Inhibition of HIV-1 tat-induced transactivation and apoptosis by the divalent metal chelators, fusaric acid and picolinic acid-implications for HIV-1 dementia.
The HIV-1 transactivator protein tat is pivotal to the pathogenesis of AIDS, exerting its effects on both viral and cellular gene expression. The basic structure of tat protein allows it to be secreted by HIV-1 infected cells and penetrate uninfected cells where it elicits its multifunctional biochemical effects. The main function of tat protein is viral transactivation which leads to the upregulation of transcription through complex interactions with RNA and host cell factors. Since HIV-1 has been widely implicated as a causative agent of HIV-1 dementia, the aim of our study was to investigate the ability of two novel metal chelators, fusaric acid (FA) and picolinic acid (PA) to firstly inhibit HIV-1 tat induced transcription and secondly, to minimize its cytotoxic effects as mediated via apoptosis. Biologically active tat protein is not freely available commercially. We therefore had to produce, isolate and purify our own protein. A cell culture system and flow cytometric techniques were used in our study. Exposure of CEM-GFP cells to exogenous recombinant tat protein induced transcription and apoptosis, and both processes were inhibited by FA and PA at concentrations that alone did not induce any cytotoxicity. Our data suggest that FA and PA may have therapeutic potential in the management of HIV-1 dementia.
Discipline of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa. ramautar@ukzn.ac.za
Atish
A
Ramautar
Musa
M
Mabandla
Jonathan
J
Blackburn
Willie M U
WM
Daniels
D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology*; D005434:Flow Cytometry; D005669:Fusaric Acid / Q000494:pharmacology; D015497:HIV-1; D006801:Humans; D008670:Metals / Q000378:metabolism*; D010848:Picolinic Acids / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002614:Chelating Agents; D008670:Metals; D010848:Picolinic Acids; D054322:tat Gene Products, Human Immunodeficiency Virus; D005669:Fusaric Acid; C030614:picolinic acid