NeuroImmunology
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HIV Hides Out In Brain-Resident Immune Cells

HIV Hides Out In Brain-Resident Immune Cells | NeuroImmunology | Scoop.it

Studies in living brain tissue found that specialized immune cells in the brain can harbor latent but replication-competent HIV.  As a part of its life cycle, human immunodeficiency virus-1 (HIV-1) inserts a copy of its DNA into human immune cells. Some of these newly infected immune cells can then transition into a dormant, latent state for a long period of time, which is known as HIV latency. Although current antiretroviral therapy (ART) against HIV can successfully block the virus from replicating further, it cannot eradicate latent HIV. If treatment is discontinued, the virus can rebound from latency and reignite the progression of HIV infection to AIDS. Scientists at the HIV Cure Center at the UNC School of Medicine, University of California, San Diego (UCSD), Emory University, and the University of Pennsylvania, have been searching for where exactly these latent cells are hiding in the body. Their newly reported studies indicate that brain microglial (BM)—specialized brain-resident immune cells with a decade-long lifespan—can serve as a stable viral reservoir for latent HIV. “We now know that microglial cells serve as a persistent brain reservoir,” said Yuyang Tang, PhD, assistant professor of medicine in the division of infectious diseases and member of the UNC HIV Cure Center. “This had been suspected in the past, but proof in humans was lacking. Our method for isolating viable brain cells provides a new framework for future studies on reservoirs of the central nervous system, and, ultimately, efforts towards the eradication of HIV.” Tang is first author of the team’s published paper in The Journal of Clinical Investigation, which is titled, “Brain microglia serve as persistent HIV reservoir despite durable antiretroviral therapy.”

 

HIV is a tricky virus to study. During infection, the virus specifically targets CD4+ lymphocytes which are the key coordinators of the immune response. Over time, the virus kills enough CD4+ cells to cause immunodeficiency. Past research has shown that latent HIV can hide within a few of the surviving CD4+ T cells throughout the body and the bloodstream. However, it’s been suspected that there are other viral reservoirs hidden within the central nervous system (CNS) in people with HIV who are receiving effective ART. But as the authors noted, “… rigorous evidence of viral persistence in the CNS cells of humans on durable suppressive ART is incomplete … Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Unlike peripheral blood cells, it is extremely difficult to access and analyze brain tissues for the study of HIV reservoirs. Since these types of cells cannot be safely sampled in people taking ART, the potential viral reservoir in the brain has remained an enigma for many years. For their reported research the team first studied the brains of macaques infected with simian immunodeficiency virus (SIV), a virus that is closely related to HIV, from the Yerkes National Primate Research Center at Emory University to get a better understanding of how to extract and purify viable cells from primate brain tissue. The researchers used physical separation techniques and antibodies to selectively remove cells that were expressing microglial surface markers. Then, they isolated and separated the highly pure brain myeloid cells (BrMCs) from the CD4+ cells that were passing through the brain tissue. Using these techniques, researchers then obtained samples that were donated by HIV+ people (people with HIV; PWH) who were enrolled in “The Last Gift” Study at UCSD. As a part of this unique and important effort, altruistic HIV+ people, who are taking ART but suffering from other terminal illnesses, will their bodies to further the HIV research project.

 

“ … we first developed protocols to isolate highly pure populations of BrMCs and MG from the tissues of nonhuman primates (NHPs),” the authors explained. “We then adapted these protocols to the study of human brain tissues containing large numbers of viable cells after rapid autopsy to explore whether human BrMCs produce replication-competent HIV.” Co-author David Margolis, MD, the Sarah Kenan distinguished professor of medicine, microbiology & immunology, and epidemiology, further noted, “The samples are from people living with HIV, who are on therapy but facing a fatal disease of some kind. They were willing to not just donate their bodies to science, but also participate in the research program in the months leading up to their death. It’s an extraordinary program that made this critical research possible.” The scientists’ findings confirmed that MGs from an individual with HIV, being treated using ART, harbored replication-competent HIV. They acknowledged that although their study was limited by the small number of available samples from human donors on ART, they believe that the findings are consistent with NHP studies. “Our observations support the concept that brain MG are a stable reservoir of quiescent infection and may be a source of viral rebound upon treatment interruption,” they concluded. “Future efforts to clear HIV infection will have to include assessments of the persistence of HIV within CNS MG.” Now that the researchers know that latent HIV can take refuge in microglial cells in the brain, they are now considering plans to target this type of reservoir. Since latent HIV in the brain is radically different from the virus in the periphery, researchers believe that it has adapted special characteristics to replicate in the brain.

 

Reporting in their paper, the team noted, “Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions.” NF-κB signaling is one of the critical signaling pathways that control HIV expression elsewhere in the body. When NF-κB signaling is “turned off,” HIV enters latency in the peripheral blood. However, latent HIV in the brain is not impacted by the activation of NF-κB signaling. Researchers are unsure why that is, but once an answer is found, they will be one step closer to knowing how to selectively target and eradicate the virus in the brain or peripheral blood. In addition to understanding the inner workings of the brain reservoir, the researchers are also trying to determine the true size of the latent HIV brain reservoir. “HIV is very smart,” said senior author Guochun Jiang, PhD, assistant professor in the UNC department of biochemistry and biophysics and member of the UNC HIV Cure Center. “Over time, it has evolved to have epigenetic control of its expression, silencing the virus to hide in the brain from immune clearance. We are starting to unravel the unique mechanism that allows latency of HIV in brain microglia”. Added Margolis, who is also the director of the UNC HIV Cure Center, “It is very hard to know how big the reservoir is. The problem with trying to eradicate HIV is like trying to eradicate cancer. You want to be able to get it all, so it won’t come back.”

 

Original research published in The Journal of Clin. Investigation (June 15, 2023):

https://doi.org/10.1172/JCI167417 

 


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COVID-19 Virus Can Spread to Organs, Including Brain; Live There for Months

COVID-19 Virus Can Spread to Organs, Including Brain; Live There for Months | NeuroImmunology | Scoop.it

New research helps explain why long COVID can occur in people who had mild or asymptomatic COVID-19 cases.  The coronavirus that causes COVID-19, SARS-CoV-2, can spread within days from the airways to the heart, brain and almost every organ system in the body, where it may persist for months, a study found. In what they describe as the most comprehensive analysis to date of the virus’s distribution and persistence in the body and brain, scientists at the U.S. National Institutes of Health said they found the pathogen is capable of replicating in human cells well beyond the respiratory tract. The results, released online Saturday in a manuscript under review for publication in the journal Nature, point to delayed viral clearance as a potential contributor to the persistent symptoms wracking so-called long COVID sufferers. Understanding the mechanisms by which the virus persists, along with the body’s response to any viral reservoir, promises to help improve care for those afflicted, the authors said. “This is remarkably important work,” said Ziyad Al-Aly, director of the clinical epidemiology center at the Veterans Affairs St. Louis Health Care System in Missouri, who has led separate studies into the long-term effects of COVID-19. “For a long time now, we have been scratching our heads and asking why long COVID seems to affect so many organ systems. This paper sheds some light, and may help explain why long COVID can occur even in people who had mild or asymptomatic acute disease.” The findings haven’t yet been reviewed by independent scientists, and are mostly based on data gathered from fatal COVID cases, not patients with long COVID or “post-acute sequelae of SARS-CoV-2,” as it’s also called.

 

Contentious Findings

The coronavirus’s propensity to infect cells outside the airways and lungs is contested, with numerous studies providing evidence for and against the possibility.  The research undertaken at the NIH in Bethesda, Maryland, is based on extensive sampling and analysis of tissues taken during autopsies on 44 patients who died after contracting the coronavirus during the first year of the pandemic in the U.S.  The burden of infection outside the respiratory tract and time to viral clearance isn’t well characterized, particularly in the brain, wrote Daniel Chertow, who runs the NIH’s emerging pathogens section, and his colleagues. The group detected persistent SARS-CoV-2 RNA in multiple parts of the body, including regions throughout the brain, for as long as 230 days following symptom onset. This may represent infection with defective virus, which has been described in persistent infection with the measles virus, they said.  In contrast to other COVID autopsy research, the NIH team’s post-mortem tissue collection was more comprehensive and typically occurred within about a day of the patient’s death. 

Culturing Coronavirus

The NIH researchers also used a variety of tissue preservation techniques to detect and quantify viral levels, as well as grow the virus collected from multiple tissues, including lung, heart, small intestine and adrenal gland from deceased COVID patients during their first week of illness. “Our results collectively show that while the highest burden of SARS-CoV-2 is in the airways and lung, the virus can disseminate early during infection and infect cells throughout the entire body, including widely throughout the brain,” the authors said. The researchers posit that infection of the pulmonary system may result in an early “viremic” phase, in which the virus is present in the bloodstream and is seeded throughout the body, including across the blood-brain barrier, even in patients experiencing mild or no symptoms. One patient in the autopsy study was a juvenile who likely died from unrelated seizure complications, suggesting infected children without severe COVID-19 can also experience systemic infection, they said.

 

Immune Response

The less-efficient viral clearance in tissues outside the pulmonary system may be related to a weak immune response outside the respiratory tract, the authors said.  SARS-CoV-2 RNA was detected in the brains of all six autopsy patients who died more than a month after developing symptoms, and across most locations evaluated in the brain in five, including one patient who died 230 days after symptom onset. The focus on multiple brain areas is especially helpful, said Al-Aly at the Veterans Affairs St. Louis Health Care System.  “It can help us understand the neurocognitive decline or ‘brain fog’ and other neuropsychiatric manifestations of long COVID,” he said. “We need to start thinking of SARS-CoV-2 as a systemic virus that may clear in some people, but in others may persist for weeks or months and produce long COVID -- a multifaceted systemic disorder.”

 

Preprint (Dec. 20, 2021) of the research cited available at:

https://assets.researchsquare.com/files/rs-1139035/v1_covered.pdf?c=1640020576 


Via Juan Lama
Howhighcenter's curator insight, January 11, 2022 9:52 PM

 

Magic Mushroom Compound Called Psilocybin May Help Treat Depression
 

The psychedelic substance found in magic mushrooms, also known as shrooms, can relieve symptoms in people with major depressive disorder, according to a new studyTrusted Source.

While additional research is needed, this study shows the clinical potential of psilocybin, particularly for treating depression that’s resistant to other therapies.

The study was published on November 4 in JAMA Psychiatry.

“This is an extremely important study that advances the study of psychedelics and mental health, but more importantly, offers a new and novel treatment for major depressive disorder,” said Dr. Rakesh Jetly, chief medical officer at Mydecine, who wasn’t involved in the new study.

Twenty-four people completed the study, which involved receiving two doses of psilocybin along with supportive psychotherapy.

Johns Hopkins Medicine researchers reported that the participant’s depressive symptoms improved rapidly, with over two-thirds responding well to the treatment.

Four weeks after psilocybin treatment, over half of the participants met the criteria for remission of their depression.