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Updated: Oct 6, 2025
Evaluation of the Efficacy And Toxicity of RNAs Targeting HIV-1 Production for Use in Gene or Drug Therapy
Published on: September 5, 2016
The ingenol-based protein kinase C agonist GSK445A is a potent inducer of HIV and SIV RNA transcription
Afam A Okoye1,2, Rémi Fromentin3,4, Hiroshi Takata1
1Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America.
Abstract:
Activation of the NF-κB signaling pathway by Protein Kinase C (PKC) agonists is a potent mechanism for human immunodeficiency virus (HIV) latency disruption in vitro. However, significant toxicity risks and the lack of evidence supporting their activity in vivo have limited further evaluation of PKC agonists as HIV latency-reversing agents (LRA) in cure strategies. Here we evaluated whether GSK445A, a stabilized ingenol-B derivative, can induce HIV/simian immunodeficiency virus (SIV) transcription and virus production in vitro and demonstrate pharmacological activity in nonhuman primates (NHP). CD4+ T cells from people living with HIV and from SIV+ rhesus macaques (RM) on antiretroviral therapy (ART) exposed in vitro to 25 nM of GSK445A produced cell-associated viral transcripts as well as viral particles at levels similar to those induced by PMA/Ionomycin, indicating that GSK445A can potently reverse HIV/SIV latency. Importantly, these concentrations of GSK445A did not impair the proliferation or survival of HIV-specific CD8+ T cells, but instead, increased their numbers and enhanced IFN-γ production in response to HIV peptides. In vivo, GSK445A tolerability was established in SIV-naïve RM at 15 μg/kg although tolerability was reduced in SIV-infected RM on ART. Increases in plasma viremia following GSK445A administration were suggestive of increased SIV transcription in vivo. Collectively, these results indicate that GSK445A is a potent HIV/SIV LRA in vitro and has a tolerable safety profile amenable for further evaluation in vivo in NHP models of HIV cure/remission.
Insights
GSK445A effectively reverses HIV and SIV latency in vitro by reactivating viral transcription. This compound also shows promising pharmacological activity and a tolerable safety profile in nonhuman primates, suggesting potential for HIV cure strategies.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Protein Kinase C (PKC) agonists activate NF-κB signaling, disrupting human immunodeficiency virus (HIV) latency in vitro.
- Toxicity and lack of in vivo data limit PKC agonists as HIV latency-reversing agents (LRAs).
Purpose of the Study:
- Evaluate GSK445A, an ingenol-B derivative, for its ability to induce HIV/simian immunodeficiency virus (SIV) transcription and virus production in vitro.
- Assess GSK445A's pharmacological activity and safety in nonhuman primates (NHP).
Main Methods:
- Exposed CD4+ T cells from people with HIV and SIV+ rhesus macaques (RM) on antiretroviral therapy (ART) to GSK445A in vitro.
- Administered GSK445A to SIV-naïve and SIV-infected RM on ART in vivo.
- Monitored viral transcription, viral particle production, T cell proliferation, survival, and IFN-γ production.
Main Results:
- GSK445A (25 nM) potently reversed HIV/SIV latency in vitro, inducing viral transcripts and particles similar to PMA/Ionomycin.
- GSK445A enhanced HIV-specific CD8+ T cell numbers and IFN-γ production without impairing proliferation or survival.
- GSK445A demonstrated tolerability in SIV-naïve RM at 15 μg/kg, though reduced in SIV-infected RM on ART.
- In vivo administration of GSK445A led to increased plasma viremia, suggesting enhanced SIV transcription.
Conclusions:
- GSK445A is a potent in vitro HIV/SIV LRA.
- GSK445A exhibits a tolerable safety profile in NHP models.
- GSK445A warrants further in vivo evaluation for HIV cure/remission strategies.
