[69] DEACETYLASE INHIBITORS AS CANDIDATE DRUGS TO PURGE LATENTLY HIV-1-INFECTED RESERVOIRS IN HAART PATIENTS? MECHANISTIC INSIGHTS INTO REGULATION OF VIRAL REPLICATION BY DEACETYLASE INHIBITORS

2nd International AIDS Society Conference on HIV Pathogenesis and Treatment

Paris, France - July 13 - 16, 2003

[TITLE:] DEACETYLASE INHIBITORS AS CANDIDATE DRUGS TO PURGE LATENTLY HIV-1-INFECTED RESERVOIRS IN HAART PATIENTS? MECHANISTIC INSIGHTS INTO REGULATION OF VIRAL REPLICATION BY DEACETYLASE INHIBITORS

[AUTHOR(S):] Y Collette¹, V Quivy², E Adam², B Vire¹, D Demonte², V Bours³, J Piette³, D Olive¹, A Burny² and C Van Lint²
^{1 U119 INSERM, Marseille, France;} 2 Laboratoire de Virologie Moleculaire, Chimie Biologique, Universite Libre de Bruxelles, Gosselies, Belgique; and ^{3 Universite de Liege, Centre for Molecular and Cellular Therapy, Liege, Belgium}

IAS Conf HIV Pathog Treat 2003 Jul 13-16;2nd: Abstract No. 69
Antiviral Therapy 2003; 8(Suppl. 1):S202

[ABSTRACT:] HIV-1 transcription is regulated by protein acetylation, a reversible post-translational modification that regulates various biological functions such as DNA binding, protein-protein interactions, protein stability and cellular localization. Protein acetylation is controlled by the opposite effect of acetylases and deacetylases. Remarkably, deacetylases inhibitors (DACi), which act selectively on transcription of a restricted subset of genes, induce viral transcription in HIV-1 latently infected cell lines, at least partly through localized chromatin remodelling. Here, we show that DACi acted synergistically with either ectopically-expressed or TNFα-induced NF-κB to activate not only the HIV-1 promoter in a κB binding site-dependent manner, but also several NF-κB-driven promoters, including IL-8, ICAM-1 and IL- 6. We identify a new regulatory link between DACi and NF-κB-dependent gene expression, which is not at the level of NF- κB/DAC interactions but at the level of IκBα cytoplasmic content. The physiological relevance of this TNFα-DACi synergism was shown on HIV-1 replication in both acutely and latently HIV-infected cells. Not only do TNF family members activate NF-kB-dependent transcription, but their own expression (including that of TNFα) is also regulated by NF-κB. Interestingly, we show that transcription of some TNF members with pro-apoptotic activities (notably TNFα) were inhibited by DACi, whereas others members with cellular activation properties were unaffected or even up-regulated by DACi. We thus propose DACi as candidate drugs to be further evaluated as a new therapeutic strategy with the aim to decrease or eliminate the pool of latently HIV-1-infected reservoirs by forcing viral expression in HAART-treated individuals (in presence of continuous HAART).

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