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Pharmacological enhancement of IL-15 signaling to improve 'shock-and-kill' strategies against latent HIV

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BACKGROUND: Despite effective anti-retroviral therapy (ART), the largest barrier to HIV cure remains the formation of a latent reservoir early after initial infection that cannot be cleared by subsequent ART treatment. Finding novel therapeutic strategies that can Shock latent HIV, enhance Translation of viral transcripts, enhance immune Effector functions, and Sensitize reactivated cells to apoptosis could enhance Killing and elimination of latent HIV reservoirs. As such, development of STESK strategies have the potential to improve the efficacy of current 'shock and kill' strategies. Among the clinically relevant latency reversing agents (LRA) under investigation, IL-15 or the IL-15 superagonist N-803 have been shown to reactivate latent HIV ex vivo and in vivo. However, the clinical benefit of IL-15 can be hindered by the transient nature of cytokine signaling. We previously identified a small molecule, HODHBt, that enhances the biological activity of IL-15 by increasing STAT5 phosphorylation and transcriptional activity leading to enhanced IL-15- mediated viral reactivation ex vivo in cells isolated from ART-suppressed participants.
METHODS: We used the Connectivity Map to identify compounds with similar transcriptional profiles to HODHBt and identified five clinically relevant FDA-approved candidates. We evaluated their ability to promote viral reactivation from latency.
RESULTS: From the 5 tested compounds, only one, a retinoid derivative, shared a similar transcriptional profile to HODHBt in CD4T cells. Next, we tested the ability of the retinoid to reactivate latent HIV in a primary cell model of latency. The retinoid (10mM) increased viral reactivation mediated by IL-15 to a similar extent as HODHBt (100mM) but unlike HODHBt, specifically promoted cell death of latently infected cells compared to controls when combined with IL-15. In contrast to HODHBt, the retinoid did not increase IL-15-induced STAT5 phosphorylation. This indicates that the retinoid is able to reactivate latent HIV through a mechanism mediated by IL-15 but not directly dependent on STAT5 phosphorylation. There are a number of additional retinoid structural analogues, which we are now investigating for their potential LRA activity.
CONCLUSIONS: In conclusion, retinol derivatives have the potential to enhance IL-15 LRA activity and can be ideal candidates for the development of STESK strategies against latent HIV.