Novel structurally related compounds reactivate latent HIV-1 in a bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation

Abstract

Background: The latent reservoir of HIV-1 in resting memory CD4+ T cells is a major barrier to curing HIV-1 infection. Eradication strategies involve reactivation of this latent reservoir; however, agents that reactivate latent HIV-1 through non-specific T cell activation are toxic. Methods: Using latently infected Bcl-2-transduced primary CD4+ T cells, we screened the MicroSource Spectrum library for compounds that reactivate latent HIV-1 without global T cell activation. Based on the structures of the initial hits, we assembled ~50 derivatives from commercial sources and mostly by synthesis. The dose-response relationships of these derivatives were established in a primary cell model. Activities were confirmed with another model of latency (J-Lat). Cellular toxicity and cytokine secretion were tested using freshly isolated human CD4+ T cells. Results: We identified two classes of quinolines that reactivate latent HIV-1. Class I compounds are the Mannich adducts of 5-chloroquinolin-8-ol. Class II compounds are quinolin-8-yl carbamates. Most EC. 50 values were in the 0.5-10 μM range. HIV-1 reactivation ranged from 25% to 70% for anti-CD3+ anti-CD28 co-stimulation. All quinolin-8-ol derivatives that reactivate latent HIV-1 follow Lipinski's Rule of Five, and most follow the stricter rule of three for leads. After 48 h of treatment, none of the analogues induced detectable cytokine secretion in primary resting CD4+ T cells. Conclusions: We discovered a group of quinolin-8-ol derivatives that can induce latent HIV-1 in a primary cell model without causing global T cell activation. This work expands the number of latency-reversing agents and provides new possible scaffolds for further drug development research. © The Author 2011.