Administration of HDAC inhibitors to reactivate HIV-1 expression in latent cellular reservoirs: implications for the development of therapeutic strategies Dominique Demonte ´ a , Vincent Quivy a , Yves Colette b , Carine Van Lint a,* a Laboratoire de Virologie Mole ´culaire, Service de Chimie Biologique rue des Profs Jeener et Brachet 12, Institut de Biologie et de Me ´decine Mole ´culaires (IBMM), Universite ´ Libre de Bruxelles (ULB), 6041 Gosselies, Belgium b INSERM U119, 13009 Marseille, France Received 23 April 2004; accepted 7 May 2004 Abstract The discovery of powerful antiviral compounds in the 90’s raised the hope that the human immunodeficiency virus type 1 (HIV-1) might be eradicated. However, if these drugs succeed in decreasing and controlling viral replication, complete eradication of the virus is nowadays impossible. The persistence of virus even after long periods of highly active antiretroviral therapy (HAART) mainly results from the presence of cellular reservoirs that contain transcriptionally competent latent viruses capable of producing infectious particles after cellular activation. These latently infected cells are a permanent source for virus reactivation and lead to a rebound of the viral load after interruption of HAART. Activation of HIV gene expression in these cells combined with an effective HAART has been proposed as an adjuvant therapy that could lead to the elimination of the latently infected cells and then to the eradication of the infection. In this context, we have previously demonstrated that deacetylase inhibitors (HDACi) synergize with TNF-induced NF-kB to activate the HIV-1 promoter. The physiological relevance of the TNF/HDACi synergism was shown on HIV-1 replication in both acutely and latently HIV- infected cell lines. Based on these results, we propose the administration of deacetylase inhibitor(s) together with continuous HAART as a new potential therapeutic perspective to decrease the pool of latent HIV reservoirs by forcing viral expression. # 2004 Elsevier Inc. All rights reserved. Keywords: HIV-1; Transcription; Latency; Reservoirs; HDCAi; HAART 1. Introduction 1.1. The HIV-1 reservoirs: a major obstacle to the eradication of the virus The development of highly active antiretroviral thera- pies (HAART) has dramatically improved the survival and quality of life of HIV-1-infected individuals. Unfortu- nately, whereas these treatments significantly reduce the levels of viral RNA in plasma and lymphoid tissues, cessation of even prolonged highly suppressive HAART regimens results in viral load rebound to pre-therapy levels, indicating that antiretroviral therapy of this type is unable to completely eliminate HIV-1 [1–3]. This failure has been attributed in part to the presence of a long-lived, stable population of latently infected resting memory CD4 þ T cells that are not eliminated by the antiviral treatment [4–6]. Indeed, while many HIV-suscep- tible cells are fast-turnover cells, this small part of memory T cells are long-lived cells [7,8]. These infected cells can go dormant and stay in tissues for years despite effective HAART, thereby serving as the HIV-1 reservoirs in vivo [6]. These reservoirs have such a slow rate of decay during HAART that their eradication during a human lifespan is unlikely [9,10]. As with all retroviruses, HIV-1 integrates into the gen- ome of the host cell. As a consequence, the activity of the integrated viral genome, or provirus, is greatly influenced by the metabolic and activation state of the host cell. The generation of latency is thought to occur after HIV infec- tion of a transcriptionally active cell, which predominantly Biochemical Pharmacology 68 (2004) 1231–1238 0006-2952/$ – see front matter # 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2004.05.040 * Corresponding author. Tel.: þ32 2 650 9807; fax: þ32 2 650 9800. E-mail address: cvlint@ulb.ac.be (C. Van Lint).