A truncated HIV Tat demonstrates potent and specific latency reversal activity
Ellen Van Gulck, Marion Pardons, Erik Nijs, Nick Verheyen, Koen Dockx, Christel Van den Eynde, Emilie Battivelli, Jerel Vega, Éric Florence, Brigitte Autran, Nancie M. Archin, David M. Margolis, Christine Katlama, Chiraz Hamimi, Ilse Van den Wyngaert, Filmon Eyassu, Linos Vandekerckhove, Daniel Boden
Abstract
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latent reservoir is capable of producing replication-competent infectious viruses once prolonged suppressive cART is withdrawn.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 may 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-1 tat gene 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-cells ex vivo to a similar degree as the protein kinase C agonist: phorbol 12-myristate 13-acetate, without T-cell activation or any significant transcriptome perturbation.