Background: Despite the immense success of HIV anti-retroviral therapy (ART) to reduce replication to very low levels, it fails to eradicate the virus. HIV persists in latently and productively infected CD4+T cells in infected subjects undergoing ART. Thus, we need novel classes of therapeutic agents that target different stages of the virus life cycle to limit latent HIV disease.
Methods: The HIV Tat protein, binds the 5′ terminal region of HIV mRNAs, and potently activates transcription. Tat is a very attractive drug target because 1) is expressed early during virus replication, 2) has no cellular homologs and 3) direct inhibition of Tat blocks the feedback loop that drives viral exponential production. Compounds that block Tat have been highly sought after; however, none is yet in the clinic. We have shown that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid, selectively inhibits Tat-activity with no cellular associated toxicity. dCA binds specifically to the RNA-binding domain of Tat reducing HIV-1 RNA production in infected cultured and primary cells with an EC50 as low as 0.7 pM (1).
Results: Here we show that dCA abrogates antigenic virus reactivation from latently infected CD4+T primary cells explanted from patients receiving suppressive ART. dCA can reduce cell-associated HIV-1 RNA production from primary cells and cell-line models of latency by reducing RNA Polymerase II recruitment to the HIV promoter and as a result, cells become refractory to viral reactivation by several anti-latency agents (cytokines, HDAC inhibitors, PKC activators). Furthermore, arrest of dCA treatment does not result in viral rebound, as the promoter is transcriptionally shut-off. As expected, latent cell lines containing virus mutated in either TAR or Tat are insensitive to dCA.
Conclusions: dCA treatment combined with ART may inhibit and persistently abrogate residual HIV production from cellular reservoirs in blood and tissues from virally suppressed subjects, block viral reactivation, reduce reservoir replenishment, and may ultimately decrease the size of the latent reservoir. Our experiments provide a proof-of-concept for the use of transcriptional suppressors in therapeutic approaches for a functional HIV cure.
1. Mousseau et al., Cell Host Microbe (2012). 12(1): 97-108