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

This work aims at identifying the thymocyte subpopulation able to support h uman immunodeficiency virus (HIV) replication under the biological stimuli of the thymic microenvironment. In this report we demonstrate that interact ion with thymic epithelial cells (TEC) induces a high-level replication of the T-tropic primary isolate HIV-1(B-LAIp) exclusively in the mature CD4(+) CD8(-) CD3(+) thymocytes. Tumor necrosis factor (TNF) and interleukin-7 (I L-7), secreted during this interaction, are critical cytokines for HIV long terminal repeat transactivation through NF-kappa B-dependent activation. T NF is the major inducer of. NF-kappa B and particularly of the p50-p65 comp lex, whereas IL-7 acts as a cofactor by sustaining the expression of the p7 5 TNF receptor. The requirement for TNF is further confirmed by the observa tion that the inability of the intermediate CD4(+) CD8(-)CD3(-) thymocytes to replicate the virus is associated with a defect in TNF production during their interaction with TEC and correlates with the absence of nuclear NF-k appa B activity in these freshly isolated thymocytes. Addition of exogenous TNF to the intermediate thymocyte cultures induces NF-kappa B activity and is sufficient to promote HIV replication in the cocultures with TEC. The o ther major subpopulation expressing the CD4 receptor, namely, the double-po sitive (DP) CD4(+) CD8(+) CD3(+/-) thymocytes, despite the entry of the vir us, do not produce a significant level of virus, presumably because they ar e unresponsive to TNF and IL-7. Together, these data suggest that in vivo, despite an efficient entry of the virus in all the CD4(+) subpopulations, a high viral load may be generated exclusively within the mature CD4(+) CD8( -) CD3(+) subset of thymocytes. However, under conditions of inflammatory r esponse after infection, TNF might also be present in the intermediate thym ocyte compartment, leading to efficient HIV replication in these cells.