Identification of isoform-selective hydroxamic acid derivatives that potently reactivate HIV from latency

Author List
Elleard FW Heffern
Rashmi Ramani
Garland Marshall
George B Kyei

Abstract

Objectives: Current antiretroviral therapy can suppress HI V replication, increase CD4 count and result in increased lifespan. However, it cannot eradicate the virus due to the presence of latent provirus in cellular reservoirs, such as resting CD4+ T cells. Using combination latency-reversing agents to shock the virus out of latency for elimination through immune clearance or viral cytopathic effect is one of the most promising strategies for HI V eradication. Specifically, recent evidence shows that isoform-selective histone deacetylase inhibitors may be more effective than their non-selective counterparts. Therefore, identification and characterisation of new isoform-selective compounds are of prime importance. Here, we sought to determine the ability of two new isoform-targeted hydroxamic acid derivatives to reactivate HI V from latency. Methods: We used cell lines and infected primary resting CD4+ T cells. These were treated with these compounds with HI V reactivation measured using fluorescence-activated cell sorting, Western blots and luciferase luminescence. Isoform selectivity and acetylation of the HI V promoter were measured by Western blotting and chromatic immunoprecipitation. Results and conclusions: The two new hydroxamic acid derivatives, MC2625 and MC1742, potently reactivate HI V from latency. These compounds are isoform-selective histone deacetylate inhibitors that increase the levels of histone acetylation at the HI V promoter. In addition, they synergise effectively with the protein kinase C modulators bryostatin-1 and IN DY, an inhibitor of the dual-specificity tyrosine phosphorylation regulated kinase 1A. We conclude that the combinations of new hydroxamic acid derivatives and bryostatin-1 or IN DY could be a new tool for HI V reactivation in the cure efforts.

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