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 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.


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.


RESULTS
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.


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 cause of viral latency and transcriptional activation accounts for massive viral production in activated T lymphocytes.
Mouzaki
A
A
Department of Medicine, University of Patras, Greece.
Doucet
A
A
Mavroidis
E
E
Muster
L
L
Rungger
D
D
D000328:Adult; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D005312:Fetal Blood; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007376:Interleukin-2 / Q000235:genetics; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D013601:T-Lymphocytes / Q000821:virology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors