The progress of science, is driven by hypotheses and experimentation, however, it is also limited by available technology. The explosion of molecular biology, initiated by Watson and Crick's discovery of the structure of DNA, was possible and advanced by the analytical and separation technologies of water-soluble chemistries. Over the past decade and a half, advances in lipid separation and analytical technologies have opened a new world of investigation. One of the most profound discoveries was that of the endocannabinoid system1 and subsequently, its associated lipid biochemical pathways2. Simultaneously, a tremendous amount of work and expense has provided an enormous amount of information regarding the infectious process of the Human Immunodeficiency Virus (HIV). These two avenues of investigation have largely occurred in parallel. At this point in time, there is sufficient evidence for these paths to now be integrated.
The development of anti-retroviral therapies has been profoundly successful in saving the lives of many thousands of individuals infected with HIV. Unfortunately, the solutions thus far developed for the AIDS crisis have not been complete, nor without complications. For example Highly Active Anti-Retroviral Therapy (HAART) associated dyslipidemia (HAL), HIV-associated neurocognitive disorder (HAND) results from activated macrophage and microglial cells, and the subsequent inflammatory responses that they generate. HAND typically develops later during infection as the CD4+ count decreases and the viral load increases. There are important biological parameters to be considered when looking for an effective pharmaceutical solution for this problem. Firstly, can we modify the biology via appropriate drug development in order to inhibit the viral expansion and disease? Additionally, can we protect the neurons that are lost as a result of the inflammatory conditions, and can we inhibit inflammatory immune responses that are at the heart of this problem?
One cannot consider the viral suppression without considering the development of drug resistance. There are hundreds of thousands of HIV-infected individuals who have been treated with a variety of anti-retroviral drugs who now, unfortunately, are beginning to develop resistance to these otherwise successful treatment modalities. One of the most dramatic indicators of viral resistance has been the return of Kaposi sarcoma, an opportunistic herpes infection characterized by well-vascularized skin lesions. We will return to consider Kaposi’s later in this article. For now we will focus on the critical activities of the multi functional viral trans activator protein (Tat) and a novel drug development program being launched by Cannabis Science (CSTATI-1) that will inhibit Tat activities.
Tat is a peptide of variable length with complex functionality. Tat regulates the phosphorylation of cellular proteins, including cyclin complexes and RNA polymerase3 that in turn promote viral infectivity. Additionally, Tat has direct cytotoxic affects on T cells4 and neurons5, and also acts as an attractant for macrophage6. Cannabis Science is developing CSTATI-1 as an anti-Tat pharmaceutical because significant NIH funds have been used to demonstrate the inhibitory effects of phytocannabinoids on many of these Tat activities. Phytocannabinoids inhibit the chemoattractive properties of Tat7,8. Cannabinoids are well known for their neuro-protective properties. In fact in 2003, the U.S. Government, as represented by the Department of Health and Human Services, filed for, and was awarded, a patent on cannabinoids as antioxidants and neuroprotectants (U.S. Patent 6630507). With respect to HIV, the neuroprotective properties of phytocannabinoids were demonstrated in a murine model for neuro-aids9. Furthermore, they inhibit the activation of microglial cells that are important mediators of inflammation10 and its associated oxidative consequences11.
Additionally, phytocannabinoids exhibit direct anti-viral actions. Phytocannabinoids were recently demonstrated to inhibit CXCR4-Tropic HIV infection in primary CD4+ T Cells12 which is consistent with their demonstrated inhibitory activity against SIV progression13,14 and neurological consequences15.
Returning to Kaposis sarcoma, the high degree of vascularization that characterizes the viral lesions is the end product of viral-directed signaling that tells the body to do so16. Specific biochemical messengers, such as vascular endothelial growth factor (VEGF), are involved in this biocommunication process17. In synergy with KSHV, HIV-Tat induces VEGF as part of the process by which monocyte chemotaxis occurs6. The inhibition of VEGF is a natural target for anti-HIV drug development16. Phytocannabinoids have been shown to inhibit VEGF dependent tumor growth18.
Both HIV and KSHV share the common requirement for the transcription factor NF-kappaB to activate biochemical pathways required for viral development. HIV infection induces NF-kappaB via Tat19,20. Additionally, NF-kappaB is a controlling agent for KSHV-infected primary effusion lymphoma cells21. Phytocannabinoids inhibit NF-kappaB22.
The safety of phytocannabinoids has been demonstrated in humans infected with HIV. In general, phytocannabinoids have been shown to have a positive effect on HIV patients including increased caloric intake, weight gain and improved sleep23. Furthermore their safety when used with retroviral therapies has also been confirmed24.
In conclusion, while phytocannabinoids can inhibit HIV, they also have the ability to simultaneously inhibit KSHV. They impact both infections via multiple routes. Therefore, phytocannabinoids have the potential to make a dramatic impact on the progression of these infections and unlike most existing drugs that typically act on a single target, phytocannabinoids by acting via multiple pathways can reduce the probability of developing drug resistance while still inhibiting critical targets such as Tat.
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- Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946-1949 (1992).
- Kim, J. B. & Sharp, P. A. Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase. J Biol Chem 276, 12317-12323 (2001).
- Campbell, G. R. et al. The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis. J Biol Chem 279, 48197-48204 (2004).
- New, D. R., Maggirwar, S. B., Epstein, L. G., Dewhurst, S. & Gelbard, H. A. HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and activation of non-N-methyl-D-aspartate receptors by a NFkappaB-independent mechanism. J Biol Chem 273, 17852-17858 (1998).
- Mitola, S. et al. Tat-human immunodeficiency virus-1 induces human monocyte chemotaxis by activation of vascular endothelial growth factor receptor-1. Blood 90, 1365-1372 (1997).
- Raborn, E. S. & Cabral, G. A. CANNABINOID INHIBITION OF MACROPHAGE MIGRATION TO THE TAT PROTEIN OF HIV-1 IS LINKED TO THE CB2 CANNABINOID RECEPTOR. J Pharmacol Exp Ther (2010).
- Fraga, D., Raborn, E. S., Ferreira, G. A. & Cabral, G. A. Cannabinoids Inhibit Migration of Microglial-like Cells to the HIV Protein Tat. J Neuroimmune Pharmacol (2011).
- Gorantla, S. et al. Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS. J Neuroimmune Pharmacol 5, 456-468 (2010).
- Cabral, G. A. & Marciano-Cabral, F. Cannabinoid Receptors in Microglia of the Central Nervous System: Immune Functional Relevance. J Leukoc Biol 78, 1192-1197 (2005).
- Pacher, P. & Mackie, K. Interplay of cannabinoid 2 (CB(2)) receptors with nitric oxide synthases, oxidative and nitrative stress, and cell death during remote neurodegeneration. J Mol Med (Berl) (2012).
- Costantino, C. M. & Chen, B. K. Cannabinoid Receptor 2-Mediated Attenuation of CXCR4-Tropic HIV Infection in Primary CD4+ T Cells. PLOS Biol (2012).
- Molina, P. E. et al. Cannabinoid administration attenuates the progression of simian immunodeficiency virus. AIDS Res Hum Retroviruses 27, 585-592 (2011).
- Molina, P. E. et al. Cannabinoid Administration Attenuates the Progression of Simian Immunodeficiency Virus. AIDS Res Hum Retroviruses (2010).
- Molina, P. E. et al. Cannabinoid Neuroimmune Modulation of SIV Disease. J Neuroimmune Pharmacol (2011).
- Dai, L., Bratoeva, M., Toole, B. P., Qin, Z. & Parsons, C. KSHV activation of VEGF secretion and invasion for endothelial cells is mediated through viral upregulation of emmprin-induced signal transduction. Int J Cancer (2011).
- Sinkovics, J. G. Kaposi's sarcoma: its 'oncogenes' and growth factors. Crit Rev Oncol Hematol 11, 87-107 (1991).
- Blazquez, C. et al. Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64, 5617-5623 (2004).
- Chihara, T. et al. HIV-1 Proteins Preferentially Activate Anti-Inflammatory M2-Type Macrophages. J Immunol 188, 3620-3627 (2012).
- Fiume, G. et al. Human immunodeficiency virus-1 Tat activates NF-kappaB via physical interaction with IkappaB-alpha and p65. Nucleic Acids Res 40, 3548-3562 (2012).
- Keller, S. A., Schattner, E. J. & Cesarman, E. Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96, 2537-2542 (2000).
- Herring, A. C. & Kaminski, N. E. Cannabinol-mediated inhibition of nuclear factor-kappaB, cAMP response element-binding protein, and interleukin-2 secretion by activated thymocytes. J Pharmacol Exp Ther 291, 1156-1163 (1999).
- Haney, M. et al. Dronabinol and Marijuana in HIV-Positive Marijuana Smokers: Caloric Intake, Mood, and Sleep. J Acquir Immune Defic Syndr (2007).
- James, J. S. Marijuana safety study completed: weight gain, no safety problems. AIDS Treat News 348, 3-4 (2000).
Robert Melamede PhD - Associate Professor University of Colorado at Colorado Springs and CEO/President Cannabis Science