T Lymphocytes Transduced with a Lentiviral Vector Expressing F12-vif Are Protected from HIV-1 Infection in an APOBEC3G-Independent Manner

Vallanti, Giuliana; Lupo, Rossella; Federico, Maurizio; Mavilio, Fulvio; Bovolenta, Chiara

doi:10.1016/j.ymthe.2005.05.014

Cited by 20 publications

(33 citation statements)

References 41 publications

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“…Previous studies identified a Vif variant (F12 Vif) with dominant negative properties (51,65); however, the dominant negative effect of F12 Vif was A3G independent (51,65). This resembles our own observation of the A3G-independent inhibition of viral infectivity by high-level expression of Vif (2).…”

supporting

confidence: 84%

Identification of Dominant Negative Human Immunodeficiency Virus Type 1 Vif Mutants That Interfere with the Functional Inactivation of APOBEC3G by Virus-Encoded Vif

Walker

Khan

Kao

et al. 2010

J Virol

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APOBEC3G (A3G) is a host cytidine deaminase that serves as a potent intrinsic inhibitor of retroviral replication. A3G is packaged into human immunodeficiency virus type 1 virions and deaminates deoxycytidine to deoxyuridine on nascent minus-strand retroviral cDNA, leading to hyper-deoxyguanine-to-deoxyadenine mutations on positive-strand cDNA and inhibition of viral replication. The antiviral activity of A3G is suppressed by Vif, a lentiviral accessory protein that prevents encapsidation of A3G. In this study, we identified dominant negative mutants of Vif that interfered with the ability of wild-type Vif to inhibit the encapsidation and antiviral activity of A3G. These mutants were nonfunctional due to mutations in the highly conserved HCCH and/or SOCS box motifs, which are required for assembly of a functional Cul5-E3 ubiquitin ligase complex. Similarly, mutation or deletion of a PPLP motif, which was previously reported to be important for Vif dimerization, induced a dominant negative phenotype. Expression of dominant negative Vif counteracted the Vif-induced reduction of intracellular A3G levels, presumably by preventing Vif-induced A3G degradation. Consequently, dominant negative Vif interfered with wild-type Vif's ability to exclude A3G from viral particles and reduced viral infectivity despite the presence of wild-type Vif. The identification of dominant negative mutants of Vif presents exciting possibilities for the design of novel antiviral strategies.

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supporting

confidence: 84%

Identification of Dominant Negative Human Immunodeficiency Virus Type 1 Vif Mutants That Interfere with the Functional Inactivation of APOBEC3G by Virus-Encoded Vif

Walker

Khan

Kao

et al. 2010

J Virol

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“…Vallunti et al recently reported that F12-Vif from a nonproducer HIV-1 provirus clone F12 has anti-HIV-1 activity despite degrading A3G as efficiently as NL4-3 Vif does (46). The F12-Vif derivative Chim3-Vif is a chimera Vif generated by replacing the domain (aa 126-170) of wild-type Vif with that of F12-Vif.…”

Section: Discussionmentioning

confidence: 99%

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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“…25 In this configuration, eGFP is driven by the unmodified 5Ј LTR of the vector. 293T cells were seeded at a concentration of 10 5 cells/well in 24-well plastic plates (Corning Inc., New York, NY) 24 hours before transfection.…”

Section: Ltr-gfp Assaymentioning

confidence: 99%

Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression

Crotti

Lušić

Lupo

et al. 2007

Blood

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CD4+ cells of most individuals infected with HIV-1 harbor a C-terminally truncated and constitutively activated form of signal transducer and activator of transcription-5 (STAT5Δ). We report that the chronically HIV-infected U1 cell line expresses STAT5Δ but not full-length STAT5. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation of U1 cells promoted early activation of STAT5Δ and of extracellular signal regulated kinases (ERKs), followed by later activation of activator protein 1 (AP-1) and HIV expression. Inhibition of ERK/AP-1 by PD98,059 abolished, whereas either tyrphostin AG490 or a STAT5 small interfering RNA (siRNA) enhanced, virion production in GM-CSF–stimulated U1 cells. Chromatin immunoprecipitation demonstrated the induction of STAT5Δ binding to STAT consensus sequences in the HIV-1 promoter together with a decreased recruitment of RNA polymerase II after 1 hour of GM-CSF stimulation of U1 cells. Down-regulation of STAT5Δ by siRNA resulted in the up-regulation of both HIV-1 gag-pol RNA and p24 Gag antigen expression in CD8-depleted leukocytes of several HIV-positive individuals cultivated ex vivo in the presence of interleukin-2 but not of interleukin-7. Thus, the constitutively activated STAT5Δ present in the leukocytes of most HIV-positive individuals acts as a negative regulator of HIV expression.

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T Lymphocytes Transduced with a Lentiviral Vector Expressing F12-vif Are Protected from HIV-1 Infection in an APOBEC3G-Independent Manner

Cited by 20 publications

References 41 publications

Identification of Dominant Negative Human Immunodeficiency Virus Type 1 Vif Mutants That Interfere with the Functional Inactivation of APOBEC3G by Virus-Encoded Vif

Identification of Dominant Negative Human Immunodeficiency Virus Type 1 Vif Mutants That Interfere with the Functional Inactivation of APOBEC3G by Virus-Encoded Vif

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

Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression

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