[Nikolas]

HIV, the causative agent of AIDS has long presented a problem for treatment, showing extraordinary resilience to any kind of drugs. It has long been known that it infects an organisam and persists in certain cells, despite any attempts to drive it out.. But researchers at Temple University School of Medicine's Department of Pathology and Laboratory Medicine and Center for Substance Abuse Research (CSAR) have discovered that synthetic anti-inflammatory substances derived and somewhat related to the active ingredient of marijuana may be able to tackle HIV while inside one of its major hideouts, immune cells known as macrophages.

"Powerful antiretroviral drug cocktails have allowed many HIV patients to live longer," explained Servio H. Ramirez, PhD, Assistant Professor of Pathology and Laboratory Medicine at Temple University School of Medicine (TUSM), and first author on the study. This breakthrough comes at a crucial time in HIV research. But the main problem with living longer with an HIV infection is the low level of replication and ever-present week inflammation which eventually causes much damage to the organism, predominantly nerve tissue. In the central nervous system, this inflammatory process is thought to be the main underlying cause of HIV-associated neurocognitive disorder (HAND), a syndrome that appears after more than 10 years of the advent of an HIV infection.

To be able to better study the connection between inflammation and neurocognitive conditions linked to long-term exposure to HIV, Ramirez and colleagues turned specifically at the CB2 receptor, a protein located on the surface of the immune cells macrophages. CB2 is a binding site for cannabinoids, the primary active compounds of cannabis(marijuana), and it may potentially play a role in blocking inflammation in the central nervous system. Unlike its twin and counterpart, the CB1 receptor, which is found primarily on neurons in the brain, which is its primary target, CB2 does not mediate the psychoactive effects for which cannabis is popularly known.

Ramirez says that there has been much pharmacological interest in developing agents that selectively target CB2 over the recent years. In an ideal system, these compounds would help limit and alleviate chronic inflammatory responses and would not bind to CB1, not causing any adverse reactions. The most promising compounds are those derived from THC (tetrahydrocannabinol), the main active substance in cannabis.

The potential development of such drugs, however, depends largely on knowing which cells exactly harbor HIV. Earlier studies suggested that T cells, integral components of the immune system, are among the main HIV reservoirs. The Temple research team, however, chose to focus on macrophages, which are a type of white blood cell that primarily performs phagocytosys, it engulfs and destroys foreign agents. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals.

According to Ramirez and the study's senior investigator, Yuri Persidsky, MD, PhD, Chair of the Department of Pathology and Laboratory Medicine at TUSM, macrophages likely present the primary reservoir for HIV. They are among the first cells to become infected following sexual transmission of the virus, largely due to their primary function, and they are found in every organ of the human body and circulate in the blood and move more-less freely though tissues.. It is currently thought that macrophages may be responsible for introducing HIV into the brain, eventually initiating HIV-associated cognitive decline.

The research teams made this discovery by conducting a series of experiments in a well-established, often used and non-clinical HIV macrophage cell model. The experiments began by treating the HIV-infected cells with one of three different synthetic CB2-activating compounds. The cells were then sampled and tested periodically to measure the activity of an enzyme called reverse transcriptase, which is essential for HIV replication. After seven days, the team found that all three compounds had successfully attenuated HIV replication, slowing it down considerably.

The results suggest that selective CB2 agonists could potentially be used in tandem with existing antiretroviral drugs, opening the door to the creation of new drug therapies for HIV/AIDS. The data also supports the idea that the human immune system could be utilized to fight HIV infection.
"Our study suggests that the body's own natural defenses can be made more powerful to fight some of the worst symptoms of HIV," Persidsky said. He also noted that stimulating CB2 receptors in a similar manner in white blood cells could produce similar benefits against other viral infections.
The new research further highlights the important work being carried out at Temple's Center for Substance Abuse Research. "The compounds we had available through CSAR formed an important aspect of this research," Ramirez said, "From our perspective we were in a better position for in vitro research. We have interesting models and were able to take advantage of our colleagues' knowledge of receptors and cannabinoids to make a unique contribution."

The team plans next to perform further screening studies using other novel CB2 agonists in parallel with studies that can help uncover the molecular events within the cell that regulate the effect of CB2 on HIV.


The experiments and findings are detailed in the May issue of the Journal of Leukocyte Biology.