Intracellular expression of cellular eIF-5A mutants inhibits HIV-1 replication in human T cells: a feasibility study.
Previously, we described two mutants of the cellular Rev co-factor, eukaryotic initiation factor 5A (eIF-5A M13 and M14), which suppress human immunodeficiency virus type 1 (HIV-1) SF2 replication in clonal T cell lines. This study introduced the notion that it is possible to develop gene therapies against infectious agents on the basis of mutant host factors required for viral replication. In this report, we provide further evidence to support this new paradigm and describe murine leukemia virus (MLV)-based retroviral vectors expressing three different eIF-5A mutants from the viral long terminal repeat (LTR). HIV-1 replication (SF2, HXB-3) was reduced up to 2 orders of magnitude in transduced, polyclonal T cell populations. All eIF-5A mutants also showed antiviral activity (approximately seven-fold reduction) in a chronic HIV-1 infection model. Expression of eIF-5A mutant M13 delta in peripheral blood lymphocytes (PBLs) showed no difference in proliferation and metabolic activity as determined in a 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT)-assay, suggesting that expression of this type of mutant protein is not associated with cellular toxicity. In summary, these data suggest that gene therapy for HIV-1 infection can be developed on the basis of mutants of the Rev co-factor eIF-5A.
Progenesys program at Systemix, Palo Alto, CA 94304.
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U
Junker
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D
Bevec
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Barske
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Kalfoglou
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Escaich
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Dobrovnik
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Hauber
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Böhnlein
D015152:Blotting, Northern; D015139:Blotting, Southern; D005240:Feasibility Studies; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010448:Peptide Initiation Factors / Q000235:genetics*; D016601:RNA-Binding Proteins; D012190:Retroviridae; D014779:Virus Replication / Q000187:drug effects*; D000097574:Eukaryotic Translation Initiation Factor 5A
D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A