Compositions and methods for reactivating latent immunodeficiency virus
Inventors
Assignees
Publication Number
US-11098309-B2
Publication Date
2021-08-24
Expiration Date
2035-10-13
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Abstract
The present disclosure provides compositions and methods for reactivating latent immunodeficiency virus and/or reducing transcription of HIV integrated into the genome of an HIV-infected cell. The present disclosure provides compositions and methods for treating an immunodeficiency virus infection.
Core Innovation
The invention provides compositions and methods for reactivating latent human immunodeficiency virus (HIV) integrated into the genome of infected cells and reducing HIV transcription. Specifically, it involves contacting HIV-infected cells with inhibitors targeting the methyltransferase activity of proteins SMYD2, ASH1L, SUV420H1, or SUV39H1. These inhibitors can reactivate latent HIV, thus potentially facilitating treatment of HIV infections.
Current combination antiretroviral therapies can suppress HIV replication but cannot eradicate the latent viral reservoir primarily composed of latently infected resting memory CD4+ T cells. This reservoir's long half-life makes complete eradication challenging. HIV latency is maintained by transcriptional silencing linked to chromatin modifications and cellular factors. The invention addresses this problem by targeting specific histone methyltransferases responsible for maintaining latency and thereby reactivating the virus for effective clearance.
Claims Coverage
The patent contains one independent claim describing a method of treating HIV infection using two main inventive features.
Use of SET domain-containing methyltransferase inhibitors to reactivate latent HIV
Administering to an individual an effective amount of a first active agent that is a SET domain-containing methyltransferase inhibitor selected from SMYD2 inhibitor, ASH1L inhibitor, and SUV420H1 inhibitor, which reactivates latent HIV integrated into the genome of a cell in the individual.
Use of an agent inhibiting immunodeficiency virus functions
Administering to the individual an effective amount of a second active agent that inhibits an immunodeficiency virus function selected from viral replication, viral protease activity, viral reverse transcriptase activity, viral entry into a cell, viral integrase activity, viral Rev activity, viral Tat activity, viral Nef activity, viral Vpr activity, viral Vpu activity, and viral Vif activity.
The claimed invention covers a therapeutic method involving co-administration of a SET domain-containing methyltransferase inhibitor that reactivates latent HIV and a second agent that inhibits HIV viral functions to treat HIV infection.
Stated Advantages
SMYD2 inhibitors specifically reactivate latent HIV from latency in infected cell models and primary cells.
Combination therapies involving SMYD2 inhibitors and other latency reversing agents (e.g., JQ1, SAHA) exhibit synergistic or enhanced effects in reactivating latent HIV.
SMYD2 inhibitors increase intracellular HIV-1 mRNA levels without inducing global T-cell activation or significant cytotoxicity at effective concentrations.
Documented Applications
Reactivate latent HIV integrated in the genome of infected cells to facilitate treatment of HIV infection.
Use treatment methods combining methyltransferase inhibitors to activate latent HIV alongside antiviral agents that inhibit various HIV viral functions.
Use small molecule inhibitors or siNA targeting SMYD2, ASH1L, SUV420H1 or SUV39H1 to reduce the reservoir of latent HIV in individuals.
Ex vivo and in vivo treatment applications involving administration via multiple routes including vaginal, rectal, oral, and intravenous routes.
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