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Suppression of HIV-1 transcription and replication by a Vpr mutant

Gene Therapy volume 6, pages 947–950 (1999)Cite this article

Abstract

Vpr, the 96 amino acid long protein represents one of the auxiliary proteins of human immunodeficiency virus type-1 (HIV-1), which exhibits the ability to increase the rate of replication of the virus in T cells. Structurally, this protein is composed of several regions such as the acidic domain with alpha helix at the amino terminus, leucine-isoleucine-rich domain (LR) near the carboxyl terminus and an arginine-rich domain at the C-terminus. Here, we evaluated the ability of wild-type and a spectrum of Vpr mutants with altered amino acid residues within the three major domains of Vpr to regulate of transcription of the HIV-1 LTR. Our results revealed that alterations of amino acids within the LR domain at position 73 from arginine to serine, renders Vpr defective in stimulating transcription of the viral pro- moter in human T-lymphocytic and astrocytic cells. Mutations within the N- and C-terminal domains had little or no effect on the transcriptional activity of Vpr. Of interest, ectopic expression of this mutant protein exerts a negative effect on the ability of wild-type Vpr, as well as the viral transactivator, Tat, in augmenting viral gene transcription. Production of the mutant Vpr interferes with the replication of the wild-type and ΔVpr virus in the cells. Accordingly, a Vpr mutant virus containing the transition of arginine to serine at position 73 exhibited an inhibitory effect on the replication of wild-type virus. Our results provide a new avenue for the utilization of the variant of the HIV-1 regulatory protein, Vpr, in suppressing replication of the viral genome in infected cells.

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Acknowledgements

The authors wish to thank Dr John Brady, past and present members of the Center for NeuroVirology and NeuroOncology for their insightful discussion and sharing of ideas. We appreciate the technical assistance of Lyudmilla Denisova in CAT assay and Max Richardson for help with p24 assay. We acknowledge Cynthia Schriver for preparation of this manuscript. This work was made possible by grants awarded by NIH to KK and SA.

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Authors and Affiliations

  1. Center for NeuroVirology and NeuroOncology, MCP Hahnemann University, Philadelphia, PA, USA

    B E Sawaya, K Khalili, J Rappaport, W Chen & S Amini

  2. Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA

    D Serio & A Srinivasan

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  1. B E Sawaya
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  2. K Khalili
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  3. J Rappaport
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  4. D Serio
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  5. W Chen
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  6. A Srinivasan
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  7. S Amini
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Sawaya, B., Khalili, K., Rappaport, J. et al. Suppression of HIV-1 transcription and replication by a Vpr mutant. Gene Ther 6, 947–950 (1999). https://doi.org/10.1038/sj.gt.3300907

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