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A Repression-derepression Mechanism Regulating the Transcription of Human Immunodeficiency Virus Type 1 In Primary T Cells

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Abstract

Background

Despite some controversy regarding the preferential infection and replication of human immunodeficiency virus type 1 (HIV-1), it appears that primary T lymphocytes, in their quiescent state, are nonpermissive for viral expression and propagation. Massive activation of viral gene expression occurs only when the host lymphocyte is activated. These observations prompted us to investigate the transcriptional regulation of HIV-1 in resting or activated T cells that were isolated from cord blood or adult peripheral blood.

Materials and Methods

To this end, we employed cellular purification and phenotyping techniques, in vitro protein-DNA binding studies, functional transactivation assays using proteins isolated from cord blood or adult peripheral blood T lymphocytes, and transfection experiments in primary T cells.

Results

We showed that transcription from the HIV-1 long terminal repeat is repressed in resting naive T lymphocytes; whereas, mitogenically stimulated CD4+ cells form an activator that derepresses transcription. Negative and positive regulation act through a repressor-activator target sequence (RATS), which shares homology with the interleukin-2 (IL-2) purine-rich response element, through the adjacent binding site of the nuclear factor of activated T cells (NFAT), and weakly, through the κB region.

Conclusions

This regulation exerted by cellular transcription factors can account for several important features of HIV-1 expression in primary CD4+ cells. Tight repression in resting naive T helper cells may be a main cause of viral latency and transcriptional activation accounts for massive viral production in activated T lymphocytes.

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Acknowledgments

We thank Dr. G. Pavlakis, Maryland, and Dr. R. Zufferey, Geneva, for critical comments on the manuscript, Dr. S. Thymianou, Patras, Mr. George Balanos, Patras, and Mr. M. Bacchetta, Geneva, for help with some of the experiments and Mr. S. Chraiti, Geneva, for the artwork. This work was supported by grants PENED/1274 from the Greek Ministry of Research and Technology and KARATHEODORIS/1952 from the University of Patras to A.M., by grant 31.46946.96 of the Swiss National Foundation, by the Sandoz Foundation, Basel, the Georges and Antoine Claraz Foundation, Zurich and the Societé Académique de Genève to D.R.

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Authors and Affiliations

  1. Experimental Hematology and Transfusion Medicine, Department of Medicine, University of Patras, Patras, Greece

    Athanasia Mouzaki & Emmanuel Mavroidis

  2. Division of Hematology, Department of Medicine, Geneva University Hospital, Geneva, Switzerland

    Arlette Doucet

  3. Station de Zoologie Expérimentale, University of Geneva, 154, route de Malagnou, CH-1224, Chêne-Bougeries, Switzerland

    Lisbeth Muster & Duri Rungger

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  1. Athanasia Mouzaki
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  2. Arlette Doucet
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  5. Duri Rungger
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Correspondence to Duri Rungger.

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Mouzaki, A., Doucet, A., Mavroidis, E. et al. A Repression-derepression Mechanism Regulating the Transcription of Human Immunodeficiency Virus Type 1 In Primary T Cells. Mol Med 6, 377–390 (2000). https://doi.org/10.1007/BF03401782

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