bix-01294 and prostratin

After entry into the target cell and reverse transcription, HIV-1 genes are integrated into the host genome. It is now well established that the viral promoter activity is directly governed by its chromatin environment. Nuc-1, a nucleosome located immediately downstream of the HIV-1 transcriptional initiation site directly impedes long-terminal repeat (LTR) activity. Epigenetic modifications and disruption of Nuc-1 are a prerequisite to the activation of LTR-driven transcription and viral expression. The compaction of chromatin and its permissiveness for transcription are directly dependent on the post-translational modifications of histones such as acetylation, methylation, phosphorylation and ubiquitination. Understanding the molecular mechanisms underlying HIV-1 transcriptional silencing and activation is thus a major challenge in the fight against AIDS and will certainly lead to new therapeutic tools.

Topics: Azepines; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Viral; Histone Acetyltransferases; Histone Deacetylase Inhibitors; Histone Deacetylases; Histone-Lysine N-Methyltransferase; Histones; HIV Infections; HIV-1; Humans; Nucleosomes; Phorbol Esters; Piperazines; Quinazolines; tat Gene Products, Human Immunodeficiency Virus; Transcription, Genetic; Virus Integration

A shock-and-kill approach involving the simultaneous treatment of HIV-1-infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1-infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3. Results show that prostratin and bryostatin-1 can significantly damage the integrity of an endothelial monolayer. Moreover, prostratin and bryostatin-1 induce secretion of some proinflammatory cytokines and an increase of ICAM-1 expression. Additional studies demonstrated that prostratin and bryostatin-1 also affect adhesion and transmigration of CD4

Topics: Acetamides; Azacitidine; Azepines; Blood-Brain Barrier; Bryostatins; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Cells, Cultured; Chemokine CCL2; Cytokines; Decitabine; HIV-1; Humans; Inflammation; Intercellular Adhesion Molecule-1; Leukocytes; Phorbol Esters; Quinazolines; Receptors, Cell Surface; Virus Latency