HIV, the virus that causes AIDS, is shown budding out of an immune cell, which the virus infects and uses to replicate.NIH, via Wikimedia Commons
For more than 20 years, powerful drug combinations of antiretroviral drugs have been available to treat people with HIV infection, and these agents have dramatically raised life expectancy for HIV-infected patients from 36 to 49 years of age.
Though combinatorial antiretroviral therapies (CART) reduces viral
loads to undetectable levels in the blood, HIV can hide within the
central nervous system, where it can integrate into the genomes of brain
cells called microglia – the immune cells of the brain.
In the brain, HIV continues to produce viral proteins and damage both
infected and non-infected cells in the brain, boosting the risk for
dementia, addiction and other neurological problems. Everyone with HIV
will experience this, since HIV integrates into the genome and CART has
issues crossing into the brain. The question is: why?
HIV proteins dysregulate dopamine signaling
To answer this, we used a mouse in which we can control the levels of
HIV viral protein in order to probe the link between HIV infection and
neurological disease.
Our lab discovered that an HIV protein, called HIV-1 Tat, reduces the
level of an important protein required for the production of a
dopamine, a neurotransmitter, in the brain.
Dopamine is produced by neurons in the central nervous system and by immune cells in the blood. Using a confocal microscope
to see fine details, my colleagues and I carefully examined the
dopamine producing areas in the brains of mice containing HIV-1 Tat
protein and were surprised to discover that the neurons were alive. But,
many that normally produced dopamine were unable to produce as much. We
also found that an enzyme necessary to make dopamine, called tyrosine
hydroxylase, was no longer detectable in some neurons. This suggests
that the mice can’t make as much dopamine.
When microglial cells secrete the HIV-1 Tat protein, it is able to
enter dopamine neurons and lower their activity so that they produce
less dopamine. That reduces their ability to communicate with other
cells in the brain, which can disrupt the ability to move and reward
related behaviors. Also, low levels of dopamine in an area of the brain
called the substantia nigra is a hallmark of Parkinson’s and
predisposes patients to depression and addiction to drugs like methamphetamine and cocaine.
The results of our research, published in the journal Glia,
reveal how HIV patients are more vulnerable to neurological and
neuropsychiatric conditions that are somehow tied to disrupting dopamine
levels in the brain.
There is clearly more to treating HIV that curbing levels of the
virus in the blood. The medical community needs treatments that reverse
the long-term consequences of HIV infection in the brain.
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