Intracellular Expression of Cellular eIF-5A Mutants Inhibits HIV-1 Replication in Human T Cells: A Feasibility Study

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Abstract
Previously, we described two mutants of the cellular Rev co-factor, eukaryotic initiation factor 5A (eIF-5AM13 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 (~seven-fold reduction) in a chronic HIV-1 infection model. Expression of eIF-5A mutant M13Δ 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. Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by mutant cellular proteins is a new antiviral strategy. In this study, three mutants of the cellular Rev co-factor eIF-5A were evaluated for their potential to inhibit HIV-1 replication. Expression of eIF-5A mutants in human T cell lines suppressed HIV-1 replication in de novo and chronic HIV-1 infection experiments. Furthermore, expression of eIF-5A mutant protein M13Δ in PBLs was not associated with any apparent cytotoxicity. In summary, our study suggests that anti-HIV genetic intervention strategies based on cellular mutants of essential HIV-1 co-factors can be developed.