Inhibition of HIV-1 replication by combined expression of gag dominant negative mutant and a human ribonuclease in a tightly controlled HIV-1 inducible vector

Cara, Andrea; Sm, Rybak; Dl, Newton; Crowley, R. Webster; Se, Rottschafer; Ms, Reitz; Gl, Gusella

doi:10.1038/sj.gt.3300545

Cited by 19 publications

(10 citation statements)

References 3 publications

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“…Thus, higher levels of steady-state mRNA can be obtained with basal expression from the HIV promoter. Additionally the inducibility of the HIV promoter to highly transactivate transcription of HIV inhibitory genes in the presence of Tat has been shown [55][56][57] and is confirmed for the constructs used in this study. Quantification of steady-state mRNA from pVA-HIV vectors after Tat-mediated induction in the presence of extracellular Tat peptide shows a two-to four-fold increase of expression of RRE in cells carrying pVA-HIV-3′-TAR+RRE and pVA-HIV-TAR+RRE, respectively.…”

Section: Discussionsupporting

confidence: 73%

High level inhibition of HIV replication with combination RNA decoys expressed from an HIV-Tat inducible vector

Fraisier

Irvine²,

Wrighton³

et al. 1998

Gene Ther

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Section: Discussionsupporting

confidence: 73%

High level inhibition of HIV replication with combination RNA decoys expressed from an HIV-Tat inducible vector

Fraisier

Irvine²,

Wrighton³

et al. 1998

Gene Ther

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“…Previous demonstrations of lentiviral vectors rescue relied on RNA and PCR analysis (Dropulic et al, 1996;Cara et al, 1998), and it has been shown that HIV-1 can mobilize HIV-based vectors that do not have a deletion in the U3 region of the 39 LTR (Bukovsky et al, 1999). Here, we directly demonstrate by functional and molecular assays that these vectors can undergo a complete cycle of replication and maintain their structures without rearrangem ents.…”

Section: Discussionmentioning

confidence: 98%

Modified Human Immunodeficiency Virus-Based Lentiviral Vectors Display Decreased Sensitivity toTrans-Dominant Rev

et al. 2000

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As a first step toward the development of HIV-based conditionally replicating defective interfering particles expressing trans-dominant Rev (TdRev), we studied whether mutation of the splicing signals and replacement of the RRE by the SRV-1 CTE would render these vectors less sensitive to TdRev. Vectors with mutations in the splicing signals (SD-/RRE+) yielded high titers (5 X 10(6) CFU/ml) and showed higher levels of cytoplasmic unspliced mRNA than the corresponding SD+/RRE+ vectors either in the absence of Rev, in the presence of TdRev, or in the presence of both TdRev and Rev. Proviral copies of SD-/RRE+ vectors were rescued more efficiently than SD+/RRE+ vectors when TdRev was expressed. Vectors with the SRV-1 CTE (SD+/CTE+ and SD-/CTE+) expressed high levels of cytoplasmic unspliced mRNA in the absence of Rev expression. Titers obtained with the SD-/CTE+ vectors (10(6) CFU/ml) were higher than the titers obtained with SD+/CTE+ vectors. We also tested the effect of other structural modifications such as the orientation of the expression cassette and the presence of the central polypurine tract (cPPT/CTS). We show that an expression cassette cloned in the reverse orientation with respect to the LTRs or elimination of the cPPT/CTS element severely affected vector titers. We also demonstrated that these vectors can be efficiently mobilized from their proviral state by HIV trans-complementing functions, and transduced into secondary target cells without suffering any genomic rearrangement.

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“…The data are representative of two independent PCR analyses. type genome into virions, it would be conceivable that this vector can be further modified to contain genetic elements, such as ribozymes or antisense RNAs, that may act upon wildtype RNA copackaged in the same virion (9,13,14). Further understanding of the mechanism of action and optimization of its effects will be critical for consideration of the use of such a vector in clinical applications.…”

Section: Discussionmentioning

confidence: 99%

An Inducible Human Immunodeficiency Virus Type 1 (HIV-1) Vector Which Effectively Suppresses HIV-1 Replication

Morizono

et al. 1999

J Virol

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Recently, gene therapy vectors based upon the human immunodeficiency virus type 1 (HIV-1) genome have been developed. Here, we create an HIV-1 vector which is defective for all HIV-1 genes, but which maintains cis-acting elements required for efficient packaging, infection, and expression. In T cells transduced by this vector, vector expression is low but efficiently induced following HIV-1 infection. Remarkably, although the HIV-1 vector does not contain specific anti-HIV-1 therapeutic genes, the presence of the vector alone is sufficient to inhibit the spread of HIV-1 infection. The mechanism of inhibition is likely to be at the level of competition for limiting substrates required for either efficient packaging or reverse transcription, thereby selecting against propagation of wild-type HIV-1. These results provide proof of a concept for potential application of a novel HIV-1 vector in HIV-1 disease.

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Inhibition of HIV-1 replication by combined expression of gag dominant negative mutant and a human ribonuclease in a tightly controlled HIV-1 inducible vector

Cited by 19 publications

References 3 publications

High level inhibition of HIV replication with combination RNA decoys expressed from an HIV-Tat inducible vector

High level inhibition of HIV replication with combination RNA decoys expressed from an HIV-Tat inducible vector

Modified Human Immunodeficiency Virus-Based Lentiviral Vectors Display Decreased Sensitivity toTrans-Dominant Rev

An Inducible Human Immunodeficiency Virus Type 1 (HIV-1) Vector Which Effectively Suppresses HIV-1 Replication

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