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Activation of Cannabinoid Receptors May Fight HIV Reservoirs
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One of the hardest challenges to curing human immunodeficiency virus (HIV) infection is removing the viral reservoirs in the host. HIV is a retrovirus. This means that unlike normal cells which use a DNA genome to store information, HIV uses an RNA genome to hold its genetic information. Once the virus has entered the cell, the RNA is reverse transcribed into DNA by viral proteins. The DNA is then inserted into the host cell’s genome, becoming a more or less permanent part of the cell. The HIV DNA is replicated along with the host cell DNA, and passed into new daughter cells. In addition, the HIV DNA is transcribed by the host cell’s enzymes into messenger RNA, which is then used to direct translation of HIV proteins. New viral particles are assembled and released from the host cell to find new cells to infect. Because the HIV genome can remain quiescently in the host cell’s genome, it is possible that viral reservoirs continue to exist, even after aggressive antiretroviral therapy reduces detectable viral loads in plasma to zero.

Antiretroviral drugs can keep plasma virus levels low and delay the progression to acquired immunodeficiency syndrome (AIDS) in HIV positive patients. However, because the virus is not completely removed from the body, antiretroviral medications are needed indefinitely. The constant presence of the virus in the body can cause excessive inflammation and immune cell exhaustion. The best way to combat HIV infection would require removing viral reservoirs from cells. The constant inflammation caused by low level HIV replication can cause problems in many parts of the body, including the central nervous system (CNS). Inflammation of the CNS appears to be involved in the development of HIV-associated neurocognitive disorder (HAND). When viral mediated inflammation of the CNS occurs, patients develop varying levels of dementia.

Researchers at Temple University School of Medicine wanted to determine if activation of the cannabinoid receptor CB2 could prevent inflammation of the CNS seen during HIV infection, and thereby prevent neurocognitive defects. They chose to study macrophages, which are a type of cell that could act as a reservoir for HIV. Macrophages are found throughout the body, and are believed to be the cells that transport HIV to the brain. They hoped that by treating infected macrophages with CB2 activators, they could prevent low level viral replication and associated inflammation.

Macrophages grown in vitro and infected with HIV were treated with one of three synthetic CB2 activators. The researchers measured levels of reverse transcriptase, to use as a measurement of how actively the virus was replicating in the cell. All three of the receptors decreased reverse transcriptase activity in the cells. This indicates that CB2 activators could potentially be used to prevent replication of HIV in cellular reservoirs. By inhibiting replication, associated inflammation would also be controlled, and HAND could potentially be prevented in patients.

While this study provides interesting preliminary data about the use of synthetic agents, there is still a great deal of research that needs to be performed, and many questions are left unanswered. Using reverse transcriptase activity as a marker of viral replication is not an ideal choice. As mentioned above, reverse transcriptase is an enzyme used to change the viral RNA genome into DNA. This is an indirect measure of how efficiently HIV is infecting new cells. It might be more accurate to measure production of a viral protein, such as the envelope protein, to determine how well new HIV particles are being produced. However, reduced activity of reverse transcriptase does indicate that fewer new cells are becoming infected with HIV, which translates into fewer reservoirs. In addition, the mechanism by which CB2 activation inhibits HIV replication would need to be studied as well. CB2 is a cannabinoid receptor, which is normally activated by the active components in marijuana. While it is known that activation of these receptors does reduce inflammation, it is not at all clear how this could result in reduced HIV replication. Researchers would also need to determine if CB2 activation can indeed decrease dementia symptoms in HIV infection. During these studies, it would also be beneficial to determine if CB2 activation inhibits viral replication throughout the body. This could be a potential adjunctive therapy to current retroviral treatments available to help slow disease progression even further.



References:

http://www.sciencedaily.com/releases/201...132053.htm

http://neurology.about.com/od/ID/a/HIV-A...orders.htm
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