Compositions and methods for reactivating latent immunodeficiency virus using a GSK-3 inhibitor
Inventors
Gramatica, Andrea • Greene, Warner C.
Assignees
Publication Number
US-11590110-B2
Publication Date
2023-02-28
Expiration Date
2038-06-05
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Abstract
The present disclosure provides compositions and methods for reactivating latent immunodeficiency virus using a glycogen synthase kinase 3α inhibitor, such as a glycogen synthase kinase 3α (GSK-3α) or a glycogen synthase kinase 3β (GSK-3β) inhibitor. In some embodiments, the glycogen synthase kinase 3 inhibitor is a glycogen synthase kinase antagonist, e.g., Tideglusib (4-benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione), or a pharmaceutically acceptable salt or derivative thereof. In other embodiments, the glycogen synthase kinase 3 inhibitor is a maleimide-based glycogen synthase kinase 3 inhibitor, e.g., SB-216763 (3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione) or a pharmaceutically acceptable salt or derivative thereof.
Core Innovation
The invention provides compositions and methods for reactivating latent immunodeficiency virus, including human immunodeficiency virus (HIV), using glycogen synthase kinase 3 (GSK-3) inhibitors. Specifically, the invention relates to inhibiting one or more isoforms of GSK-3, such as glycogen synthase kinase 3α (GSK-3α) or glycogen synthase kinase 3β (GSK-3β), using compounds including but not limited to Tideglusib and SB-216763 or their pharmaceutically acceptable salts or derivatives. The methods involve contacting cells harboring latent HIV with these inhibitors to reactivate the latent virus, enabling reduction of the latent viral reservoir in vitro and in vivo.
The problem addressed is the persistence of latent HIV reservoirs in cells, primarily memory CD4+ T cells in lymphoid tissues, which remain transcriptionally silent yet capable of producing infectious virus once reactivated. Existing therapies like Highly Active Antiretroviral Therapy (HAART) suppress active viral replication but do not eliminate these latent reservoirs. Previous latency reversal agents (LRAs) such as cytokines, T cell receptor activators, HDAC inhibitors, and protein kinase C activators have limitations including low efficacy, cellular toxicity, and broad T cell activation, which compromise immune function and safety. There remains an unmet need for safe and potent LRAs that effectively reactivate latent HIV without causing cellular toxicity, broad immune activation, or impairment of cytotoxic lymphocyte function.
The invention solves this problem by employing GSK-3 inhibitors, such as Tideglusib and maleimide-based inhibitors like SB-216763, to reactivate latent HIV. These inhibitors demonstrate potent latency reversal activity ex vivo in cells from HIV-infected individuals on suppressive antiretroviral therapy, including CD4+ T cells derived from blood and gut-associated lymphoid tissue (GALT), without significant cytotoxicity or undesired T cell activation. The agents activate the AKT/mTOR and NF-κB pathways, which contribute to HIV transcription reactivation, while preserving viability and cytotoxic effector functions of CD8+ T cells, cytotoxic T lymphocytes (CTLs), and natural killer (NK) cells. These findings indicate GSK-3 inhibitors as promising LRAs with favorable safety and efficacy profiles for reactivating latent HIV and reducing the viral reservoir.
Claims Coverage
The claims include 5 independent claims. They cover methods of reactivating latent HIV in cells, methods of reducing latent HIV cells in individuals, methods of treating HIV infection with combination therapy, and drug delivery devices comprising the inhibitors.
Method of reactivating latent HIV with a specific GSK-3 inhibitor
A method of reactivating latent HIV integrated into the genome of an infected cell by contacting the cell with a glycogen synthase kinase 3 inhibitor, specifically Tideglusib or its pharmaceutically acceptable salt, thereby reactivating the latent HIV.
Method of reactivating latent HIV in lymphoid tissue
The contacting step of the method occurs in lymphoid tissue, targeting latent HIV reservoirs located in such tissues.
Method of reducing latent HIV reservoir in an individual by administration of GSK-3 inhibitor
Administration to an individual of an effective amount of a glycogen synthase kinase 3 inhibitor, specifically Tideglusib or its pharmaceutically acceptable salt, to reactivate latent HIV in cells and reduce the number of cells containing latent HIV by at least 20%.
Method of treating HIV infection with GSK-3 inhibitor and second active anti-HIV agent
A method of treating HIV infection by administering to an individual an effective amount of a glycogen synthase kinase 3 inhibitor, specifically Tideglusib or its pharmaceutically acceptable salt, in combination with an effective amount of a second active agent that inhibits one or more immunodeficiency virus functions including viral replication, protease activity, reverse transcriptase activity, viral entry, integrase activity, and others.
The claims cover methods using GSK-3 inhibitors, notably Tideglusib, to reactivate latent HIV and reduce viral reservoirs ex vivo and in vivo, alone or in combination with other anti-HIV agents, and associated drug delivery systems.
Stated Advantages
GSK-3 inhibitors effectively reactivate latent HIV in CD4+ T cells without causing significant cytotoxicity or reducing cell viability.
The inhibitors do not induce broad T-cell activation or expression of activation markers CD69 and CD25, minimizing potential immune activation side effects.
Treatment with GSK-3 inhibitors preserves cytotoxic effector functions of CD8+ T cells, CTLs, and NK cells, which are critical for immune clearance of reactivated latent HIV.
GSK-3 inhibitors demonstrate higher or comparable potency for latency reversal compared to current latency reversal agents with a better safety profile.
Tideglusib, a GSK-3β inhibitor, has shown good tissue permeability and a favorable safety profile in humans, with low incidence of reversible side effects.
Documented Applications
Reactivation of latent immunodeficiency virus, including latent HIV, in cells harboring transcriptionally silent provirus.
Reduction of latent HIV reservoirs in individuals by administration of effective amounts of GSK-3 inhibitors.
Combination therapy for treating HIV infection by co-administering a GSK-3 inhibitor and an anti-HIV agent targeting various viral functions.
Detection of cells harboring latent HIV by contacting cells with GSK-3 inhibitors and detecting viral gene expression.
Screening assays to identify candidate anti-HIV agents by evaluating their effect on HIV production in the presence of GSK-3 inhibitors.
Use of GSK-3 inhibitors as latency reversal agents (LRAs) for HIV cure strategies to induce virus expression without toxicity or undesirable immune activation.
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