While anti-retroviral therapy (ART) has been successful in controlling virus replication in HIV-1 positive individuals, HIV-1 is suppressed rather than eradicated. It is believed that latent HIV-1 reservoirs are responsible for the persistent infection. Therefore, strategies that eliminate HIV-1 from latent reservoirs are needed to cure/functionally cure persistent HIV-1 infection. Our long term goal is to develop a selective protein kinase C agonist gnidimacrin (GM) as an adjuvant therapeutic for HIV-1 eradication. GM is an unusually potent natural product that activates latent HIV-1 replication at picomolar concentrations. It is not toxic to uninfected cells until it reaches micromolar concentrations. GM is at least 4 log10 more potent than the most well studied histone deacetylase inhibitor vorinostat (SAHA) for latent HIV-1 activation. More importantly, GM induces approximately 10-fold more virus production than SAHA in a latently infected cell line model. Although SAHA was shown to disrupt HIV-1 latency, it appears to be ineffective in reducing latent HIV reservoirs through autologous CTL responses or cytopathic effect following latent viral activation. Thus, it was proposed that other strategies, such as CTL activation, might be needed to eliminate latently infected cells following SAHA treatment. Since GM is much stronger than SAHA in latent virus activation, we hypothesize that strong activation by GM will result in robust HIV-1 production from HIV-1 latently infected cells, which will render the latently infected cells susceptible to CTL responses and/or cytopathic effects of the activated latent viruses. Therefore, the goal of this study is to determine the effect of GM on reducing latent viral reservoirs using primary PBMCs from HIV-1 positive patients, and to establish crucial pharmacology and toxicology profiles that are needed for future in vivo pre-clinical studies. The goals will be achieved with the following Specific Aims: 1) determining the effectiveness of GM on reducing HIV-1 reservoirs in primary resting CD4 cells from patients. Our approaches to accomplish this aim are to determine the susceptibility of latently infected CD4 cells to CTL responses and cytopathic effects of GM-activated latent viruses;2) establishing the preclinical pharmacokinetic and toxicology profiles of GM. Since PKC belongs to a family of serine/threonine kinases involved in vital cellular functions, it is essential to determine the preclinical pharmacological and toxicological properties of GM before in vivo animal studies for efficacy. Small animal models will be used to establish the pharmacokinetic and toxicology profiles of GM. In addition to its strong anti-latency activity, GM also has advantage over HDAC inhibitors in that it inhibits re-infection of HIV-1 R5 viruses at pM concentrations. The proposed study will allow us to determine whether GM can reduce/eliminate latently infected resting CD4 cells without additional immunological interventions. Thus GM has the potential to be an attractive drug candidate for HIV-1 eradication.
The AIDS pandemic is a serious public health problem for many countries in the world. Persistent HIV-1 infection, especially in viral reservoirs, remains a challenge for effective AIDS therapy. This study is expected to determine the feasibility of using a potent protein kinase C agonist, gnidimacrin, as a powerful adjuvant therapeutic candidate for HIV-1 eradication.
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| Lai, Weihong; Huang, Li; Zhu, Lei et al. (2015) Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C ?. J Med Chem 58:8638-46 |
