Daidzein and its analogs reactivate HIV replication from latently infected CD4 T cells

Abstract

Human immunodeficiency virus (HIV) persists in a latent form in infected individuals under antiretroviral therapy (ART) through integrating proviral DNA into the genome of host immune cells. In these latently infected cells, the transcription of HIV proviral DNA remains silent, which enables the infected cells to escape from the killing by anti-viral CD8+ T cells. One of the recent new therapeutic strategies for HIV eradication aims to reactivate HIV production in the latently infected cells, so that these cells could be detected and eliminated by the immune system. Here we show that small molecules isolated from Spatholobus suberectus Dunn., Daidzein and its analogues, reactivate HIV replication from latency. Daidzein reactivates HIV replication in latently infected CD4 T cell lines J lat and A72 dose dependently, but not monocytes. Moreover, by using cells that contain an integrated HIV LTR linked to the luciferase reporter gene, we found that Daidzein activates HIV replication at the level of transcription. This effect is through Akt signaling pathway, and do not induce T cell activation. Structure-activity relationships (SARs) analysis of Daidzein and its five analogues revealed that three analogues, Daidzin, Glycitein and Glycitin, reactivate HIV replication without obvious cell toxicity observed, and 4′-hydroxyisoflavone is their bio functional core structure. Therefore, Daidzein and its analogues have potential to be modified to improve their potency and developed into significant components for HIV therapy.