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Journal of Virology, March 1999, p. 2064-2073, Vol. 73, No. 3
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

High-Level Replication of Human Immunodeficiency Virus in Thymocytes Requires NF-kappa B Activation through Interaction with Thymic Epithelial Cells

Laurent Chêne, Marie-Thérèse Nugeyre, Françoise Barré-Sinoussi, and Nicole Israël*

Unité de Biologie des Rétrovirus, Institut Pasteur, 75724 Paris Cedex 15, France

Received 6 August 1998/Accepted 23 November 1998

We have previously demonstrated that interaction of infected thymocytes with autologous thymic epithelial cells (TEC) is a prerequisite for a high level of human immunodeficiency virus type 1 (HIV-1) replication in thymocytes (M. Rothe, L. Chêne, M. Nugeyre, F. Barré-Sinoussi, and N. Israël, J. Virol. 72:5852-5861, 1998). We report here that this activation of HIV replication takes place at the transcriptional level through activation of the Rel/NF-kappa B transcription factors. We first demonstrate that an HIV-1 provirus (SF-2 strain) very effectively replicates in thymocytes cocultured with TEC whereas this provirus, with kappa B sites deleted, fails to replicate. We provide evidence that several NF-kappa B complexes are constitutively found in the nuclei of thymocytes either freshly isolated from the thymus or maintained in coculture with autologous or heterologous TEC. The prevalent complex is the heterodimer p50-p65. NF-kappa B activity is tightly correlated with the transcriptional activity of a long terminal repeat (LTR) of HIV-1 transfected in thymocytes. The cotransfection of this LTR with a mutated Ikappa Balpha molecule formally demonstrates that LTR transactivation is regulated by members of the Rel/NF-kappa B family in thymocytes. We also showed that tumor necrosis factor (TNF) and to a lesser extent interleukin-1 (IL-1), secreted within the coculture, induce NF-kappa B activity and a correlative LTR transactivation. However IL-7, a crucial factor for thymopoiesis that is secreted mainly by TEC, is a necessary cofactor for NF-kappa B activation elicited by TNF or IL-1. Together, these data indicate that NF-kappa B activation, required for a high level of HIV replication in thymocytes, is regulated in a specific manner in the thymic microenvironment which provides the necessary cytokines: TNF, IL-1, and IL-7.

* Corresponding author. Mailing address: Unité de Biologie des Rétrovirus, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France. Phone: 33 1 45 68 89 44/87 33. Fax: 33 1 45 68 89 57. E-mail: nisrael{at}pasteur.fr.

Journal of Virology, March 1999, p. 2064-2073, Vol. 73, No. 3
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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