HIV, the virus that causes AIDS, is
notorious for hiding within certain types of cells, where it reproduces at a
slowed rate and eventually gives rise to chronic inflammation, despite drug
therapy. But researchers at Temple University School of Medicine's Department
of Pathology and Laboratory Medicine and Center for Substance Abuse Research
(CSAR) recently discovered that synthetic anti-inflammatory substances
distantly related to the active ingredient of marijuana may be able to take the
punch out of HIV while inside one of its major hideouts -- immune cells known
as macrophages.
The breakthrough comes at a crucial
time in the HIV/AIDS pandemic. "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. But
living longer with HIV means extended exposure to low levels of HIV replication
and associated inflammation. In the central nervous system (CNS), this
inflammatory process is thought to be the underlying cause of HIV-associated
neurocognitive disorder (HAND), a spectrum of conditions that is on the rise
again after more than a decade of decline following the advent of
antiretroviral therapy.
To better understand the connection
between inflammation and neurocognitive conditions linked to long-term exposure
to HIV, Ramirez and colleagues looked specifically at the CB2 receptor, a
protein located on the surface of macrophages. CB2 is a binding site for
substances called cannabinoids, the primary active compounds of cannabis
(marijuana), and it may play a role in blocking inflammation in the CNS. Unlike
its counterpart, the CB1 receptor, which is found primarily on neurons in the
brain, CB2 does not mediate the psychoactive effects for which cannabis
is popularly known.
Ramirez explained that there has
been much pharmacological interest in developing agents that selectively target
CB2. Ideally, these compounds would help limit chronic inflammatory responses
and would not bind to CB1. The most promising compounds are those derived from
THC (tetrahydrocannabinol), the main active substance in cannabis.
The development of such drugs,
however, hinges largely on knowing which cells harbor HIV. Earlier studies
suggested that T cells, central components of the immune system, are HIV
reservoirs. The Temple team, however, chose to focus on macrophages, which are
a type of white blood cell that engulfs and destroys foreign agents.
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 are the primary
reservoir for HIV. They are among the first cells to become infected following
sexual transmission of the virus, and they are found in every organ of the
human body and circulate in the blood. It is currently thought that macrophages
may be responsible for introducing HIV into the brain, ultimately initiating
HIV-associated cognitive decline.
The scientists landed on their
discovery by conducting a series of experiments in a well-established,
non-clinical HIV macrophage cell model. They began by treating the HIV-infected
cells with one of three different synthetic CB2-activating compounds. The cells
were then sampled 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. The experiments and findings are detailed in the May issue of the Journal
of Leukocyte Biology.
The results suggest that selective
CB2 agonists could potentially be used in tandem with existing antiretroviral
drugs, opening the door to the generation of new drug therapies for HIV/AIDS.
The data also support the idea that the human immune system could be leveraged
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 explained. He also noted that
stimulating CB2 receptors 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 (CSAR). "The compounds we had available through CSAR formed an
important aspect of this research," Ramirez said.
Persidsky added, "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.
SOURCE: http://www.sciencedaily.com/releases/2013/05/130501132053.htm
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