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(American Journal of Pathology. 1999;155:275-284.)
© 1999 American Society for Investigative Pathology

Regular Articles

Nitric Oxide Inhibits HIV Tat-Induced NF-B Activation

Fei Chen^*, Yongju Lu^*, Vince Castranova^*, Yon Rojanasakul, Kaoru Miyahara, Yutaka Shizuta, Val Vallyathan^*, Xianglin Shi^* and Laurence M. Demers^§

From the Pathology and Physiology Research Branch,^*
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, and the Department of Basic Pharmaceutical Sciences,
West Virginia University, Morgantown, West Virginia, the Department of Medical Chemistry,
Kochi Medical School, Kochi, Japan, and the Department of Pathology,^§
The Pennsylvania State University College of Medicine, Hershey, Pennsylvania

To evaluate the roles of nitric oxide (NO) on human immunodeficiency virus (HIV) Tat-induced transactivation of HIV long terminal repeat (HIV-LTR), we examined the effect of NO in the regulation of nuclear factor (NF)-B, a key transcription factor involved in HIV gene expression and viral replication. In the present study, we demonstrate that HIV Tat activates NF-B and that this activation can be attenuated by endogenous or exogenous NO. Inhibition of endogenous NO production with the NO synthase (NOS) inhibitor L-NMMA causes a significant increase in Tat-induced NF-B activity. In addition, NO attenuates signal-initiated degradation of IB, an intracellular inhibitor of NF-B, and blocks the DNA binding activity of the NF-B p50/p50 homodimer and p50/p65 heterodimer. To determine how NO is induced by HIV Tat, reverse transcription polymerase chain reaction was used to demonstrate the induction of NOS-2 and NOS-3 mRNA by Tat. Although a putative NF-B binding site was identified in the -74 GGAGAGCCCCC -64 region of the NOS-3 gene promoter, gel mobility shift assays and site-directed mutation analyses suggest that the putative NF-B site is not of primary importance. Rather, several Sp-1 sites adjoining the putative NF-B binding site in the promoter region of NOS-3 gene are required for the induction of NOS-3 gene expression by Tat.

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