Transcriptional regulation of human immunodeficiency viruses in T lymphocytes.

Abstract

The human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS), belong to two distinct subgroups of primate immunodeficiency viruses. The HIV-1 and HIV-2 long terminal repeats (LTRs) contain multiple cis-acting DNA elements that bind cellular transcription factors and mediate the transcriptional response to T cell stimulation. An element in the HIV-2 LTR that mediates part of the transcriptional response to T cell antigen receptor-CD3 (TCR-CD3) complex stimulation, the CD3R site, is bound by a constitutive nuclear factors. Partial purification of a factor which binds to the CD3R element of HIV-2 yielded predominantly a 42 kilodalton protein. To understand more about the differences between the HIV-1 and HIV-2, the activation of HIV transcription during T cell stimulation by antigen or tumor necrosis factor-$\alpha$ (TNF$\alpha$) was investigated. HIV LTR-directed transcription can be efficiently studied in the antigen-specific T cell hybridoma, 2B4.11. Antigen-activated HIV transcription partially depends on the tandem pair of $\kappa$B sites in the HIV-1 LTR and the single functional $\kappa$B site in the HIV-2 LTR. In addition to the $\kappa$B site in the HIV-2 LTR, three other DNA elements help mediate this transcriptional induction. These elements are two purine box sequences, the PuB1 (CD3R) site and PuB2 site, along with an interposed pets element. HIV-2 LTR transcription responds more strongly than HIV-1 LTR transcription to TCR-CD3 signal transduction in Jurkat T cells and 2B4.11 cells. Contrary to TCR-CD3 activation, TNF$\alpha$ treatment of T cell lines increases HIV-1 LTR transcription more than HIV-2 transcription. This suggests that TNF$\alpha$ acts predominantly through the transcription factor NF-$\kappa$B, while TCR-CD3 signalling modulates a larger number of transcription factors, including those which bind the other enhancer elements in the HIV-2 LTR. Overexpression of cloned NF-$\kappa$B subunits also activates HIV-1 LTR transcription more than HIV-2 LTR transcription. These results suggest that the HIV-2 LTR transcription responds to signals which activate multiple cellular factors in T cells, while HIV-1 LTR transcriptional induction depends on signals which preferentially activate NF-$\kappa$B.