Nuclear Factor Kappa B: A Potential Target for Anti-HIV Chemotherapy

V.      Pande; M.   J.   Ramos

Abstract

The Nuclear Factor Kappa B (NF-κB) is a lymphoid-specific transcription factor, which is sequestered in the cytoplasm by the protein IκB. NF-κB plays a major role in the regulation of HIV-1 gene expression. Upon activation, NF-κB is released from IκB, moves to the nucleus, and binds to its sites on the HIV long terminal repeat to start transcription of integrated HIV genome. The present review focuses on the NF-κB as a potential target for the development of chemotherapy against HIV-1. Beginning from the viral-binding to reverse transcription, integration, and gene expression, to the virion maturation, the life cycle of HIV presents drug-targets at all the stages. As a result, many drugs have been developed and have entered clinical trials. Some of the most important of these are reverse transcriptase and protease inhibitors, which have been used mostly in clinical studies in the form of combined therapy. But, this combined therapy has presented the problem of resistance, due to mutations in the virus. However, targeting NF-κB for the suppression of virus does not present the problem of resistance, as NF-κB is a normal part of the human T-4 cell, and is not subject to mutations, as is the virus. An overview of the NF-κB system and its role in HIV-1 is presented, followed by a critical review of its current and potential synthetic inhibitors. The drugs studied against NF-κB fall mainly into three categories: (1) Antioxidants, against oxidative stress conditions, which aid in NF-κB activation, (2) IκB phosphorylation and degradation inhibitors (the phosphorylation and degradation of IκB is necessary to make NF-κB free and move to the nucleus), and (3) NF-κB-DNA binding inhibitors. The antioxidants include N-Acetyl-L-cysteine (NAC), α-Lipoic acid, glutathione monoester, pyrrolidine dithiocarbamate, and tepoxalin, of which NAC is the best studied. The IκB phosphorylation and degradation inhibitors, which have been studied in the context of HIV-1 include the salicylates (sodium salicylate, and acetylsalicylic acid (aspirin)). Finally, the NF-κB-DNA binding inhibitors, which have received attention only recently, are reviewed. These include the most potential, aurine tricarboxylic acid (ATA), a chelating agent, which has been found to inhibit NF-κB-DNA binding at a low concentration of 30 μM. The probable mechanism of action of these drugs is discussed alongwith relevant suggestions and conclusions.

Keywords: nuclear factor kappa b, hiv-1, kinases, antioxidants, phosphorylation, salicylates

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