Thymocyte-Thymic Epithelial Cell Interaction Leads to High-Level Replication of Human Immunodeficiency Virus Exclusively in Mature CD4+ CD8- CD3+ Thymocytes: a Critical Role for Tumor Necrosis Factor and Interleukin-7

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Journal of Virology, September 1999, p. 7533-7542, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Thymocyte-Thymic Epithelial Cell Interaction Leads to High-Level Replication of Human Immunodeficiency Virus Exclusively in Mature CD4⁺ CD8 CD3⁺ Thymocytes: a Critical Role for Tumor Necrosis Factor and Interleukin-7

L. Chêne,¹ M.-T. Nugeyre,¹ E. Guillemard,¹ N. Moulian,² F. Barré-Sinoussi,¹ and N. Israël¹^,^*

Unité de Biologie des Rétrovirus, Institut Pasteur, 75724 Paris Cedex 15,¹ and Laboratoire de Physiologie Thymique, Hôpital Marie-Lannelongue, CNRS ESA-8078, 92350 Le Plessis-Robinson,² France

Received 8 March 1999/Accepted 1 June 1999

This work aims at identifying the thymocyte subpopulation able to support human immunodeficiency virus (HIV) replication underthe biological stimuli of the thymic microenvironment. In thisreport we demonstrate that interaction with thymic epithelialcells (TEC) induces a high-level replication of the T-tropic primaryisolate HIV-1_B-LAIp exclusively in the mature CD4⁺ CD8 CD3⁺ thymocytes. Tumor necrosis factor (TNF) and interleukin-7 (IL-7),secreted during this interaction, are critical cytokines for HIVlong terminal repeat transactivation through NF- $kappa$ B-dependent activation.TNF is the major inducer of NF- $kappa$ B and particularly of the p50-p65complex, whereas IL-7 acts as a cofactor by sustaining the expressionof the p75 TNF receptor. The requirement for TNF is further confirmedby the observation that the inability of the intermediate CD4⁺ CD8 CD3 thymocytes to replicate the virus is associated with a defectin TNF production during their interaction with TEC and correlateswith the absence of nuclear NF- $kappa$ B activity in these freshly isolatedthymocytes. Addition of exogenous TNF to the intermediate thymocytecultures induces NF- $kappa$ B activity and is sufficient to promote HIVreplication in the cocultures with TEC. The other major subpopulationexpressing the CD4 receptor, namely, the double-positive (DP)CD4⁺ CD8⁺ CD3^± thymocytes, despite the entry of the virus, do not produce asignificant level of virus, presumably because they are unresponsiveto TNF and IL-7. Together, these data suggest that in vivo, despitean efficient entry of the virus in all the CD4⁺ subpopulations, a high viral load may be generated exclusivelywithin the mature CD4⁺ CD8 CD3⁺ subset of thymocytes. However, under conditions of inflammatoryresponse after infection, TNF might also be present in the intermediatethymocyte compartment, leading to efficient HIV replication inthesecells.

^* Corresponding author. Mailing address: Unité de Biologie des Rétrovirus, Institut Pasteur, 25 rue du Dr Roux, 75724 ParisCedex 15, France. Phone: 33 1 45 68 89 44/87 33. Fax: 33 1 4568 89 57. E-mail: nisrael{at}pasteur.fr.

Journal of Virology, September 1999, p. 7533-7542, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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Thymocyte-Thymic Epithelial Cell Interaction Leads to High-Level Replication of Human Immunodeficiency Virus Exclusively in Mature CD4+ CD8 CD3+ Thymocytes: a Critical Role for Tumor Necrosis Factor and Interleukin-7

Thymocyte-Thymic Epithelial Cell Interaction Leads to High-Level Replication of Human Immunodeficiency Virus Exclusively in Mature CD4⁺ CD8 CD3⁺ Thymocytes: a Critical Role for Tumor Necrosis Factor and Interleukin-7