Compositions and methods for reactivating latent immunodeficiency virus
Inventors
Assignees
Publication Number
US-11807852-B2
Publication Date
2023-11-07
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 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 disclosure includes methods of treating an immunodeficiency virus infection by contacting a cell harboring latent HIV with inhibitors of specific lysine methyltransferases, particularly SMYD2, ASH1L, SUV420H1, or SUV39H1, to reactivate the latent virus or reduce its transcription.
The problem being solved addresses the persistence of latent HIV reservoirs despite combination antiretroviral therapy, which effectively suppresses viral replication but does not eradicate latent virus integrated in resting memory CD4+ T cells. These reservoirs, due to their longevity and latent state mediated by transcriptional repression mechanisms, lead to rapid viral rebound when treatment stops, making eradication with current treatments impractical.
The invention identifies key epigenetic regulators, especially the histone methyltransferase SMYD2, as mediators of HIV transcriptional latency. Inhibitors of SMYD2 and related methyltransferases are shown to reverse this latency by reactivating HIV transcription. The methods also describe combination therapies incorporating these inhibitors with other latent HIV activators or antiviral agents. Furthermore, novel drug delivery devices comprising these inhibitors and anti-HIV agents are described.
Claims Coverage
The patent contains one independent claim directed to a drug delivery device. The claim includes main inventive features relating to the combination of containers comprising specific agents and their administration routes.
Combination of a SMYD2 inhibitor and an anti-immunodeficiency virus agent in a drug delivery device
The drug delivery device comprises a first container holding a SMYD2 inhibitor that reactivates latent immunodeficiency virus transcription and a second container holding an agent that inhibits various immunodeficiency virus functions, including viral replication and multiple viral protein activities.
Configuration of containers and routes of administration
The first and second containers can be syringes, vials, or ampules, and the device is configured for delivery by vaginal, rectal, oral, or intravenous routes.
Specification of types of agents in the device
The SMYD2 inhibitor can be a small molecule. The agent inhibiting immunodeficiency virus functions can be a histone deacetylase (HDAC) inhibitor such as suberoylanilide hydroxamic (SAHA), romidepsin, or sodium butyrate; a protein kinase C (PKC) activator such as prostratin or bryostatin or their analogs; or a bromodomain inhibitor such as JQ1.
The claims cover a device comprising separate containers for SMYD2 inhibitors that reactivate latent virus and agents that inhibit a broad range of viral functions, packaged for various routes of administration, emphasizing a combination approach to treating immunodeficiency virus infection.
Stated Advantages
SMYD2 inhibition effectively reverses HIV latency in cell lines and primary cells without inducing global T cell activation or significant cytotoxicity at effective concentrations.
Combination of SMYD2 inhibitors with other latency reversing agents, such as bromodomain inhibitors or HDAC inhibitors, results in enhanced reactivation of latent HIV.
Documented Applications
Reactivation of latent HIV integrated in infected cells to reduce the latent reservoir in HIV-infected individuals.
Treatment of immunodeficiency virus infections through combination therapy including SMYD2 inhibitors and antiviral agents targeting viral replication or specific viral protein functions.
Use of drug delivery devices comprising a SMYD2 inhibitor and an immunodeficiency virus function inhibitor for multiple administration routes (vaginal, rectal, oral, intravenous).
Screening methods for identifying agents that reactivate latent HIV or reduce latent infected cells by inhibiting the methyltransferase activity of lysine methyltransferases such as SMYD2.
Use of small molecule SMYD2 inhibitors and nucleic acid-mediated inhibition (e.g. siRNA) for HIV latency reactivation.
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