HIV Infects Astrocytes, Moves From Brain to Periphery

By Will Boggs MD

June 22, 2020

NEW YORK (Reuters Health) - Astrocytes can be infected with HIV and release virus that can move from the brain to the rest of the body, according to a new study in mice.

"We were surprised that a small fraction of infected astrocytes (roughly 2,500 infected astrocytes in a mouse brain that has millions of astrocytes) can still facilitate HIV extravasation from the brain back to the periphery," said Dr. Lena Al-Harthi of Rush University Medical Center, in Chicago.

"Interestingly, the human brain has billions of astrocytes," she told Reuters Health by email. "As such, even with a low rate of HIV infection of astrocytes and mechanisms that induce HIV latency in these cells, bursts of HIV from astrocytes can contribute to the overall viral reservoir outside of the brain."

HIV is known to infect the brain in acute disease, but it has remained unclear whether long-lived infected brain cells release productive virus that can egress from the brain to reseed peripheral organs and whether astrocytes are productively infected in vivo.

Dr. Al-Harthi and colleagues developed a chimeric human astrocytes/human peripheral blood mononuclear cell (PBMC) mouse model to assess the role of astrocytes in supporting productive HIV replication in vivo and their role in disseminating HIV to tissues outside of the brain.

HIV-infected human astrocytes engrafted into NSG mice brains survived and supported HIV replication in vivo without disrupting the blood-brain barrier.

Transplantation of HIV-infected astrocytes into neonatal or adult NSG mice brain resulted in HIV egress from the brain into peripheral organs, the researchers report in PLOS Pathogens.

Virus initiated from astrocytes continued to replicate and evolve/mutate to mimic the viral evolution observed in early peripheral infection.

Depleting PBMCs of both CD4+ T cells and monocytes prior to reconstitution of HIV-infected astrocytes in NSG mice significantly reduced HIV egress into peripheral organs, suggesting that trafficking of infected T cells is responsible for HIV egress out of brain in this model.

Additional experiments showed that astrocytes can be infected as a result of systemic HIV infection and that HIV-infected astrocytes can support low levels of HIV egress from the brain during antiretroviral therapy.

Human brain from HIV-infected donors under effective combination antiretroviral therapy (cART) showed evidence of HIV infection in as many as 7% of astrocytes.

"As astrocytes, microglia/macrophages have all been shown to harbor productive HIV, 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," the authors conclude.

"People living with HIV (PLWH) under anti-HIV therapy and maximum viral suppression experience viral blips and the virus does come back after treatment interruption," Dr. Al-Harthi said. "The field has largely focused on the role of resting memory T cells as a reservoir of HIV, which is targeted for HIV cure strategies. While this focus is justified, it does not address the overall picture of sanctuary sites and especially the role of the brain as an HIV reservoir nor consequence of treatments on the brain."

"The brain is impacted by HIV, both due to direct (virus infection) and indirect (inflammation) effects on the brain, and these effects persist even in the era of" combination antiretroviral therapy, she said. "PLWH may complain of depression and/or neurocognitive impairment, and it is important for physicians to seek the support of neurologists specializing in HIV treatment to support these patients."

SOURCE: PLoS Pathogens, online June 11, 2020.