However, the inability of VPA to reactivate latent reservoirs when used alone showed potentiating results when used in combination with prostratin . the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-B signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway. A quarter of a century after the discovery of HIV-1, we are still unable to eradicate the virus from infected patients. Highly active antiretroviral therapy (HAART) consists of combinations of antiretroviral therapeutics targeting different steps of the virus life cycle (e.g. entry, reverse transcription, integration and maturation) used simultaneously to reduce the risk of viral replication and the development of drug resistance conferred by the emergence of mutant strains [1-3]. HAART results in a four-phase decay of viremia [4-7]: (1) an initial rapid loss of virus due to the clearance of infected PG 01 activated CD4+ T cells, which have PG 01 a very short half-life and survive for about one day because of viral cytopathic effects or host cytolytic effector mechanisms; Ctnnb1 (2) a slower phase PG 01 of viral decay owing to the clearance of several cell populations with a half-life of one to four weeks, such as infected macrophages, partially activated CD4+ T cells and follicular dendritic cells (FDCs); (3) a third phase of decay corresponding to cells with a half-life of approximately 39 PG 01 weeks; and (4) a constant phase with no appreciable decline, caused (at least partially) by the activation of resting memory CD4+ T cells. During the fourth phase, HIV-1 plasma viremia normally ranges from 1 to 5 copies of viral RNA/mL as detected by extremely sensitive RT-PCR assays [8-10]. Despite the observation that prolonged HAART treatment is associated with many metabolic disorders and toxicities [11,12], the prospect of lifelong treatment is today a necessary evil because interrupting HAART leads to a rapid viral rebound, attributable to the persistence of latently-infected cellular reservoirs notably in resting memory CD4+ T cells [13-15] and probably in other cell populations [16-18]. Viral reservoirs include cell types or anatomical sites where a replication-competent form of the virus persists with more stable kinetics than the main pool of actively replicating virus [5,19]. Because they express no viral protein, latently-infected reservoir cells are immunologically indistinguishable from uninfected cells and are insensitive to immune clearance and HAART. The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in HAART-treated infected individuals represents a major hurdle to virus eradication. To address this problem, a first approach has consisted of strengthening HAART. This intensification strategy relied on the administration of additional viral inhibitors in association with HAART. Despite their cytotoxicity, candidate drugs have included hydroxyurea and cyclophosphamide. Hydroxyurea inhibits the cellular enzyme ribonucleotide reductase, thereby decreasing intracellular deoxyribonucleotide pools and indirectly impeding viral reverse transcriptase activity [20,21]. Cyclophosphamide is an alkylating agent that results in cytoreduction and cell growth arrest, and is used to treat various types of cancers and immune diseases. However, these compounds have not been found to decrease the latently-infected reservoirs in HIV-infected patients [22,23]. The source of the observed persistent steady-state viremia in HAART-treated patients has been attributed, on the one hand, to a non-fully suppressive HAART following poor drug penetration in anatomical sanctuaries such as the central nervous system (CNS)[24,25]; and, on the other hand, to the release of virus due to the reactivation of latently-infected resting CD4+ T cells (or other cellular reservoirs) despite fully suppressive therapy. Several groups have proposed the existence of a residual continuous PG 01 HIV-1 replication, which could constantly replenish the latent pool. This proposition was based on the observation of so-called 2-LTR cirle forms of the provirus, whose half-life should be less than one day reflecting recent rounds of.