Methamphetamine drastically increases virus’ ability to replicate in brain tissue

A controversial research study here has found that exposing cells infected with feline immunodeficiency virus – a surrogate for HIV – to methamphetamine increases those cells’ ability to replicate the deadly virus as much as 15-fold.

The finding, if confirmed by ongoing animal studies, could answer important questions about how lentiviruses such as FIV and HIV can gain a foothold in the brain. That knowledge is vital in slowing or lessening the dementia that often accompanies AIDS and similar diseases.

Ohio State University researchers reported this finding in a paper to be published in the next issue of the Journal of NeuroVirology.

The paper also reports that before a nerve cell can become infected with the virus, it must be associated with a specific type of lymphocyte, or immune cell. Lastly, the researchers discovered that once the virus infects the cells, it mutates into a form that no longer needs this immune-cell association to reproduce.

“We found that after about two weeks of chronic methamphetamine exposure, the ability of these infected cell lines to mass-produce virus increases dramatically,” explained Michael Podell, a professor of veterinary clinical sciences and neurosciences.

The concentration of the drug the cells were exposed to was equal to an average level of methamphetamine in an adult abuser’s bloodstream, Podell said.

Like HIV, or human immunodeficiency virus, FIV belongs to a family of pathogens called lentiviruses. Lentivirus infections are particularly problematic since these viruses can escape detection by a healthy immune system, mutate quickly and lead to life-long infections in the host, Podell said.

FIV is one of the principal stand-ins for studies of HIV since the viruses are closely related. Studies of this kind using HIV cannot be done safely or ethically in humans.

Viruses spread within the body by first breaching the cell wall and taking up residence within the cellular environment. Once there, the virus begins replicating, or reproducing, until its numbers are so great the cell literally bursts, spreading the virus to nearby cells and throughout the bloodstream.

The Ohio State researchers focused on astrocytes, nerve cells that may make up as much as half of the brain but which for a long time were thought to play a minimal role. Recent research has shown that astrocytes are among the most important cells in the brain and may play a key role in immunity. While scientists had known that FIV and HIV could infect astrocytes, they believed the infection was merely a latent one with the virus remaining almost in dormancy.

Podell, along with colleagues Lawrence Mathes, professor of veterinary biosciences and director of OSU’s Center for Retroviral Research, and Mikhail A. Gavrilin, a research scientist in the Department of Veterinary Clinical Sciences, found that FIV is only able to infect astrocytes when they are associated with a peripheral blood mononuclear cell, or PBMC.

A receptor molecule on the astrocyte’s cell membrane allows the virus to enter the astrocyte, the researchers found. Both FIV and HIV are able to use the same receptor – CXCR4 – on astrocytes and on immune system cells. They believe CXCR4 may be the principal receptor for all lentiviruses on astrocytes.

The researchers noticed that once it had infected the astrocytes, the virus began to rapidly reproduce – an observation that was contrary to scientists’ belief that FIV resulted only in a latent infection. “We found that the reason the virus multiplies so rapidly is that it mutates into a different strain,” Podell said, one that isn’t dependent on the presence of the other PBMC cells.

This virus strain – MD-A – appears to be completely independent of any immune system interaction. “That means that any drugs intended to interfere with, or influence the immune system may have absolutely no effect on the astrocyte infection in the brain,” Podell said.

The experiments with methamphetamine exposure to the cells were surprising to the researchers.

“We found that if you treat these astrocyte cell lines with methamphetamine at the time that they are infected with FIV, and if you continuously expose them to the drug, you can see as much as a 15-fold increase in viral replication,” Podell said.

“You can basically take this cell that normally has a limited ability to consistantly replicate virus and just dramatically turn it on, simply by adding methamphetamine.”

The research team is now analyzing data obtained from as series of experiments that used cats as an animal model. If the findings are corroborated in the animals, Podell and his colleagues will try to unravel the precise mechanisms that are controlling FIV infection in these cells.

“The most difficult issue lies ahead, and that is understanding what mechanism is occurring and potentially discovering how to stop or block viral infection and replication in this environment,” he said.

The project was supported by grants from the National Institute on Drug Abuse and the National Institutes of Health.