Medical Research: What is the background for this study? What are the main findings?
Dr. Dandekar: Current anti-retroviral therapy is effective in suppressing HIV replication and enhancing immune functions in HIV infected individuals. However, it fails to eradicate the latent HIV reservoirs. Therapy interruption leads to a rapid viral rebound in these patients. Eradication of latent HIV reservoirs is essential to achieve HIV cure. A “shock and kill” strategy for HIV cure has been proposed that involves reactivation of latent viral reservoirs using latency reversal agents (LRA) and eradication by the immune response. This highlights the need to identify potent LRAs to optimally activate latent HIV reservoirs so that immune surveillance and clearance mechanisms can be effectively engaged in the process of viral eradication. We have found that ingenol-3-angelate (PEP005), an anti-cancer drug can effectively reactivate latent HIV. It is a protein kinase C agonist that activates NF-kB and stimulates HIV expression. In combination with another compound, JQ1, a previously known p-TEFb agonist, the efficacy of PEP005 for HIV reactivation is markedly increased. In addition, ingenol-3-angelate decreases the expression of HIV co-receptors on immune cells, which potentially will help preventing further spread of the virus. The use of ingenol-3-angelate in combination with other latency reversal agents provides an excellent opportunity to optimally activate latent HIV reservoirs and target them for eradication.
Medical Research: What should clinicians and patients take away from your report?
Dr. Dandekar: With the availability of suppressive anti-retroviral therapy, it is now possible to explore innovative approaches for HIV eradication. Identification of potent latency reversal agents and optimization of the combination of LRAs will be important to achieve full activation of the latent HIV reservoirs.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Dandekar: Ingenol-3-angelate is a potential candidate for advancing to clinical HIV cure studies based on its ability to activate latent HIV, act synergistically with other candidate LRAs and to potentially protect immune targets by down-modulation of HIV co-receptor expression. Future studies can be focused on pharmacokinetic evaluations in vivo and proof of concept experiments in the experimental models.
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Dr. Satya Dandekar PhD (2015). Cancer Drug Can Activate HIV Reservoirs To Target For Eradication