Work

Suppression of the HIV-1 reservoir with a potent Tat inhibitor

Year: 2015

Type: article

Abstract: Background: Major goals of HIV cure research are to identify latency-reversing agents (LRAs) and to characterize LRAs with unknown mechanism of action (uMOA).The Connectivity Map (CMAP) can address these goals and represents a collection of microarray gene expression profiles generated by treating cell lines with 680 different drug compounds.It is essential to evaluate compatibility between the CMAP (cell lines, microarray and fixed dose) and HIV cure studies (primary CD4 T cells, RNA-Seq, variable doses).Methods: The following studies were used to assess the utility of the CMAP for HIV cure research: (1) microarray dose response study of primary CD4 T cells from six donors treated with 0, 0.34, 1, 3 and 10 μM of vorinostat; (2) RNA-Seq study of primary CD4+ T cells from four donors treated with 0.34 μM of vorinostat; and (3) differentially expressed genes (DEGs) between latently infected and uninfected cells in the following models: Iglesias-Ussel, Mohammadi, Planelles, Spina, and latently infected cell lines.For all data sets, the top 100 up and down DEGs were queried against the CMAP using gene set enrichment analysis.Results: The CMAP was able to positively correlate the query profile with vorinostat for studies 1 and 2 when the gene expression data had been generated in primary CD4 T cells (instead of cell lines), by RNA-Seq (instead microarray) and at any dose.The CMAP was then used to identify novel LRAs by searching for negative correlations to the DEGs identified from latency model data.Although the top CMAP hit was different for each model, there were two compounds in common to all five latency models in the top 100 negatively correlated compounds.Conclusions: CMAP is robust to RNA measuring technique, cell type and dose differences, and therefore represents a useful utility for characterizing LRAs with uMOA.The CMAP may also be used to identify novel LRAs and the compounds identified in this study will be tested for their ability to activate HIV. PP 7.1In vitro analysis of different PKC agonists: latency reversal, T-cell activation, cytokine production and isoform selectivity

Source: Journal of Virus Eradication

DOI: 10.1016/s2055-6640(20)31406-0