HIV May Hide Out In Brain Cells Ready To Infect Other Organs

September 24, 2020

A new study in mice and human tissues shows that HIV can take refuge in the brain even while on antiretroviral therapy, only to later infect other organs of the body if that therapy is discontinued.

Untreated HIV, the virus that causes AIDS, cripples the immune system and leaves the body vulnerable to life-threatening diseases. Combination antiretroviral therapy, or cART, can significantly reduce the concentration of the virus in the body, to the point where the pathogen can become undetectable, symptoms essentially disappear and the treated person is no longer infectious to others. But cART must be taken daily, and if treatment is suspended, the virus may reemerge from its hidden refuge in the body.

New research published June 11 in the journal PLOS Pathogens suggests that one of these hiding places is in brain cells called astrocytes. Astrocytes make up about 60 percent of the total cells in the human brain, the report says, and the study authors estimate that in an infected person, 1 to 3 percent of these cells may harbor HIV.

“Even 1 percent could be important as a repository, a refuge, for the virus,” said study author Lena Al-Harthi, who is professor and chair of the Department of Microbial Pathogens and Immunity at Rush University Medical Center in Chicago.” If we’re going to try to find a cure for HIV, you can’t ignore the role of the brain as a reservoir.”

Al-Harthi and her colleagues drew their conclusions from HIV mouse models that were injected with human cells, as well as from examinations of postmortem human brain tissue. One expert told Live Science that while both experiments provide insight into the role of astrocytes in HIV infection, more work must be done to determine exactly how the virus takes root in human patients.

“Animal models can tell us quite a bit. They’re not human, but they can give us quite a bit of information,” said Dr. Lishomwa Ndhlovu, a professor of medical immunology at Weill Cornell Medical College, who was not involved in the study. If astrocytes can serve as a reservoir for HIV in human infections and the virus can exit the brain and trigger infections elsewhere, as mouse studies have shown, “we really need to figure out how to eliminate the virus from these compartments” to design successful therapies, he said.

lying in wait for a cure
Astrocytes, named for their star-shaped shape, have multiple subtypes and play a key role in the central nervous system, according to BrainFacts.org, a public information initiative run in part by the Society for Neuroscience. These cells help transport nutrients to neurons or brain cells that transmit electrical signals, and they can stimulate or inhibit inflammatory responses in the brain. Astrocytes also shape and maintain the wiring of the central nervous system and reinforce the blood-brain barrier, a tissue boundary that separates circulating blood from brain cells.

Scientists know that the HIV virus seeps into the brain during infection because infected people can develop dementia and other cognitive impairments.

“The role of astrocytes in HIV infection has been controversial,” Al-Harthi told Live Science.In a 2018 report published in the Journal of Neurovirology, Al-Harthi wrote: “Previous studies have shown that astrocytes can be infected with HIV, but most studies have used cells in petri dishes, which may not be possible in replicating the infection process in live animals”. A few studies have used live animals, but have used “traditional” methods, such as tagging viral proteins or genetic material with fluorescent compounds to scan for the virus, which may not be sensitive enough to accurately detect low levels of HIV present in astrocytes.No studies have attempted to address whether, once infected, astrocytes somehow release HIV into organs other than the brain.

Al-Harthi and her team have developed two new mouse models to address this critical question.

First, the authors placed human fetal astrocytes derived from extracted brain tissue in a Petri dish and infected the cells with HIV. They then injected the infected cells into the brains of laboratory mice, one group of newborn mice and one group of adult mice. They found that in both groups of mice, the infected astrocytes passed the virus on to CD4 cells – an immune cell that helps coordinate the body’s immune response and is a specific target of the HIV virus.

After receiving infection from the astrocytes, the infected CD4 cells migrate out of the brain and into other tissues. When “the brain has been seeded, the virus can come out and re-seed the surrounding organs,” Al-Harthi said.

The authors specifically note that the spleen and lymph nodes can become infected as a result of this process. By blocking the movement of CD4 cells, the authors were able to cut this chain of viral transmission.

To ensure that the virus could infect astrocytes on its own without the assistance of astrocytes, the authors also conducted an experiment in which healthy human astrocytes were injected into mice, after which the animals were infected with HIV.In this case, some human astrocytes remained infected and released HIV into other parts of the body. Notably, the virus in the brains of mice treated with cART was still able to escape, “albeit at very low levels,” compared to untreated mice. If the treatment was discontinued, the virus in the brains triggered a full-blown infection.

To confirm the aspect of their mouse experiment, the authors examined the donor brains of four HIV-infected individuals, all of whom received effective cART treatment. (The report did not specify how each donor died, but noted that the virus was effectively suppressed by cART at the time of death). The team found that the nuclei of a small group of astrocytes contained HIV genetic material, suggesting that the cells were already infected.

Working towards a cure for the virus
Many questions about astrocytes and HIV remain to be answered. For example, some subtypes of astrocytes may act as reservoirs for HIV, while others do not, Al-Harthi said. And while mouse experiments have shown that HIV can exit the brain, postmortem tissue analysis could not confirm that the same thing happens in humans.

Al-Harthi says, “Animal models, none of them are perfect.” As a result, there may be differences in the way infection unfolds in humans.

For example, during natural HIV infection, the virus accumulates genetic mutations each time it replicates, and the genetic material needed for infection is lost in the process, Ndhlovu said. To fully understand the role of astrocytes in HIV, researchers need to determine how much of the virus present in human astrocytes can actually trigger infection, he said.

Ndhlovu said Al-Harthi and her team began to address this question by examining postmortem brain tissue and analyzing what fragments of HIV genetic material could be found in it – but further research was needed to confirm that the virus found could both infect cells and migrate to other organs in the body. In addition, scientists need to determine the exact route by which HIV comes out of the brain to infect other organs, as this information is also crucial for developing treatments that target the brain and finding successful treatments, he added.