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HIV infects astrocytes in vivo and egresses from the brain to the periphery - After ATI
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Our data indicates that astrocytes, the most abundant cell type in the brain and the only source of HIV in our model, harbor HIV DNA/RNA in vivo and that HIV from infected astrocytes egresses, likely through trafficking of CD4+ T cells, into peripheral organs, as indicated by detection of HIV DNA/RNA in spleen and lymph nodes and viral outgrowth assays......When cART treatment was interrupted, HIV DNA/RNA became detectable in the spleen - indicating a rebound of the viral infection....The researchers found that the transplanted HIV-infected astrocytes were able to spread the virus to CD4+ T cells in the brain. These CD4+ T cells then migrated out of the brain and into the rest of the body, spreading the infection to peripheral organs such as the spleen and lymph nodes. They also found that HIV egress from the brain occurred, albeit at lower levels, when animals were given cART....."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," said Dr. Al-Harthi. "It also shed light on the role of astrocytes in supporting HIV replication in the brain - even under cART therapy."
To model HIV rebound after cART interruption, animals were injected with HIV+ astrocytes, began cART treatment five days later and three days after that were reconstituted with huPBMCs. Animals were treated with cART for three weeks after reconstitution then cART was interrupted for ten days till sacrifice. Rebound viral DNA and RNA were detected in the spleen at time of sacrifice (Fig 8B and 8C). These results indicate that astrocytes release low levels of HIV even under cART administration, albeit cART penetration into CNS and other tissue is less than in periphery. Following cART interruption virus rebound is likely due to new rounds of peripheral infection.
This CSF viral escape is associated with neurological impairment, suggesting that residual HIV replication within the CNS under cART drives neuropathogenesis [69] and perhaps may also contribute to HIV genetic evolution within and outside of the brain......Detection of HIV egress initiated from HIV infected astrocytes in the brain to peripheral organs under cART suggests that low level HIV production in the brain may contribute to the emergence of HIV viral blips, which are detected in the CSF and periphery during cART. cART was initiated prior to PBMC reconstitution and we used cART doses that are reported to support viral suppression [65], albeit cART in general has low penetrance into the CNS [66] and as such cART may not fully suppress HIV replication in the CNS. Although we did observe a dramatic reduction in HIV egress under cART, egress was not completely eliminated. This phenomenon is also observed in HIV+ patients in which about 20% of individuals on cART have detectable HIV in the cerebrospinal fluid (CSF) despite complete viral suppression in the periphery, including individuals on decade-long suppressive therapy [67,68]. This
Most significantly, the ability of HIV to egress from the brain to the periphery demonstrates that this sanctuary site is not an isolated viral reservoir but rather one that can contribute to ongoing HIV evolution in peripheral organs. Indeed, we demonstrated that HIV originating from astrocytes led to evolution of peripheral HIV.
The consequence of this neuroinvasion is the induction of inflammatory responses that culminate in the manifestation of HIV-Associated Neurocognitive Disorders (HAND), persistence of HIV in the CNS at a steady state despite combination antiretroviral therapy (cART), and HIV compartmentalization as indicated by the presence of HIV genetic sequences in the CNS that are distinct from those in the plasma and lymphoid tissue; although the exact source of HIV remains unidentified, some of these virus are macrophage-tropic
We demonstrate that astrocytes support HIV infection in vivo and egress to peripheral organs, at least in part, through trafficking of infected CD4+ T cells out of the brain. Astrocyte-derived HIV egress persists, albeit at low levels, under combination antiretroviral therapy (cART). Egressed HIV evolved with a pattern and rate typical of acute peripheral infection. Lastly, analysis of human cortical or hippocampal brain regions of donors under cART revealed that astrocytes harbor between 0.4–5.2% integrated HIV gag DNA and 2–7% are HIV gag mRNA positive. These studies establish a paradigm shift in the dynamic interaction between the brain and peripheral organs which can inform eradication of HIV reservoirs.
We demonstrate astrocyte-initiated HIV spread from the brain to the spleen and lymph nodes, likely through T cell trafficking out of CNS and into peripheral organs. Additionally, brain sections from patients on cART show HIV integration in astrocytes. Collectively, given that astrocytes constitute ∼60% of brain cells and even with a conservative rate of infection at >3%, astrocytes can be a significant reservoir for HIV. As such, cure initiatives must consider the contribution of the CNS to ongoing HIV replication within and outside of the brain.
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Thursday, June 11, 2020
Brain cells can harbor and spread HIV virus to the body
NIH-funded study highlights the importance of addressing the brain in HIV cure strategies.
https://www.nih.gov/news-events/news-releases/brain-cells-can-harbor-spread-hiv-virus-body
Researchers have found that astrocytes, a type of brain cell can harbor HIV and then spread the virus to immune cells that traffic out of the brain and into other organs. HIV moved from the brain via this route even when the virus was suppressed by combination antiretroviral therapy (cART), a standard treatment for HIV. The study, conducted by researchers at Rush University Medical Center in Chicago and published in PLOS Pathogens, was funded by the National Institutes of Health.
"This study demonstrates the critical role of the brain as a reservoir of HIV that is capable of re-infecting the peripheral organs with the virus," said Jeymohan Joseph, Ph.D., chief of the HIV Neuropathogenesis, Genetics, and Therapeutics Branch at NIH's National Institute of Mental Health, which co-funded the study. "The findings suggest that in order to eradicate HIV from the body, cure strategies must address the role of the central nervous system."
HIV attacks the immune system by infecting CD4 positive (CD4+) T cells, a type of white blood cell that is vital to fighting off infection. Without treatment, HIV can destroy CD4+ T cells, reducing the body's ability to mount an immune response - eventually resulting in AIDS.
cART, which effectively suppresses HIV infections, has helped many people with HIV live longer, healthier lives. But some studies have shown that many patients receiving antiretroviral drugs also show signs of HIV-associated neurocognitive disorders, such as thinking and memory problems. Researchers know that HIV enters the brain within eight days of infection, but less is known about whether HIV-infected brain cells can release virus that can migrate from the brain back into the body to infect other tissues.
The brain contains billions of astrocytes, which perform a variety of tasks-from supporting communication between brain cells to maintaining the blood-brain barrier. To understand whether HIV can move from the brain to peripheral organs, Lena Al-Harthi, Ph.D.(link is external), and her research team at Rush University Medical Center transplanted HIV-infected or noninfected human astrocytes into the brains of immunodeficient mice.
The researchers found that the transplanted HIV-infected astrocytes were able to spread the virus to CD4+ T cells in the brain. These CD4+ T cells then migrated out of the brain and into the rest of the body, spreading the infection to peripheral organs such as the spleen and lymph nodes. They also found that HIV egress from the brain occurred, albeit at lower levels, when animals were given cART. When cART treatment was interrupted, HIV DNA/RNA became detectable in the spleen - indicating a rebound of the viral infection.
"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," said Dr. Al-Harthi. "It also shed light on the role of astrocytes in supporting HIV replication in the brain - even under cART therapy."
This information has significant implications for HIV cure strategies, as such strategies need to be able to effectively target and eliminate reservoirs of HIV replication and reinfection, Dr. Al-Harthi added.
"HIV remains a major global public health concern, affecting 30 to 40 million people across the globe. To help patients, we need to fully understand how HIV affects the brain and other tissue-based reservoirs," said May Wong, Ph.D., program director for the NeuroAIDS and Infectious Diseases in the Neuroenvironment at the NIH's National Institute of Neurological Disorders and Stroke, which co-funded the study. "Though additional studies that replicate these findings are needed, this study brings us another step closer towards that understanding."
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HIV infects astrocytes in vivo and egresses from the brain to the periphery
June 11, 2020
Abstract
HIV invades the brain during acute infection. Yet, it is unknown whether long-lived infected brain cells release productive virus that can egress from the brain to re-seed peripheral organs. This understanding has significant implication for the brain as a reservoir for HIV and most importantly HIV interplay between the brain and peripheral organs. Given the sheer number of astrocytes in the human brain and their controversial role in HIV infection, we evaluated their infection in vivo and whether HIV infected astrocytes can support HIV egress to peripheral organs. We developed two novel models of chimeric human astrocyte/human peripheral blood mononuclear cells: NOD/scid-IL-2Rgc null (NSG) mice (huAstro/HuPBMCs) whereby we transplanted HIV (non-pseudotyped or VSVg-pseudotyped) infected or uninfected primary human fetal astrocytes (NHAs) or an astrocytoma cell line (U138MG) into the brain of neonate or adult NSG mice and reconstituted the animals with human peripheral blood mononuclear cells (PBMCs). We also transplanted uninfected astrocytes into the brain of NSG mice and reconstituted with infected PBMCs to mimic a biological infection course. As expected, the xenotransplanted astrocytes did not escape/migrate out of the brain and the blood brain barrier (BBB) was intact in this model. We demonstrate that astrocytes support HIV infection in vivo and egress to peripheral organs, at least in part, through trafficking of infected CD4+ T cells out of the brain. Astrocyte-derived HIV egress persists, albeit at low levels, under combination antiretroviral therapy (cART). Egressed HIV evolved with a pattern and rate typical of acute peripheral infection. Lastly, analysis of human cortical or hippocampal brain regions of donors under cART revealed that astrocytes harbor between 0.4–5.2% integrated HIV gag DNA and 2–7% are HIV gag mRNA positive. These studies establish a paradigm shift in the dynamic interaction between the brain and peripheral organs which can inform eradication of HIV reservoirs.
Author summary
HIV latency and residual low-level HIV replication is a major obstacle towards an HIV cure. HIV infects the brain in acute disease yet it is unknown whether long lived-infected brain cells release productive virus that can egress from the brain to re-seed peripheral organs and whether astrocytes are productively infected in vivo. We demonstrate astrocyte-initiated HIV spread from the brain to the spleen and lymph nodes, likely through T cell trafficking out of CNS and into peripheral organs. Additionally, brain sections from patients on cART show HIV integration in astrocytes. Collectively, given that astrocytes constitute ∼60% of brain cells and even with a conservative rate of infection at >3%, astrocytes can be a significant reservoir for HIV. As such, cure initiatives must consider the contribution of the CNS to ongoing HIV replication within and outside of the brain.
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