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Prof Damian Purcell from the Peter Doherty Institute in Melbourne presented some exciting research in this morning’s Late Breaker session looking at novel HIV latency reversing agents in the pursuit of an HIV cure. We have heard previously about the ‘shock and kill’ approach to HIV cure, where latently infected cells are stimulated to produce new virus production with the aim of inducing cell death without activation. There have been several clinical trials using a variety of latency reversing agents (LRAs) including the histone deactylase inhibitors (HDACi) vorinostat and romidepsin. However, although these drugs were able to stimulate HIV transcription, they did not reduce the pool of latently infected cells. In addition, these drugs are non-specific and have an effect on all cells, even those uninfected.
Damian spoke of a model developed by his laboratory to target latently infected cells with full-length provirus containing the viral protein Tat. Using a cell line model with various reporters, his team was able to screen a library of drug-like compounds to assess latency reversal that is specific to Tat-containing (i.e. HIV-infected) cells. Multiple ‘hits’ were obtained from the screen, and narrowed down to 1 potential compound that was tested using CD4+ T-cells obtained from virally suppressed patients. This compound was classed as an amidothiazole and was shown to increase unspliced HIV-RNA in patient-derived CD4+ T-cells ex vivo. It is thought to exert its latency reversing activity through interaction with the methyltranferase complex. This compound was also found to synergise with another class of LRA known as bromodomain inhibitors.
Identification of this this novel compound is exciting as it provides another step towards finding the ideal LRA that could be targeted towards latently infected cells while minimizing effects on uninfected cells. However, there is still further research required to see its efficacy in reversing latency – an important step would be to identify whether this compound actually stimulates production of functional virus (rather than just unspliced RNA). Further research into its safety profile would also be necessary.