A truncated HIV Tat demonstrates potent and specific latency reversal activity

Abstract

A major barrier to HIV-1 cure is caused by the pool of latently infected CD4 T-cells that persist under combination antiretroviral therapy (cART). This latent reservoir is capable of producing replication-competent infectious virus once prolonged suppressive cART is withdrawn. Inducing the reactivation of HIV-1 gene expression in T-cells harboring a latent provirus in people living with HIV-1 under cART will likely result in depletion of this latent reservoir due to cytopathic effects or immune clearance. Studies have investigated molecules that reactivate HIV-1 gene expression but to date no latency reversal agent has been identified to eliminate latently infected cells harboring replication-competent HIV in cART treated individuals. Stochastic fluctuations in HIV-1tatgene expression have been described and hypothesized to allow the progression into proviral latency. We hypothesized that exposing latently infected CD4+ T-cells to Tat would result in effective latency reversal. Our results indicate the capacity of a truncated Tat protein and mRNA to reactivate HIV-1 in latently infected T-cellsex vivoto a similar degree as the protein kinase C agonist: Phorbol 12-Myristate 13-Acetate, without T-cell activation nor any significant transcriptome perturbation.

CXCR4 Targeting Nanoplatform for Transcriptional Activation of Latent HIV-1 Infected T Cells

“…24,25 Bryostatin-1, prostratin, and phorbol 12-myristate 13-acetate (PMA) are some of the PKC analogues which have been studied in HIV reservoir activation. 26,27 However, like HDACi, studies revealed that single formulation of a PKC analogue is not sufficient to achieve the required therapeutic outcome, though combination of HDACi and a PKC analogue showed enhancement in therapeutic outcome. 28 The therapeutic application of HDACi and PMA analogues is hindered by low bioavailability and offtarget side effects, which present a significant challenge.…”

“…Vorinostat (SAHA), Romidepsin (Istodax), Panobinostat (Farydak), Givinostat (ITF2357), and Belinostat (Beleodaq) are some of the most popular HDACi that are explored in HIV reservoir activation. , However, use of HDACi alone showed poor therapeutic outcome, and use of multiple drug combinations have been suggested to enhance therapeutic efficacy. , Like HDACi, protein kinase C (PKC) analogues are another class of therapeutic agents explored to reverse latency. , PKC analogues will increase phosphorylation and degradation of NF-κB inhibitor IκB-α, resulting in accumulation of p65/p50 . This accumulated p65/p50 will bind with HIV LTRs and enhance transcription. , Bryostatin-1, prostratin, and phorbol 12-myristate 13-acetate (PMA) are some of the PKC analogues which have been studied in HIV reservoir activation. , However, like HDACi, studies revealed that single formulation of a PKC analogue is not sufficient to achieve the required therapeutic outcome, though combination of HDACi and a PKC analogue showed enhancement in therapeutic outcome . The therapeutic application of HDACi and PMA analogues is hindered by low bioavailability and off-target side effects, which present a significant challenge.…”