Current antiretroviral therapy (ART) provides potent suppression of HIV-1 replication. However, ART does not target latent viral reservoirs, so persistent infection remains a challenge. Small molecules with pharmacological properties that allow them to reach and activate viral reservoirs could potentially be utilized to eliminate the latent arm of the infection when used in combination with ART. Here we describe a cellbased system modeling HIV-1 latency that was utilized in a high-throughput screen to identify small molecule antagonists of HIV-1 latency. A more detailed analysis is provided for one of the hit compounds, antiviral 6 (AV6), which required nuclear factor of activated T cells for early mRNA expression while exhibiting RNA-stabilizing activity. It was found that AV6 reproducibly activated latent provirus from different lymphocyte-based clonal cell lines as well as from latently infected primary resting CD4 ؉ T cells without causing general T cell proliferation or activation. Moreover, AV6 complemented the latency antagonist activity of a previously described histone deacetylase (HDAC) inhibitor. This is a proof of concept showing that a high-throughput screen employing a cell-based model of HIV-1 latency can be utilized to identify new classes of compounds that can be used in concert with other persistent antagonists with the aim of viral clearance.The ability of human immunodeficiency virus type 1 (HIV-1) to establish a latent infection results in life-long virus persistence even after long-term antiretroviral therapy (ART). 4 The role that latency plays in preventing sustained clearance of the virus infection has become evident in recent years. Patients that have been successfully treated with ART, having undetectable levels of viral RNA (below 50 copies/ml) in the plasma for years, experienced rapid virus rebound upon withdrawal of therapy (1, 2). Moreover, it was found that after T cell activation, virus could be isolated from CD4 ϩ T cells taken from these patients, underscoring the need to eliminate the latently infected cells to eradicate the virus (3-5).Activation of latent proviruses from infected cells in combination with ART is part of a therapeutic strategy that may lead to the complete elimination of HIV infection. Prior attempts to "flush out" the virus by activation of latently infected resting CD4 ϩ T cells with the administration of IL-2 and/or anti-CD3 monoclonal antibodies were ultimately unsuccessful, probably because of its inability to reach all of the latent viral reservoirs and the toxicity of the regimen (6 -10). A more promising approach to complete viral clearance is the use of small molecules with pharmacological properties that allow them to access the viral reservoirs and to specifically reactivate the latent proviruses. The concept of small molecule activation of latent HIV-1 has been tested in a clinical study using the histone deacetylase (HDAC) inhibitor valproic acid (VA) (11). However, it is questionable whether VA alone can be used as a supplement to ART for succe...
BackgroundExisting highly active antiretroviral therapy (HAART) effectively controls viral replication in human immunodeficiency virus type 1 (HIV-1) infected individuals but cannot completely eradicate the infection, at least in part due to the persistence of latently infected cells. One strategy that is being actively pursued to eliminate the latent aspect of HIV-1 infection involves therapies combining latency antagonists with HAART. However, discordant pharmacokinetics between these types of drugs can potentially create sites of active viral replication within certain tissues that might be impervious to HAART.ResultsA preliminary reverse genetic screen indicated that the proteasome might be involved in the maintenance of the latent state. This prompted testing to determine the effects of proteasome inhibitors (PIs) on latently infected cells. Experiments demonstrated that PIs effectively activated latent HIV-1 in several model systems, including primary T cell models, thereby defining PIs as a new class of HIV-1 latency antagonists. Expanding upon experiments from previous reports, it was also confirmed that PIs inhibit viral replication. Moreover, it was possible to show that PIs act as bifunctional antagonists of HIV-1. The data indicate that PIs activate latent provirus and subsequently decrease viral titers and promote the production of defective virions from activated cells.ConclusionsThese results represent a proof-of-concept that bifunctional antagonists of HIV-1 can be developed and have the capacity to ensure precise tissue overlap of anti-latency and anti-replication functions, which is of significant importance in the consideration of future drug therapies aimed at viral clearance.
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