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HIV Shelters in Astrocytes and Infected T Cells Carry Virus to Peripheral Organs

Article In Brief

Investigators have found reservoirs of HIV in astrocytes and observed activated virus infecting immune cells reaching peripheral organs through leukocyte trafficking. These results may explain why patients often have neurocognitive deficits even while on antiretroviral medication.

Figure

The image show HIV infection of CD4+ T cells in the mouse brain. Human T cells (magenta), human astrocytes (red), HIV (green), nuclei (Blue). Arrows identify uptake of HIV from astrocytes into T cells.

Researchers have discovered reservoirs of human immunodeficiency virus (HIV) in astrocytes and have observed activated virus infecting immune cells that pass through the blood-brain barrier to infect peripheral organs.

Only a relatively small number of infected astrocytes were found to be reservoirs for HIV—a possible explanation for why postmortem examinations of brain tissue have yielded inconclusive or negative results of infection or dormant virus, said lead investigator Lena Al-Harthi, PhD, professor and chair of immunology at Rush Medical College in Chicago.

Dr. Al-Harthi led a group of researchers at several academic immunology centers across the United States, who transplanted HIV-infected or noninfected human astrocytes into the brains of immunodeficient mice, then observed activated virus infect CD4+ T cells and carry infection to peripheral organs. The groups' findings were reported June 11 in the journal PLOS Pathogens.

“There is considerable debate regarding the role of the brain in HIV infection, and astrocytes in particular, as a reservoir for HIV,” said Dr. Al-Harthi. “Our study demonstrates that HIV in the brain is not trapped in the brain—it can and does move back into peripheral organs through leukocyte trafficking.”

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“What is clear, moving forward, is that in developing any effective HIV therapy to potentially eradicate the virus in patients we also need to consider the brain.”—DR. BEAU M. ANCES

The findings might help explain why many patients have neurocognitive deficits despite taking the current regimens of antiretroviral drug cocktails, she told Neurology Today. Postmortem brain tissue samples from HIV-infected patients also confirmed the findings of small sanctuaries of HIV in astrocytes.

HIV DNA and RNA was found in spleen, lymph node samples, and viral outgrowth assays in the infected mice, and migration continued, at low levels, even when the mice were exposed to combination antiretroviral therapy (cART). Moreover, when cART was interrupted, HIV DNA/RNA became detectable in the spleen, an indication of viral rebound, she said.

“Our study demonstrates that HIV in the brain is not trapped in the brain; it can and does move back into peripheral organs through leukocyte trafficking,” Dr. Al-Harthi told Neurology Today. “It also sheds light on the role of astrocytes in supporting HIV replication in the brain, even under cART therapy.”

Integrated HIV DNA and RNA was detected in 0.4 percent to 5.2 percent of astrocytes in human cortical or hippocampal brain sections of patients who had been receiving cART, and 2 percent to 7 percent of tissue samples tested positive for HIV RNA. Similar levels were detected in the test mice.

“It is of interest that the reported rate of HIV infection in the animal model and postmortem human tissue is comparable,” Dr. Al-Hathi said. “This is a potential explanation for our understanding that the rate of astrocyte infection is very low, and the majority of cells are not typically infected.”

“Collectively, our studies demonstrate an in vivo role of brain astrocytes in supporting ongoing HIV replication, mediating HIV egress from the CNS to peripheral organs through T cell trafficking in and out of the CNS, and potentially creating an environment within the CNS that is supportive for low level HIV production under cART,” she explained.

“The brain must be considered as an important reservoir/sanctuary site that under the appropriate signal(s) may become reactivated and spread HIV to peripheral organs, further complicating HIV cure efforts.”

Figure

“There is considerable debate regarding the role of the brain in HIV infection, and astrocytes in particular, as a reservoir for HIV. Our study demonstrates that HIV in the brain is not trapped in the brain—it can and does move back into peripheral organs through leukocyte trafficking.”—DR. LENA AL-HARTHI

Expert Commentary

“The findings suggest that in order to eradicate HIV from the body, cure strategies must address the role of the central nervous system,” said Beau M. Ances, MD, PhD, FAAN, professor of neurology at Washington University School of Medicine Center for Advanced Medicine Neuroscience Center in St. Louis.

“A lot more work needs to be done, but this study demonstrates that astrocytes are a reservoir, and that cross-talk takes place between HIV-infected cells in the brain and immune cells, and this can go back and forth to peripheral organs like the spleen. We see HIV-related neurocognitive issues in patients despite cART, and the question is why? If it is because of small reservoirs in astrocytes, then we will really need to work on targeting them.”

However, he noted that because only a very small number of astrocytes, maybe 1 percent to 3 percent, appear to harbor HIV, it remains unclear if this alone is responsible for neurocognitive problems in infected patients.

“The question is whether this amount is enough for a clinically significant impact, and we don't know that yet.”

Some therapeutic drugs get into the brain, but others do not, and it remains unknown if higher penetrating agents might address HIV reservoirs in astrocytes, he told Neurology Today.

“What is clear, moving forward, is that in developing any effective HIV therapy to potentially eradicate the virus in patients we also need to consider the brain.”

Christina Marra, MD, FAAN, professor of neurology at the University of Washington Harborview Medical Center in Seattle, told Neurology Today that the issue of whether the brain can serve as an HIV reservoir, and needs to be taken into account in HIV eradication strategies, remains unresolved.

“Certainly, if astrocytes are a reservoir of HIV, a ‘kick and kill’ strategy, where latent cellular infection is activated and the host cell subsequently killed, could be harmful,” she said.

“The careful experiments described in this paper support the idea that astrocytes may indeed be a reservoir of HIV, and while the number of astrocytes that are HIV infected may be small, the enormous number of astrocytes in the human brain could translate into a large reservoir.”

In the researchers' mouse model, she said, astrocytes are productively infected and this infection can lead to seeding of the periphery by HIV.

“However, translating these results to the human situation is a bit tricky. In the study, mouse brains are transplanted with HIV infected human astrocytes, and the astrocyte infection occurs in vitro. But we don't know how it compares with the situation in vivo in humans,” Dr. Marra noted.

“The experimental mice were immune incompetent due to infusion of human peripheral blood mononuclear cells sometime later, which is not similar to the situation in humans.”

Disclosures

Drs. Al-Harthi, Ances, and Marra had no relevant disclosures.

Link Up for More Information

• Lutgen V, Narasipura SD, Barbian HJ, et al. HIV infects astrocytes in vivo and egresses from the brain to the periphery https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008381. PLOS Pathogens, 2020;16:e1008381.