Lessons from viral latency in T cells: manipulating HIV-1 transcription by siRNA

Abstract

Despite prolonged and intensive application, currently available combined antiretroviral therapy cannot eradicate HIV-1. It has little impact on provirus harbored within resting CD4+ T cells, which survive for long periods of time. One approach to clear this reservoir has been to administer either T cell-activating cytokines or histone deacetylase inhibitors to HIV-1 infected individuals in order to reactivate latent virus from the cellular compartment while continuing cART to avoid reseeding of the reservoir. These approaches have had limited success. Strategies for the eradication of HIV need to be refined. Rational design of these approaches requires a clear understanding of the determinants of viral latency, which is controlled, at least in part, by epigenetic modifications in histones and recruitment of suppressive proteins to form heterochromatin in the promoter region of the virus. Reactivation of virus correlates with dissociation of repressive modifications, including acetylation of histone tails. siRNA has been found to be capable of inducing heterochromatin formation. Prolonged HIV-1 transcriptional gene silencing induced by either RNA duplexes or retrovirally delivered shRNA targeting a sequence located within the HIV-1 promoter is associated with sustained RNA induction and maintenance of heterochromatin (closed) structure in the viral promoter. These changes resemble those described in the latent infection. Observations regarding epigenetic control of viral transcription may provide important insights into mechanisms to manipulate latent viral reservoirs.