PENTOXIFYLLINE INHIBITS HIV-1 LTR-DRIVEN GENE-EXPRESSION BY BLOCKING NF-KAPPA-B ACTION

Citation
Dk. Biswas et al., PENTOXIFYLLINE INHIBITS HIV-1 LTR-DRIVEN GENE-EXPRESSION BY BLOCKING NF-KAPPA-B ACTION, Journal of acquired immune deficiency syndromes, 6(7), 1993, pp. 778-786
Citations number
30
Categorie Soggetti
Immunology,"Infectious Diseases
ISSN journal
08949255
Volume
6
Issue
7
Year of publication
1993
Pages
778 - 786
Database
ISI
SICI code
0894-9255(1993)6:7<778:PIHLGB>2.0.ZU;2-R
Abstract
The drug pentoxifylline (PTX) (1-(5'-oxohexyl) 3,7-dimethylxanthine) d own-regulates human immunodeficiency virus (HIV-1) long terminal repea t (LTR)-directed gene expression in the human monocytic cell line U38. This effect of PTX has been tested in clinical trials. In this invest igation, a similar inhibitory effect of PTX on HIV-1 LTR-driven gene e xpression was observed (a) in a stable transfectant of the human embry o kidney cell line 293-27-2 carrying an expression plasmid construct w ith the HIV-1 LTR fused to the bacterial lac Z gene, and also (b) by t ransient transfection of human embryo kidney cells 293 S with fusion p lasmid constructs with wild-type [pHIV-LTR-chloramphenicol acetyltrans ferase (CAT)] or mutated (pHIV-LTR-mut-CAT) nuclear factor kappaB (NF- kappaB) motifs. In both stable and transient transfection studies, 4-b eta-phorbol-12-beta-myristate-acetate (PMA)-induced or tumor necrosis factor-alpha (TNF-alpha)-induced activation of the HIV-1 LTR was corre lated with a concomitant elevated level of NF-kappaB interaction with its motifs. The inducibility of HIV-1 LTR-driven gene expression by PM A or TNF-alpha in transiently transfected celts was completely elimina ted by point mutations in the NF-KB motifs, suggesting that NF-KB play s a major role in the activation of the HIV-1 LTR by these agents in t his cell system. Treatment of PMA-activated or TNF-alpha-activated cel ls with PFX, at concentrations that did not affect cell growth or othe r major cellular activities, strongly inhibited NF-KB interaction with its motifs and was followed by down-regulation of HIV-1 LTR-driven la c Z gene expression. PTX did not inhibit Rous sarcoma virus (RSV) LTR- driven CA T gene expression, suggesting a differential action of the d rug on the NF-kappaB motif-carrying HIV-1 LTR. It is concluded that th e antiviral action of the drug is, in a major part, mediated via inter ference with one or more of the steps of NF-kappaB activation and inte raction with its motifs in the HIV-1 LTR sequence. These results impli cate a role of the nuclear factor NF-KB in the mode of action of the d rug PTX against HIV-1.