Monday, February 22, 2010

January 2010: Cannabinoids inhibit a form of immunodeficiency due to HIV (Virginia Commonwealth University; Richmond, Virginia)

First some background: Immunodeficiency can be aptly described as the inability for the body's defense system to mount an effective response against invading pathogens, and is usually the result of a decreased number of white blood cells or a loss in ability to recognize the pathogen as foreign. HIV (Human Immunodeficiency Virus) leads to immunodeficiency via two main mechanisms: the direct killing of, or an increased rate of apoptosis (programmed cell death) in white blood cells. One of the cells that are targeted by HIV is the macrophage. Macrophages are involved in the initial response to an infection; foreign pathogens (i.e. bacteria) bind to surface receptors, causing the macrophage to envelop the bacterium and digest it. The macrophage then presents proteins of the digested pathogen to other cells, while also secreting chemical factors that attract other white blood cells. When macrophages are infected with HIV, they stop producing their own proteins and begin to produce and secrete viral toxic factors uncontrollably. One of these toxic factors is the protein Tat (transactivator), which serves as an attractant for monocytes, the precursor to macrophages. Once monocytes leave the blood stream and enter local tissues, they can develop into macrophages. By attracting other macrophages, HIV starts a vicious cycle leading to higher and higher levels of Tat in the human body. Additionally, Tat acts as a toxin by inducing apoptosis in T cells, one of the white blood cells responsible for mediating adaptive immunity. Adaptive immunity refers to the ability of the body to rapidly fight a pathogen upon re-infection. The death of the T cells leads to a loss in this adaptive immunity, which is a factor in the infection hypersensitization seen in HIV patients, especially those in which its progression has lead to the development of AIDS (Acquired Immune Deficiency Syndrome).

The new information: Administration of cannabinoids lead to an inhibition in the migration of monocytes due to Tat. By activating the CB2 cannabinoid receptor, it was shown that monocytes and macrophages did not respond to this attractive factor. The experiment proved this using three separate mechanisms. First, a cannabinoid receptor agonist was administered, which lead to the activation of the CB2 receptor on macrophages and inhibition of migration in response to Tat. Secondly, a cannabinoid receptor antagonist was administered, which blocks the CB2 receptor on macrophages and lead to migration. Lastly, the DNA of the macrophage was altered so that the CB2 receptor was not produced, and this lead to migration even in the presence of cannabinoid.

What this means: By halting one of the vicious cycles that lead to AIDS, cannabinoids can potentially stop the progression of HIV (AIDS is defined by a CD4+ (helper) T cell count below 200 cells per microliter). By decreasing the levels of HIV-induced release of Tat by macrophages, the level of T cell death due to Tat would decline. Thus, cannabis could potentially slow the progression of HIV and AIDS by disallowing widespread cellular infection. Currently, the standard treatment for HIV/AIDS is HAART (Highly Active Antiretroviral Therapy), which utilizes several of what are known as anti-retroviral drugs, which inhibit an enzyme responsible for converting the HIV genes into a format that can be read by human cells. While this form of treatment is effective in preventing cellular infection, it cannot target cells already infected with the virus. Therefore, macrophages already producing Tat will continue to produce it, attracting other macrophages for infection, and causing the continued death of white blood cells. By administering cannabis concurrently, it would add an additional level of protection by reducing the spread of HIV to attracted macrophages. Additionally, HAART is very expensive, with an approximate average cost of $1,500 per month. By utilizing cannabis in conjunction with more cost-effective anti-retroviral medications, the cost of treatment could be reduced to as little as $100 a month.

Raborn, E. and G. Cabral. “Cannabinoid Inhibition of Macrophage Migration to the Tat Protein of HIV-1 is Linked to the CB2 Cannabinoid Receptor.” The Journal of Pharmacology and Experimental Therapeutics. (2010): preprint.

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