Analysis of factor VIII mediated suppression of lentiviral vector titres

Radcliffe, Pippa A; Sion, Christelle J. M; Wilkes, Fraser; Custard, E; Beard, G L; Kingsman, Susan M.; Mitrophanous, Kyriacos

doi:10.1038/sj.gt.3303080

Cited by 32 publications

(24 citation statements)

References 33 publications

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“…Similar observations have been made for vectors containing factor VIII and factor IX cDNAs, in which codon optimization of the transgene resulted in a 10-fold increase in viral titers and improved expression levels. 38,39 Interestingly, the extent of increased transgene expression after cDNA optimization or introduction of an intron varies tremendously between different cell lines, which underlines the importance to test a vector on target cells rather than cell lines.…”

Section: Discussionmentioning

confidence: 99%

Transgene optimization significantly improves SIN vector titers, gp91phox expression and reconstitution of superoxide production in X-CGD cells

et al. 2008

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Section: Discussionmentioning

confidence: 99%

Transgene optimization significantly improves SIN vector titers, gp91phox expression and reconstitution of superoxide production in X-CGD cells

et al. 2008

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“…There have been no reported cases of EIAV infections in humans, suggesting that it is an intrinsically safe virus and of interest for use in a clinical setting. Therefore, EIAV-based lentiviral vectors for human gene therapy were recently developed (1,67,68).…”

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confidence: 99%

Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases

Zielonka

Bravo²,

Marino

et al. 2009

J Virol

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The mammalian APOBEC3 (A3) proteins comprise a multigene family of cytidine deaminases that act as potent inhibitors of retroviruses and retrotransposons. The A3 locus on the chromosome 28 of the horse genome contains multiple A3 genes: two copies of A3Z1, five copies of A3Z2, and a single copy of A3Z3, indicating a complex evolution of multiple gene duplications. We have cloned and analyzed for expression the different equine A3 genes and examined as well the subcellular distribution of the corresponding proteins. Additionally, we have tested the functional antiretroviral activity of the equine and of several of the human and nonprimate A3 proteins against the Equine infectious anemia virus (EIAV), the Simian immunodeficiency virus (SIV), and the Adeno-associated virus type 2 (AAV-2). Hematopoietic cells of horses express at least five different A3s: A3Z1b, A3Z2a-Z2b, A3Z2c-Z2d, A3Z2e, and A3Z3, whereas circulating macrophages, the natural target of EIAV, express only part of the A3 repertoire. The five A3Z2 tandem copies arose after three consecutive, recent duplication events in the horse lineage, after the split between Equidae and Carnivora. The duplicated genes show different antiviral activities against different viruses: equine A3Z3 and A3Z2c-Z2d are potent inhibitors of EIAV while equine A3Z1b, A3Z2a-Z2b, A3Z2e showed only weak anti-EIAV activity. Equine A3Z1b and A3Z3 restricted AAV and all equine A3s, except A3Z1b, inhibited SIV. We hypothesize that the horse A3 genes are undergoing a process of subfunctionalization in their respective viral specificities, which might provide the evolutionary advantage for keeping five copies of the original gene.The Equine infectious anemia virus (EIAV) (family Retroviridae, genus Lentivirus) infects equids almost worldwide, causing a persistent infection characterized by recurring viremia, fever, thrombocytopenia, and wasting symptoms (40). EIAV infections are used as a model for natural immunologic control of lentivirus replication and virus persistence and as a test system to improve vaccines against lentiviruses (10,40,41,82). In vivo EIAV replicates predominantly in macrophages (77). Interaction with the equine lentiviral receptor 1 (ELR1) has been demonstrated to be responsible for EIAV internalization (96). There have been no reported cases of EIAV infections in humans, suggesting that it is an intrinsically safe virus and of interest for use in a clinical setting. Therefore, EIAV-based lentiviral vectors for human gene therapy were recently developed (1, 67, 68).In the last few years, two cellular proteins that inhibit many different retroviruses have been characterized: tripartite motif protein 5 alpha (TRIM5␣) and apolipoprotein B mRNAediting enzyme-catalytic polypeptide 3 (APOBEC3 [A3]) (for a review, see reference 92). With respect to TRIM5␣ proteins, both human and nonhuman primate TRIM5␣ orthologues can restrict infection by EIAV (26,72). The activity of equine TRIM5␣ on EIAV infection, however, has not been described so far. With respect to A3 proteins...

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“…[1][2][3][4][5] EIAV based LVs are being developed for a number of different gene therapy applications for a variety of diseases. [6][7][8][9][10][11][12][13] Recent focus has been on the development of ProSavin, which is an EIAV-based LV for the treatment of Parkinson's disease encoding three enzymes required for the dopamine synthesis. 6 Currently, ProSavin is in phase I/II clinical trials that require relatively small amounts of vector material.…”

Section: Introductionmentioning

confidence: 99%

Development of inducible EIAV-based lentiviral vector packaging and producer cell lines

et al. 2009

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Analysis of factor VIII mediated suppression of lentiviral vector titres

Cited by 32 publications

References 33 publications

Transgene optimization significantly improves SIN vector titers, gp91phox expression and reconstitution of superoxide production in X-CGD cells

Transgene optimization significantly improves SIN vector titers, gp91phox expression and reconstitution of superoxide production in X-CGD cells

Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases

Development of inducible EIAV-based lentiviral vector packaging and producer cell lines

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