The Vif and Vpr accessory proteins independently cause HIV-1-induced T cell cytopathicity and cell cycle arrest

Sakai, Keiko; Dimas, Joseph; Lenardo, Michael J.

doi:10.1073/pnas.0509417103

Cited by 125 publications

(153 citation statements)

References 55 publications

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“…More interestingly, several groups recently reported that Vif as well as Vpr induced G2 arrest in HIV-1-infected cells (5,6). Our data clearly demonstrate that the activation of TP53 is the molecular mechanism involved in Vif-induced G2 arrest.…”

Section: Discussionsupporting

confidence: 76%

“…It has recently been shown that Vif induces G2 arrest in HIV-1-infected cells independently of Vpr (5,6). To test the possibility that Vif induced G2 arrest by stabilizing and activating TP53, we examined the effect of Vif on cell cycle in various cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…Vif forms a ubiquitin ligase (E3) complex with Cullin5 and Elongin B/C (Vif-BC-Cul5) and functions as a substrate recognition subunit of this complex to induce the ubiquitination and subsequent degradation of A3G/F (3,4). Two recent studies not only implicate Vif as a unique viral protein involved in G2 arrest, but also suggest that the induction of G2 arrest is a unique Vif function (5,6). However, neither study addresses the mechanism by which Vif induces G2 arrest or the question of why HIV-1 uses two different viral proteins to arrest cells in the G2 phase of the cell cycle.…”

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confidence: 99%

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HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

Izumi

Io²,

Matsui³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Viral infectivity factor, an accessory protein encoded in the HIV-1 genome, induces G2 cell cycle arrest; however, the biological significance and mechanism(s) remain totally unclear. Here we demonstrate that the TP53 pathway is involved in Vif-mediated G2 cell cycle arrest. Vif enhances the stability and transcriptional activity of TP53 by blocking the MDM2-mediated ubiquitination and nuclear export of TP53. Furthermore, Vif causes G2 cell cycle arrest in a TP53-dependent manner. HXB2 Vif lacks these activities toward TP53 and cannot induce G2 cell cycle arrest. Using mutagenesis, we demonstrate that the critical residues for this function are located in the Nterminal region of Vif. Finally, we construct a mutant NL4-3 virus with an NL4-3/HXB2 chimeric Vif defective for the ability to induce cell cycle arrest and show that the mutant virus replicates less effectively than the wild-type NL4-3 virus in T cells expressing TP53. These data imply that Vif induces G2 cell cycle arrest through functional interaction with the TP53/MDM2 axis and that the G2 cell cycle arrest induced by Vif has a positive effect on HIV-1 replication. This report demonstrates the molecular mechanisms and the biological significance of Vif-mediated G2 cell cycle arrest for HIV-1 infection.AIDS | NL4-3 | HXB2 | APOBEC3G | infectivity

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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

Izumi

Io²,

Matsui³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Strikingly, our results show that hnRNP A1 cytoplasmic localization is solely dependent on nucleocytoplasmic transport of the vRNA, via the CRM1-dependent or another pathway. The effects on nuclear import may, however, be a result of a combinatorial effect of viral proteins, as shown for HIV-1-induced apoptosis (76). Although this is not the first study to show hnRNP A1 cytoplasmic localization/retention imposed by a virus, it is the first to report this phenomenon in the context of HIV-1 replication.…”

Section: Discussionmentioning

confidence: 66%

Human Immunodeficiency Virus Type 1 (HIV-1) Induces the Cytoplasmic Retention of Heterogeneous Nuclear Ribonucleoprotein A1 by Disrupting Nuclear Import

Monette

Ajamian

López-Lastra

et al. 2009

Journal of Biological Chemistry

143

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Human immunodeficiency virus type 1 (HIV-1) co-opts host proteins and cellular machineries to its advantage at every step of the replication cycle. Here we show that HIV-1 enhances heterogeneous nuclear ribonucleoprotein (hnRNP) A1 expression and promotes the relocalization of hnRNP A1 to the cytoplasm. The latter was dependent on the nuclear export of the unspliced viral genomic RNA (vRNA) and to alterations in the abundance and localization of the FG-repeat nuclear pore glycoprotein p62. hnRNP A1 and vRNA remain colocalized in the cytoplasm supporting a post-nuclear function during the late stages of HIV-1 replication. Consistently, we show that hnRNP A1 acts as an internal ribosomal entry site trans-acting factor up-regulating internal ribosome entry site-mediated translation initiation of the HIV-1 vRNA. The up-regulation and cytoplasmic retention of hnRNP A1 by HIV-1 would ensure abundant expression of viral structural proteins in cells infected with HIV-1.During the late stages of the HIV-1 3 replication cycle, the full-length HIV-1 viral RNA (vRNA) must be exported from the nucleus and both translated and packaged into new viral particles (1). The orchestration of these events is directed by a diversity of viral and host proteins that interact with each other and with the vRNA to form HIV-1 ribonucleoprotein (RNP) complexes that originate in the nucleus and persist in the cytoplasm (2). Investigations into the composition and functions of the HIV-1 RNP will reveal new information about innate immunity as well as identify new potential therapeutic targets (3-6).The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a predominantly nuclear protein engaged in a number of cellular and viral RNPs for RNA-processing activities, including splicing regulation, nuclear export, microRNA processing, mRNA stability, telomere maintenance, and IRES-mediated translation initiation (7-12). What enables hnRNP A1 to have such broad functions in RNA metabolism is its ability to bind both nuclear and cytoplasmic RNAs (10). In addition to its well characterized role in nuclear RNA processing, hnRNP A1 binds to purine-rich sequences of mRNAs for mRNA turnover and translation (13,14). Close examination of the HIV-1 vRNA reveals many AG-and AU-rich sequences closely resembling hnRNP A1 binding motifs (15). In fact, hnRNP A1 binds to a number of sequences on the HIV-1 vRNA such as the cis-acting repressive sequences, instability elements, and exonic splicing silencer elements, and indeed, hnRNP A1 is implicated in the fate of HIV-1 RNA, including splicing regulation, nucleocytoplasmic export, and cytoplasmic stability (16 -21).Our previous work demonstrated that hnRNP A1 efficiently immunoprecipitated with the HIV-1 vRNA (22) and that siRNA-mediated knockdown of hnRNP A1 caused a dramatic decrease in HIV-1 structural protein, pr55Gag (herein termed Gag) expression and virus production with little effect on steady-state levels of the three HIV-1 RNA species (i.e. 9-, 4-, and 2-kb RNAs) (23). In this work, we show that HIV-1 ...

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“…Thus, G 2 arrest induced by Vpr may promote virus production by upregulating both transcription (via the LTR) and translation (via the putative HIV-1 IRES) of viral products. Recently, Sakai et al reported that deletion of Vpr, in addition to Vif, rendered HIV-1 incapable of causing G 2 arrest and eliminated the cytopathic properties of the virus, which suggests a link between viral cytopathicity and cell cycle arrest (Sakai et al, 2006). Recently, infected lymphocytes (identified by expression of Gag p24) isolated from recent HIV-1 seroconverters and stained with propidium iodide for DNA content were found to be arrested in G 2 , indicating that G 2 arrest is not merely an in vitro phenomenon (Zimmerman et al, 2006).…”

Section: Vpr-induced G 2 Arrest and Viral Replicationmentioning

confidence: 99%

HIV-1 Vpr: Mechanisms of G2 arrest and apoptosis

Andersen

Rouzic

Planelles

2008

Experimental and Molecular Pathology

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Since the first isolation of HIV-1 from a patient with generalized lymphadenopathy in 1983, great progress has been made in understanding the viral life cycle and the functional nuances of each of the nine genes encoded by HIV-1. Considerable attention has been paid to four small HIV-1 open reading frames, vif, vpr, vpu and nef. These genes were originally termed "accessory" because their deletion failed to completely disable viral replication in vitro. More than twenty years afte the cloning and sequencing of HIV-1, a great deal of information is available regarding the multiple functions of the accessory proteins and it is well accepted that, collectively, these gene products modulate the host cell biology to favor viral replication, and that they are largely responsible for the pathogenesis of HIV-1. Expression of Vpr, in particular, leads to cell cycle arrest in G 2 , followed by apoptosis.Here we summarize our current understanding of Vpr biology with a focus on Vpr-induced G 2 arrest and apoptosis.

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The Vif and Vpr accessory proteins independently cause HIV-1-induced T cell cytopathicity and cell cycle arrest

Cited by 125 publications

References 55 publications

HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication

Human Immunodeficiency Virus Type 1 (HIV-1) Induces the Cytoplasmic Retention of Heterogeneous Nuclear Ribonucleoprotein A1 by Disrupting Nuclear Import

HIV-1 Vpr: Mechanisms of G2 arrest and apoptosis

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