [8]. Whereas these observations raise the possibility that Vpx could act by counteracting TRIM5α, we note that this is not likely, because TRIM5α is expressed in Jurkat T cells [29], which we found not to restrict Vpx-deficient SIVmac virions.…”

Section: Discussionsupporting

confidence: 88%

Lentiviral Vpx Accessory Factor Targets VprBP/DCAF1 Substrate Adaptor for Cullin 4 E3 Ubiquitin Ligase to Enable Macrophage Infection

Srivastava

Swanson

Manel³

et al. 2008

PLoS Pathog

192

230

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Vpx is a small virion-associated adaptor protein encoded by viruses of the HIV-2/SIVsm lineage of primate lentiviruses that enables these viruses to transduce monocyte-derived cells. This probably reflects the ability of Vpx to overcome an as yet uncharacterized block to an early event in the virus life cycle in these cells, but the underlying mechanism has remained elusive. Using biochemical and proteomic approaches, we have found that Vpx protein of the pathogenic SIVmac 239 strain associates with a ternary protein complex comprising DDB1 and VprBP subunits of Cullin 4–based E3 ubiquitin ligase, and DDA1, which has been implicated in the regulation of E3 catalytic activity, and that Vpx participates in the Cullin 4 E3 complex comprising VprBP. We further demonstrate that the ability of SIVmac as well as HIV-2 Vpx to interact with VprBP and its associated Cullin 4 complex is required for efficient reverse transcription of SIVmac RNA genome in primary macrophages. Strikingly, macrophages in which VprBP levels are depleted by RNA interference resist SIVmac infection. Thus, our observations reveal that Vpx interacts with both catalytic and regulatory components of the ubiquitin proteasome system and demonstrate that these interactions are critical for Vpx ability to enable efficient SIVmac replication in primary macrophages. Furthermore, they identify VprBP/DCAF1 substrate receptor for Cullin 4 E3 ubiquitin ligase and its associated protein complex as immediate downstream effector of Vpx for this function. Together, our findings suggest a model in which Vpx usurps VprBP-associated Cullin 4 ubiquitin ligase to enable efficient reverse transcription and thereby overcome a block to lentivirus replication in monocyte-derived cells, and thus provide novel insights into the underlying molecular mechanism.

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Section: Discussionsupporting

confidence: 88%

Lentiviral Vpx Accessory Factor Targets VprBP/DCAF1 Substrate Adaptor for Cullin 4 E3 Ubiquitin Ligase to Enable Macrophage Infection

Srivastava

Swanson

Manel³

et al. 2008

PLoS Pathog

192

230

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“…Cell lysates were prepared from the target LuSIV cells 24 h post-infection, and luciferase activity was measured to assess the efficiency of SIV infection (Figure 2A). Similar to the results in Jurkat cells [27], CsA treatment of either the producer cells or the target cells resulted in suppression of HIV-1 infection confirming the importance of CypA both in producer and target human cells for efficient HIV-1 replication [16,30]. In contrast, SIVagm infection was not inhibited but rather enhanced by CsA treatment of target cells although it was decreased by CsA treatment of producer cells.…”

Section: Resultssupporting

confidence: 76%

“…A recent study has shown a suppressive effect of CypA on replication of vif -deleted SIV in human Jurkat cells, which was counteracted by SIV Vif inhibiting CypA incorporation during virus assembly [27]. This Vif function can be distinguished from its anti-human APOBEC3G (apolipoprotein B mRNA-editing enzyme-catalytic subunit 3G) function.…”

Section: Introductionmentioning

confidence: 99%

Host cell species-specific effect of cyclosporine A on simian immunodeficiency virus replication

et al. 2012

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BackgroundAn understanding of host cell factors that affect viral replication contributes to elucidation of the mechanism for determination of viral tropism. Cyclophilin A (CypA), a peptidyl-prolyl cis-trans isomerase (PPIase), is a host factor essential for efficient replication of human immunodeficiency virus type 1 (HIV-1) in human cells. However, the role of cyclophilins in simian immunodeficiency virus (SIV) replication has not been determined. In the present study, we examined the effect of cyclosporine A (CsA), a PPIase inhibitor, on SIV replication.ResultsSIV replication in human CEM-SS T cells was not inhibited but rather enhanced by treatment with CsA, which inhibited HIV-1 replication. CsA treatment of target human cells enhanced an early step of SIV replication. CypA overexpression enhanced the early phase of HIV-1 but not SIV replication, while CypA knock-down resulted in suppression of HIV-1 but not SIV replication in CEM-SS cells, partially explaining different sensitivities of HIV-1 and SIV replication to CsA treatment. In contrast, CsA treatment inhibited SIV replication in macaque T cells; CsA treatment of either virus producer or target cells resulted in suppression of SIV replication. SIV infection was enhanced by CypA overexpression in macaque target cells.ConclusionsCsA treatment enhanced SIV replication in human T cells but abrogated SIV replication in macaque T cells, implying a host cell species-specific effect of CsA on SIV replication. Further analyses indicated a positive effect of CypA on SIV infection into macaque but not into human T cells. These results suggest possible contribution of CypA to the determination of SIV tropism.

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“…For example, similar to our findings with Cpr1p CypA-like proteins and Cyp40 homologs, cyclophilins have been shown to inhibit accumulation of several RNA viruses, including influenza A virus, West Nile virus, alfanodaviruses, and HIV-1 (5,52,69). Interestingly, HIV targets CypA via the retroviral Vif protein, which inhibits the incorporation of CypA into the viral particles (70). Overall, cyclophilins are potent inhibitors of several RNA viruses, and they might be part of the innate response of the host against some viruses.…”

Section: Discussionsupporting

confidence: 72%

Cyclophilin A Binds to the Viral RNA and Replication Proteins, Resulting in Inhibition of Tombusviral Replicase Assembly

Kovalev

Nagy

2013

J Virol

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Replication of plus-stranded RNA viruses is greatly affected by numerous host-encoded proteins that act as restriction factors. Cyclophilins, which are a large family of cellular prolyl isomerases, have been found to inhibit Tomato bushy stunt tombusvirus (TBSV) replication in a Saccharomyces cerevisiae model based on genome-wide screens and global proteomics approaches. In this report, we further characterize single-domain cyclophilins, including the mammalian cyclophilin A and plant Roc1 and Roc2, which are orthologs of the yeast Cpr1p cyclophilin, a known inhibitor of TBSV replication in yeast. We found that recombinant CypA, Roc1, and Roc2 strongly inhibited TBSV replication in a cell-free replication assay. Additional in vitro studies revealed that CypA, Roc1, and Roc2 cyclophilins bound to the viral replication proteins, and CypA and Roc1 also bound to the viral RNA. These interactions led to inhibition of viral RNA recruitment, the assembly of the viral replicase complex, and viral RNA synthesis. A catalytically inactive mutant of CypA was also able to inhibit TBSV replication in vitro due to binding to the replication proteins and the viral RNA. Overexpression of CypA and its mutant in yeast or plant leaves led to inhibition of tombusvirus replication, confirming that CypA is a restriction factor for TBSV. Overall, the current work has revealed a regulatory role for the cytosolic single-domain Cpr1-like cyclophilins in RNA virus replication. Among the identified host factors, there are numerous inhibitory host proteins that serve as restriction factors for (ϩ)RNA viruses. However, the functions of the majority of these host proteins during (ϩ)RNA virus replication have not been fully revealed. The restriction factors likely interfere with the viral replication process, which takes place in membrane-bound viral replicase complexes (VRCs) in the cytoplasm of infected cells. The restriction factors potentially target the viral replication proteins, the viral RNA, or host-encoded proteins usurped by (ϩ)RNA viruses to aid the replication process (10-19).Recently, a major effort to dissect host restriction factors has been conducted with TBSV, which is a small (ϩ)RNA virus that is used as a model virus to study virus replication, recombination, and virus-host interactions, based on a yeast (Saccharomyces cerevisiae) model host (20-25). Genome-wide screens of yeast genes and global proteomics approaches have led to the identification of over 500 host genes/proteins that affect TBSV replication or recombination or interact with the viral replication proteins or viral RNA (1, 3, 24-32). Interestingly, ϳ25% of the identified factors seem to inhibit TBSV replication or recombination, suggesting that many host proteins might work as intrinsic restriction factors.The tombusvirus VRC consists of two viral replication proteins (p33 and p92 pol ) and ϳ10 host proteins (18,30,31,33). The auxiliary p33 replication protein is an RNA chaperone involved in recruitment of TBSV (ϩ)RNA to the site of replication, which is the c...

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Vif Counteracts a Cyclophilin A-Imposed Inhibition of Simian Immunodeficiency Viruses in Human Cells

Cited by 16 publications

References 59 publications

Lentiviral Vpx Accessory Factor Targets VprBP/DCAF1 Substrate Adaptor for Cullin 4 E3 Ubiquitin Ligase to Enable Macrophage Infection

Lentiviral Vpx Accessory Factor Targets VprBP/DCAF1 Substrate Adaptor for Cullin 4 E3 Ubiquitin Ligase to Enable Macrophage Infection

Host cell species-specific effect of cyclosporine A on simian immunodeficiency virus replication

Cyclophilin A Binds to the Viral RNA and Replication Proteins, Resulting in Inhibition of Tombusviral Replicase Assembly

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