HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication

Nicot, Christophe; Dundr, Miroslav; Johnson, Julie; Fullen, Jake; Alonzo, Norma; Fukumoto, Risaku; Princler, Gerald L.; Derse, David; Misteli, Tom; Franchini, Genoveffa

doi:10.1038/nm984

Cited by 160 publications

(212 citation statements)

References 27 publications

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“…In addition to Tax, HTLV-1 and HTLV-2 genomes also encode the p30 and p28 proteins, respectively (Nicot et al, 2004;Younis et al, 2004). Each of these two proteins has been shown to retain the doubly spliced mRNA encoding the Tax and Rex proteins in the nucleus.…”

Section: Characterization Of the Htlv/stlv-3 Tax Proteinmentioning

confidence: 99%

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

et al. 2006

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Human T-cell leukemia virus and simian T-cell leukemia virus (STLV) form the primate T-cell lymphotropic viruses group. Human T-cell leukemia virus type 1 and type 2 (HTLV-1 and HTLV-2) encode the Tax viral transactivator (Tax1 and Tax2, respectively). Tax1 possesses an oncogenic potential and is responsible for cell transformation both in vivo and in vitro. We and others have recently discovered the existence of human Tcell lymphotropic virus type 3. However, there is currently no evidence for the presence of a Tax protein in HTLV-3-infected individuals. We show that the serum of an HTLV-3 asymptomatic carrier and the sera of two STLV-3-infected monkeys contain specific anti-Tax3 antibodies. We also show that tax3 mRNA is present in the PBMCs obtained from an STLV-3-infected monkey, demonstrating that Tax3 is expressed in vivo. We further demonstrate that Tax3 intracellular localization is very similar to that of Tax1 and that Tax3 binds to both CBP and p300 coactivators. Using purified Tax3, we show that the protein increases transcription from a 4TxRE G-free cassette plasmid in an in vitro transcription assay. In all cell types tested, including transiently transfected lymphocytes, Tax3 activates its own promoter STLV-3 long terminal repeat (LTR), which contains only two Tax Responsive Elements (TREs), and activates also HTLV-1 and HTLV-2 LTRs. In addition, Tax3 also activates the NF-jB pathway. We also show that Tax3 possesses a PDZ-binding sequence at its C-terminal end. Our results demonstrate that Tax3 is a transactivator, and that its properties are more similar to that of Tax1, rather than of Tax2. This suggests the possible occurrence of lymphoproliferative disorders among HTLV-3-infected populations.

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Section: Characterization Of the Htlv/stlv-3 Tax Proteinmentioning

confidence: 99%

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

et al. 2006

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“…In fact, studies of clonal expansion of HTLV-I-infected cells in HTLV-I carriers, demonstrate some clones persist for over 7 years in the same individual [86,87]. We have recently found that the virally encoded p30 protein prevents nuclear export of the tax/rex RNA and suppresses viral gene expression in vitro [88]. Whether or not p30 may act as latency factor in vivo remains to be investigated.…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Current views in HTLV-I-associated adult T-cell leukemia/lymphoma

Nicot

2005

Am. J. Hematol.

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103

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Epidemiological studies have demonstrated that the relative percentage of malignant lymphoid proliferations varies widely according to geographical location and ethnic populations. HTLV-I is the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and is also associated with cutaneous T-cell lymphoma (CTCL). However, a definite role of HTLV-I in mycosis fungoides (MF) and/or Sezary syndrome (SS) remains controversial. While most HTLV-I-infected individuals remain asymptomatic carriers, 1-5% will develop ATLL, an invariably fatal expansion of virus-infected CD4 + T cells. This low incidence and the long latency period preceding occurrence of the disease suggest that additional factors are involved in development of ATLL. In this review, diagnosis, clinical features, and molecular pathogenesis of HTLV-I are discussed. Am.

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“…p30, expressed from a doubly-spliced mRNA, is a multifunctional regulator that differentially modulates viral and/or cellular gene expression at the transcriptional level through association with cellular proteins including p300/CBP and TIP60 (Awasthi et al, 2005;Zhang et al, 2001;Zhang et al, 2000) and post-transcriptionally via binding and retaining tax/rex mRNA in the nucleus (Nicot et al, 2004;Younis et al, 2006;Younis et al, 2004). Although p30 is dispensable in vitro for replication and cellular transformation (Derse et al, 1997;Robek et al, 1998), it is required to promote virus survival and persistence in infected animals (Silverman et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Detection and quantitation of HTLV-1 and HTLV-2 mRNA species by real-time RT-PCR

Green

2007

Journal of Virological Methods

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SummaryHTLV-1 and HTLV-2 are highly related delta-retroviruses that infect and transform T-lymphocytes, but have distinct pathogenic properties. HTLV replication and survival requires the expression of multiple gene products from an unspliced and a series of highly related alternatively spliced mRNA species. To date, the comparative levels of all known HTLV-1 and HTLV-2 viral mRNAs in different transformed cell lines and at different stages of virus infection have not been assessed. In this study, we compiled a series of oligonucleotide primer pairs and probes to quantify both HTLV-1 and HTLV-2 mRNA species using real-time RT-PCR. The optimized reaction for detection of each mRNA had amplification efficiency greater than 90% with a linear range spanning 25 to 2.5 × 10 7 copies. The R 2 s of all standard curves were greater than 0.97. Quantitation of HTLV mRNAs between different cell lines showed variability (gag/pol ≥ tax/rex > env ≥ accessory proteins), but the overall levels of each mRNA relative to each other within a cell line were similar. These results provide a method to quantify all specific mRNAs from both HTLV-1 and HTLV-2, which can be used to evaluate further viral gene expression and correlate transcript levels to key stages of the virus life cycle and ultimately, pathogenesis.

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HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication

Cited by 160 publications

References 27 publications

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

Current views in HTLV-I-associated adult T-cell leukemia/lymphoma

Detection and quantitation of HTLV-1 and HTLV-2 mRNA species by real-time RT-PCR

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