Block of Tat-mediated transactivation of tumor necrosis factor beta gene expression by polymeric-TAR decoys.
The tat gene product (Tat) of human immunodeficiency virus type 1 (HIV-1) is an early regulatory protein which transactivates HIV-1 gene expression by interacting with the trans-activation response element (TAR) present in the HIV-1 long terminal repeat (LTR). In HIV-1-infected cells Tat can also activate the expression of tumor necrosis factor (TNF). Recent results indicate that essential for this effect is the interaction of Tat with a TAR-like structure present in the TNF beta messenger RNA leader region that closely resembles the TAR of the HIV-LTR. Here we show that because of this similarity of mechanisms, the expression of an RNA species encoding polymeric-TAR sequences and known to inhibit Tat-mediated HIV-1 gene expression also blocks TNF gene expression in response to Tat, but not TNF promoter activation induced by human T cell leukemia/lymphotropic virus type I Tax protein. Since TNF is increased in HIV-1-infected individuals and can activate HIV-1 gene expression or rescue Tat-defective HIV-1 proviruses, activation of TNF by Tat may be part of a complex pathway in which HIV-1 uses its own expression to increase infectivity and to induce disease. This study shows a dual role for the polymeric-TAR construct in inhibiting HIV-1 replication and strengthens the potential use of this protective gene in gene therapy for AIDS.
Brother
M B
MB
Howard Hughes Medical Institute, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chang
H K
HK
Lisziewicz
J
J
Su
D
D
Murty
L C
LC
Ensoli
B
B
D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000235:genetics* / Q000378:metabolism; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016356:Gene Products, tax; D008233:Lymphotoxin-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus