Late Breaker - Novel agents to reverse HIV latency

Damian Purcell from the Doherty presented the story of discovery of a new latency reversing agent, currently in the process of in vitro experimentation using ex-vivo patient cells.

Background : agents trialled to reverse latency - PKC activators, HDAC inhibitors, Bromodomain inhibitors 

So why is a novel agent needed? Lack of specificity and potency have been a significant problem in agents to date, many of which have come from the cancer field.

For example - Work from the Purcell/Lewin labs at the Doherty has shown that HDACi inhibit expression of key HIV splicing proteins; HDAC inhibitors in vitro are unable to elucidate expression of spliced RNA, Bromodomain inhibitors on the other hand are able to lead to spliced RNA; this is rescued by the addition of tat protein.

Considering Tat ; 'the master regulator of HIV-1' - (its own latency reversing agent?) by recruiting kinases which help in regulating HIV transcription and RNA processing; Tat itself is also acetylated (thereby activated), which could also be inhibited by HDACi.

So what about new drugs? What do we want?

Tat can be produced without production of virus - and is a neuropathic protein...

Tat induces LTR specific response specifically. This is important, considering that what we are interested in is finding HIV-specific activation pathway 

A drug library was screened to look for agents activating tat in particular - (WEHI) - resulting in an amidothiazole being identified. Medicinal chemistry was used to increase the potency of the compound, which was then trailed on patient derived cells (obtained via leukapheresis); this demonstrated reactivation.

These agents appear to synergise strongly with bromodomain inhibitors (currently trailed agents) and appear to be specific for HIV reactivation, and selective for HIV containing cells that contain tat.