Abstract
Despite some controversy regarding the preferential infection and replication of human immunodeficiency virus type 1 (HIV-1), it appears that primary T lymphocytes, in their quiescent state, are nonpermissive for viral expression and propagation. Massive activation of viral gene expression occurs only when the host lymphocyte is activated. These observations prompted us to investigate the transcriptional regulation of HIV-1 in resting or activated T cells that were isolated from cord blood or adult peripheral blood. To this end, we employed cellular purification and phenotyping techniques, in vitro protein-DNA binding studies, functional transactivation assays using proteins isolated from cord blood or adult peripheral blood T lymphocytes, and transfection experiments in primary T cells. We showed that transcription from the HIV-1 long terminal repeat is repressed in resting naive T lymphocytes; whereas, mitogenically stimulated 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 response element, through the adjacent binding site of the nuclear factor of activated T cells (NFAT), and weakly, through the KB region. 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 cause of viral latency and transcriptional activation accounts for massive viral production in activated T lymphocytes.
Highlights
Cells such as T lymphocytes and monocytederived macrophages, bearing the CD4 recep-378 Molecular Medicine, Volume 6, Number 5, May 2000 appears that in their quiescent state, T lymphocytes are non-permissive for viral expression and propagation
human immunodeficiency virus type 1 (HIV-1) gene transcription is controlled by the interplay of viral and cellular transcription factors (TFs) interacting with sequence elements in the viral long terminal repeat (LTR), most of which interact with the core promoter and the upstream enhancer region [7,8,9]
Among the numerous binding sites for cellular TFs that exist within the HIV-1 LTR, several sites share homology with the IL-2 promoter, in particular with signals that respond to mitogenic stimulation
Summary
Cells such as T lymphocytes and monocytederived macrophages, bearing the CD4 recep-378 Molecular Medicine, Volume 6, Number 5, May 2000 appears that in their quiescent state, T lymphocytes are non-permissive for viral expression and propagation. The activation of HIV-1 transcription in response to mitogenic stimulation is triggered by the signaling pathways of the infected host cell [11]. Despite some controversy regarding the preferential infection and replication of human immunodeficiency virus type 1 (HIV-1), it appears that primary T lymphocytes, in their quiescent state, are nonpermissive for viral expression and propagation. Massive activation of viral gene expression occurs only when the host lymphocyte is activated These observations prompted us to investigate the transcriptional regulation of HIV-1 in resting or activated T cells that were isolated from cord blood or adult peripheral blood. Materials and Methods: To this end, we employed cellular purification and phenotyping techniques, in vitro protein-DNA binding studies, functional transactivation assays using proteins isolated from cord blood or adult peripheral blood T lymphocytes, and transfection experiments in primary T cells
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