A repression-derepression mechanism regulating the transcription of human immunodeficiency virus type 1 in primary T cells

Background: Despite some controversy regarding the preferential infection a nd replication of human immunodeficiency virus type 1 (HIV-1), it appears t hat primary T lymphocytes, in their quiescent stare, are nonpermissive for viral expression and propagation. Massive activation of viral gene expressi on occurs only when the host lymphocyte is activated. These observations pr ompted us to investigate the transcriptional regulation of HIV-1 in resting or activated T cells that were isolated from cord blood or adult periphera l blood. Materials and Methods: To this end, we employed cellular purification and p henotyping techniques, in vitro protein-DNA binding studies, functional tra nsactivation assays using proteins isolated from cord blood or adult periph eral blood T lymphocytes, and transfection experiments in primary T cells. Results: We showed that transcription from the HIV-1 long terminal repeat i s repressed in resting naive T lymphocytes; whereas, mitogenically stimulat ed CD4(+) cells form an activator that derepresses transcription. Negative and positive regulation act through a repressor-activator target sequence ( RATS), which shares homology with the interleukin-2 (IL-2) purine-rich resp onse element, through the adjacent binding site of the nuclear factor of ac tivated T cells (NFAT), and weakly, through the kappa B region. Conclusions: This regulation exerted by cellular transcription factors can account for several important features of HIV-1 expression in primary CD4() cells. Tight repression in resting naive T helper cells may be a main cau se of viral latency and transcriptional activation accounts for massive vir al production in activated T lymphocytes.