L. Chene et al., High-level replication of human immunodeficiency virus in thymocytes requires NF-kappa B activation through interaction with thymic epithelial cells, J VIROLOGY, 73(3), 1999, pp. 2064-2073
We have previously demonstrated that interaction of infected thymocytes wit
h autologous thymic epithelial cells (TEC) is a prerequisite for a high lev
el of human immunodeficiency virus type 1 (HIV-1) replication in thymocytes
(M. Rothe, L. Chene, M, Nugeyre, F. Barre-Sinoussi, and N. Israel, J. Viro
l. 72:5852-5861, 1998). We report here that this activation of HIV replicat
ion takes place at the transcriptional level through activation of the Rel/
NF-kappa B transcription factors. We first demonstrate that an HIV-1 provir
us (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 fo
und 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 correla
ted with the transcriptional activity of a long terminal repeat (LTR) of HI
V-1 transfected in thymocytes. The cotransfection of this LTR with a mutate
d I kappa B alpha molecule formally demonstrates that LTR transactivation i
s 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 c
orrelative LTR transactivation. However IL-7, a crucial factor for thymopoi
esis 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 thymocy
tes, is regulated in a specific manner in the thymic microenvironment which
provides the necessary cytokines: TNF, IL-1, and IL-7.