HIV-1 proprotein processing as a target for gene therapy

Cordelier, Pierre; Zern, Mark Α.; Strayer, David S.

doi:10.1038/sj.gt.3301891

Cited by 25 publications

(7 citation statements)

References 47 publications

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“…Recovery of rSV40s exceeds 10 11 infectious units (IU)/ml, and often exceeds 10 12 IU/ml. These vectors have been used with various constitutive and conditional pol II promoters, to produce protein products as well as untranslated transcripts Cordelier, et al, 2003a;Strayer, et al, 1997b;. As well, pol III promoters of several types have been used to deliver untranslated transcripts [Zern, et al, 1999;Cordelier, et al, 2003b] .…”

Section: Sv40-derived Vectors: What They Are?mentioning

confidence: 99%

What they are, How they Work and Why they do What they do? The Story of SV40-derived Gene Therapy Vectors and What They Have to Offer

Strayer

Cordelier²,

Kondo³

et al. 2005

CGT

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The natural function of viruses is to deliver their genetic material to cells. Among the most effective of viruses in doing that is Simian Virus-40 (SV40). The properties that make SV40 a successful virus make it an attractive candidate for use as a gene delivery vehicle: high titer replication, infectivity for almost all nucleated cell types whether the cells are dividing or resting, potential for integration into cellular DNA, a peculiar pathway for entering cells that bypasses the cells' antigen processing apparatus, very high stability, and the apparent ability to activate expression of its own capsid genes in trans. Exploiting these and other characteristics of wild type (wt) SV40, increasing numbers of laboratories are studying recombinant (r) SV40-derived vectors. Among the uses to which these vectors have been applied are: delivering therapy to inhibit HIV, hepatitis C virus (HCV) and other viruses; correction of inherited hepatic and other protein deficiencies; immunizing against lentiviral and other antigens; treatment of inherited and acquired diseases of the central nervous system; protecting the lung and other organs from free radical-induced injury; and many others. The effectiveness of these vectors is a reflection of the adaptive evolution that produced their parent virus, wt SV40. This article explores how and why these vectors work, their strengths and their limitations, and provides a functional model for their exploitation for experimental and clinical applications.

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Section: Sv40-derived Vectors: What They Are?mentioning

confidence: 99%

What they are, How they Work and Why they do What they do? The Story of SV40-derived Gene Therapy Vectors and What They Have to Offer

Strayer

Cordelier²,

Kondo³

et al. 2005

CGT

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“…Processing of both gp160 and p55 were reduced. 22 HIV-1 replication may be blocked or decreased by interfering with cellular serine proteases or viral aspartyl proteases. 23 Possibly by targeting multiple aspects of viral postprocessing one might attain a synergistic effect with more standard orally delivered protease inhibitors.…”

Section: Dominant-negative Effectors Against Hiv-1 Inhibit Viral Replmentioning

confidence: 99%

Gene therapy progress and prospects: Novel gene therapy approaches for AIDS

Wolkowicz

Nolan

2005

Gene Ther

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“…NF-AT2 positively regulates HIV-1 replication in T cells (36) and cooperates with NF-kB and Tat in HIV-1 LTR transcriptional activation. (37) These data, in addition to the nonspecific response to transfection (38) and transduction, (39) could explain why wtHIVLTR and muHIVLTR may be active in the absence of the direct NF-kB activator (i.e., HBV). Thus, although its specificity for HBV is not perfect, the HIVLTR is an improvement over high-level constitutive promoters for driving IFN production as a conditional promoter responsive to HBV.…”

mentioning

confidence: 93%

Conditional Expression of IFN-α and IFN-γ Activated by HBV as Genetic Therapy for Hepatitis B

Matskevich

Cordelier

Strayer

2003

Journal of Interferon & Cytokine Research

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Chronic infection with hepatitis B virus (HBV) has potentially devastating consequences and is very difficult to treat. Therapy with recombinant interferons (IFN), especially IFN-alpha, may be effective. The blood IFN-alpha levels that are needed to maintain therapeutic IFN-alpha levels in the liver, however, often cause severe side effects. Gene delivery to the liver may provide a solution. Using a long-term expression construct could provide the desired levels of IFN locally without the need to maintain potentially problematic blood levels. Recombinant, Tag-deleted SV40-derived vectors transduce hepatocytes efficiently and provide permanent transgene expression. We designed an expression construct that was effective against HBV and whose activity was limited to HBV-infected cells. To do this, we exploited the ability of HBV X protein to activate NF-kappaB and, via NF-kappaB, to activate promoter activity of HIV long terminal repeat (LTR) in hepatocytes. Using HIVLTR as a conditional promoter upstream of human and murine IFN-alpha and IFN-gamma cDNAs, rSV40 vectors were used to test the responsiveness of IFN to HBV and the ability of these IFNs to inhibit HBV transcripts and protein production and to activate IFN signaling in neighboring untransduced cells. We found that in hepatocyte cell lines and in primary hepatocytes, HBV activated the promoter activity of the HIVLTR via NF-kappaB. When whole HBV genome was delivered to cells by transfection to simulate HBV infection, IFN expression was activated, IFNs were produced and secreted, and they protected cells from HBV. Levels of IFN proteins that were secreted in this context were comparable to targeted blood levels needed to control chronic hepatitis viral infection. Further, IFNs that were elicited and secreted in this manner were able to activate IFN-induced signaling pathways in neighboring, untransduced cells and so were likely to provide protection even to cells that the rSV40 vector did not transduce. Gene delivery using such rSV40 vectors expressing IFNs conditionally in response to HBV may be an attractive therapeutic option for the treatment of chronic hepatitis B.

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HIV-1 proprotein processing as a target for gene therapy

Cited by 25 publications

References 47 publications

What they are, How they Work and Why they do What they do? The Story of SV40-derived Gene Therapy Vectors and What They Have to Offer

What they are, How they Work and Why they do What they do? The Story of SV40-derived Gene Therapy Vectors and What They Have to Offer

Gene therapy progress and prospects: Novel gene therapy approaches for AIDS

Conditional Expression of IFN-α and IFN-γ Activated by HBV as Genetic Therapy for Hepatitis B

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