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An atlas of HIV’s favorite targets in the blood of infected individuals

Gladstone researchers have identified the blood cells most likely to be targeted by HIV during a real-life infectionCredit: Photo: Gladstone

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Gladstone researchers have identified the blood cells most likely to be targeted by HIV during a real-life infection

SAN FRANCISCO, CA–April 27, 2021–In the 40-some years since the beginning of the HIV/AIDS epidemic, scientists have learned a lot about the virus, the disease, and ways to treat it. But one thing they still don’t completely understand is which exact cells are most susceptible to HIV infection.

Without this knowledge, it is difficult to envision targeting these cells to protect the millions of people who encounter the virus for the first time every year, or the infected people in which infection will likely rebound if they go off therapy.

Scientists have known for a long time that the virus homes in on so-called memory CD4+ T cells, a type of cell that helps the human body build lasting immunity against pathogens. But that is still too broad a category to target for therapy.

“CD4+ T cells orchestrate the immune response against all kinds of pathogens, so you can’t just eliminate them to prevent HIV infections,” says Gladstone Associate Investigator Nadia Roan, PhD. “But if you can find the more specific subsets of CD4+ T cells that are highly susceptible to HIV infection, you may be able to specifically target those cells without detrimental side effects.”

Much knowledge about HIV infection comes from in vitro experiments (in a petri dish), where scientists expose CD4+ T cells cultured in the lab to the virus. These cell cultures are not a perfect model for the human body’s complex ecosystems in which infection normally takes place. Might in vitro infection yield a skewed view of the virus’s preference?

To answer this question, Roan and her team compared CD4+ T cells infected in vitro to the CD4+ T cells circulating in the blood of 11 individuals at various stages of infection. Some blood samples were taken before the donors had started treatment with antiretroviral therapy, some after. Yet others came from individuals who had stopped their treatment and were experiencing new rounds of infection.

Using technology they have honed over the years, the researchers established a detailed atlas of the CD4+ T cells in individuals not on antiretroviral treatment, which they have now published in the scientific journal Cell Reports.

“Our work affords novel insight into the basics of how HIV behaves in the human body, rather than just in a lab dish,” says Roan, who is also an associate professor of urology at UC San Francisco. “It informs our understanding of what really happens during an active infection, which is interesting in its own right. Moreover, we know that some infected cells become reservoirs of latent virus, so our work could help us better understand how the reservoir forms during an infection.”

The technology Roan and her team deployed, called CyTOF/PP-SLIDE, distinguishes cells with exquisite precision based on the proteins they contain or carry on their surface. With this information, the scientists can classify CD4+ T cells into myriad subsets, and then determine whether some subsets are more susceptible to infection than others.

A crucial perk of this technology is that it can trace infected cells back to their original state prior to infection.

“That’s important,” says Guorui Xie, PhD, a postdoctoral researcher in Roan’s lab and the first author of the study. “We know that when HIV infects cells, it remodels the cells such that they no longer contain the exact same levels of proteins as they did before infection. With CyTOF/PP-SLIDE, we can identify the uninfected cells that most closely match the infected ones in the same patient. These uninfected cells can give us important information about what the cells targeted by HIV resembled before the virus remodeled them.”

Roan’s team found that remodeling was indeed extensive in blood CD4+ T cells infected in vivo (in people) as well as in vitro. In the process, they made a surprising finding about one of HIV’s preferred targets. Prior studies have suggested that HIV prefers to infect a subtype of CD4+ T cells, called Tfh, and Roan’s team confirmed these cells to be susceptible to HIV. However, they also discovered that the virus can infect non-Tfh cells and remodel them such that they adopt features of Tfh cells.

“This result strikes a cautionary note in our field,” says Roan. “You really can’t tell which cells HIV prefers to target simply by looking at infected cells. You need to know what the cells looked like before remodeling.”

The scientists also found that remodeling causes infected blood cells to alter their surface in ways that may change how they move through the body. Roan prudently speculates that this might help the virus steer infected cells toward sites where it can infect even more cells.

“Whatever its exact purpose, remodeling is probably not just a chance event,” adds Roan. “A virus as small as HIV depends crucially on the resources provided by its host to grow and spread. It’s likely that nothing the virus does to its host cell is an accident.”

The profile of HIV’s favorite cells differed somewhat between in vitro and in vivo infections. Nevertheless, the researchers found one subset of cells that was preferentially infected in both cases, and could become a useful model for further lab studies.

The team also confirmed that not all CD4+ T cells are equally susceptible to HIV infection in vivo, which gives them hope that the most susceptible cells could eventually become targets of preventive interventions.

Xie and Roan are now planning to obtain blood samples from more donors to see whether HIV’s targets differ between a first infection and the return of the virus after a lapse in therapy, or between men and women. Ultimately, they would also like to look at in vivo-infected cells from mucosal tissues such as the gut and genital tract, where most HIV infections begin. But these samples are much harder to procure.

In the meantime, the researchers are making public the atlas of all the cells they have analyzed, along with the dozens of proteins they found to be affected in these cells after HIV infection, which they hope will be a valuable resource for the HIV research community.

“There is still much to discover in this atlas that may help uncover new insights into HIV infection and how it develops, and perhaps lead to the identification of new approaches for HIV/AIDS prevention,” says Roan.

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About the Study

The paper “Characterization of HIV-induced remodeling reveals differences in infection susceptibility of memory CD4+ T cell subsets in vivo” was published in Cell Reports on April 27, 2021: https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00354-5.

Other authors include Xiaoyu Luo, Tongcui Ma, Julie Frouard, Jason Neidleman, and Warner C. Greene from Gladstone Institutes; and Rebecca Hoh and Steven G. Deeks from UC San Francisco.

This work was supported by the National Institutes of Health (R01AI127219, R01AI147777, P01AI131374, and S10-RR028962), the amfAR Institute for HIV Cure Research (109301), the UCSF-Gladstone Center for AIDS Research (P30AI027763), and the James B. Pendleton Charitable Trust.

About Gladstone Institutes

To ensure our work does the greatest good, Gladstone Institutes (https://gladstone.org) focuses on conditions with profound medical, economic, and social impact–unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco.

https://gladstone.org/news/atlas-hivs-favorite-targets-blood-infected-individuals

Source: https://bioengineer.org/an-atlas-of-hivs-favorite-targets-in-the-blood-of-infected-individuals/

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What factors put Philippine birds at risk of extinction?

Credit: Ça?an ?ekercio?lu The lush forests and more than 7,000 islands of the Philippines hold a rich diversity of life,

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The lush forests and more than 7,000 islands of the Philippines hold a rich diversity of life, with 258 bird species who live nowhere but the Philippine archipelago. A new study from University of Utah researchers suggests that, due to deforestation and habitat degradation, more bird species may be endangered that previously thought – including species that may not have been discovered yet. The study is published in Frontiers in Ecology and Evolution.

“Our study provides a roadmap for not only which species may warrant heightened conservation attention,” says Kyle Kittelberger, a doctoral student in the University of Utah School of Biological Sciences, “but which traits a species may have that can help inform if it may likely be more at risk of extinction.”

Birds of the Philippines

Located in Southeast Asia, the Philippines is considered a global biodiversity hotspot and one of the most biodiverse countries in the world, hosting nearly 600 bird species. A high proportion of the wildlife is endemic to the country, meaning that it is found nowhere else. The Philippines also hosts some of the highest richness of species recently identified as distinct from other closely related species, showing that scientists still have much to learn about the Philippine ecosystems.

Within the last decade the number of endemic species has risen from 172 to 258. This increase of 86 endemic species is more than all the endemic bird species in China (67) or India (75) and more than any country in South America or Africa.

Çağan Şekercioğlu, an associate professor in the School of Biological Sciences who has done ornithological field work in over 90 countries on all continents cannot forget his first visit to the islands.

“When I first visited the Philippines in 2008, I was awestruck by the diversity and especially the endemism of its avifauna but also greatly depressed by the rapid loss of habitat,” he says. Excursions into the field took hours due to extensive deforestation. “While looking for rare forest birds in the lowlands of Mindanao, we were literally trying to keep ahead of the loggers that were cutting down century-old rainforest trees within a couple hundred meters of us,” he adds. Despite that, in 13 days he saw 161 bird species he had never seen before- and still has 163 bird species to go.

Deforestation, habitat degradation and wildlife exploitation, however, threatens that biodiversity. Southeast Asia, the authors write, is forecast to lose over a third of its biodiversity over the next century. The Philippines in particular ranks 8th in the world for the number of globally threatened bird species.

“There is a pressing need to assess what traits make some species more at risk of extinction than others,” Kittelberger says, and use this understanding to help inform conservation efforts.”

Traits of threatened birds

To understand the status of Philippine birds, the researchers first determined the bird traits most predictive of extinction risk by correlating bird species’ ecological and life history traits, including body mass, diet, elevation range, and clutch size (the number of eggs laid in a nesting season) with their conservation status. A species endemic to the Philippines was significantly more likely to face an extinction risk, they found. Narrow elevation ranges, dependence on forests and high body mass also put birds at risk for extinction.

Then the researchers turned around and evaluated Philippine birds’ expected conservation status using those traits, comparing predicted conservation status with the IUCN Red List conservation designations. They found that 84 species were predicted to be in worse shape than their Red List designation, with 14 species predicted to be globally threatened (i.e. vulnerable, endangered, or critically endangered) that aren’t currently classified as such.

“We predicted that the Philippine Serpent-eagle and Writhed Hornbill, two species that are not currently recognized as being globally threatened, are respectively endangered and critically endangered,” Kittelberger says. “We also predicted that the Palawan Peacock-pheasant, Calayan Rail and Philippine Eagle-owl, three species currently recognized internationally as being vulnerable, are likely endangered species. All these birds therefore warrant heightened conservation attention as they may be more threatened than currently believed.”

Lost before they’re found

Among the 84 species predicted to be more threatened, 12 were recently recognized as separate species, and three of those were predicted to be “vulnerable.”

“The Philippines have a very high level of endemism and it is currently estimated that there are twice as many bird species in the Philippines that have not yet been split and officially recognized, so there is a real risk of losing species before they are described,” Kittelberger says.

Kittelberger says that their research can be applied broadly to assess the conservation status of birds throughout the region.

“The most important thing that the Philippines can do to protect birds,” Kittelberger says, “is to address the high levels of deforestation, habitat degradation, and wildlife exploitation, and to increase land protection for wildlife and increase funding for conservation efforts.”

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Find the full study here.

Co-authors also include Montague H. C. Neate-Clegg, J. David Blount and Çağan Şekercioğlu of the U’s School of Biological Sciences, Mary Rose C. Posa of the California Botanic Garden and John McLaughlin of the University of California, Santa Barbara. The study was supported by the Christensen Fund.

Within the last decade the number of endemic species has risen from 172 to 258. This increase of 86 endemic species is more than all the endemic bird species in China (67) or India (75) and more than any country in South America or Africa.

Source: https://bioengineer.org/what-factors-put-philippine-birds-at-risk-of-extinction/

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Stem cells may hold a key to developing new vaccines against COVID-19

Coronavirus activates a stem cell-mediated defense mechanism that reactivates dormant TB in a mouse model and has implications for developing

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Coronavirus activates a stem cell-mediated defense mechanism that reactivates dormant TB in a mouse model and has implications for developing new vaccines and avoiding a global TB pandemic, report investigators in The American Journal of Pathology

Philadelphia, June 16, 2021 – The SARS-CoV-2 virus that causes COVID-19 may have the ability to reactivate dormant tuberculosis (TB). In a novel study scientists report in The American Journal of Pathology that infection with a specific coronavirus strain reactivated dormant Mycobacterium tuberculosis (MTB) in mice. This knowledge may help to develop new vaccines for COVID-19 and avoid a potential global tuberculosis epidemic.

The COVID-19 pandemic caused by the SARS-CoV-2 virus demonstrates the ability of an emerging virus to affect masses and strain and disrupt the workings of modern healthcare systems around the world. A significant number of infected COVID-19 individuals have recovered. However, a possible host defense or antiviral mechanism against the virus is yet to be identified. There are concerns that in the long-term, the virus might activate dormant bacterial infections such as TB in select infected individuals, as alarmingly, TB is already present in one quarter of the world population. Viral infections such as the influenza virus or SARS-CoV-1 are known to cause transient immune suppression that leads to reactivation of dormant bacterial infection. The highest death rate during the Spanish flu pandemic of 1918 was in patients with TB, and patients with TB or multidrug-resistant TB had a worse prognosis than others during the influenza A (H1N1) pandemic in 2009.

“There is an urgent need to study the association of COVID-19 with dormant TB reactivation to avoid a potential global TB pandemic,” explained lead investigator Bikul Das, MD, PhD, Department of Stem Cell and Infectious Diseases, KaviKrishna Laboratory, Guwahati Biotech Park, Indian Institute of Technology, Guwahati, India; and Department of Stem Cell and Infection, Thoreau Lab for Global Health, University of Massachusetts, Lowell, MA, USA. “It is important to understand the host defense mechanism against this disease to develop a better vaccine and/or treatment. We therefore postulated that, similar to bacteria, adult stem cells may also exhibit an altruistic defense mechanism to protect their niche against external threat.”

Investigators studied the coronavirus strain murine hepatitis virus-1 (MHV-1) infection in the lung in a mouse model (dMtb) of mesenchymal stem cell (MSC)-mediated MTB dormancy. This showed 20-fold lower viral loads than the dMtb-free control mice by the third week of viral infection and a six-fold increase of altruistic stem cells (ASCs), thereby enhancing the defense. Tuberculosis was reactivated in the dMtb mice, suggesting that dormant TB bacteria hijack these ASCs to replicate in the lung to cause pulmonary TB. Results suggest that these ASCs are transient (they expand for two weeks and then undergo apoptosis or cellular suicide) and exhibit antiviral activities against MHV-1 by secreting soluble factors.

“These findings are important because they reveal a novel ASC defense mechanism against mouse coronavirus infection, which could be used to develop novel therapeutic approaches against COVID-19,” noted Bikul Das. “The finding of TB reactivation in a stem cell-mediated Mtb dormancy mouse model during MHV-1 coronavirus infection indicates that in the long-term, post-pandemic, the SARS-CoV-2 virus might activate dormant bacterial infections. This is a significant finding considering the current coronavirus pandemic, where many individuals in India and other developing countries with dormant TB infection may see an increase in active TB cases post COVID-19. The ASC-mediated defense mechanism may be targeted to develop vaccines against viral infections and avoid a potential global TB pandemic.”

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Background notes

This study of stem cell altruism was inspired by the Indian Vedantic Philosophical theory of altruistic behavior, which was referred to in the poem “Fire of Golden Nail” written by Vedic philosopher and poet Krishna Ram Das of Kamrupa, India, noted the study’s authors. Poet Krishna Ram Das conceptualized the idea while undergoing surgery for throat cancer and initiated the KaviKrishna Foundation to test his idea through vigorous scientific research.

“Proving altruism in mammalian cell biology is a challenging task, as we faced years of resistance from colleagues,” commented Bikul Das. “Altruism is about group selection, which is very challenging to demonstrate at the molecular level. However, the idea of altruism that we are describing here is the philosophical view of Vedic Jiva Upakarvada (Vedic altruism), a part of Vedantic thought that states that during stress, the living organism acquires a higher state, known as ‘Avatar.’ The mandate of the KaviKrishna laboratory is to take this philosophical view forward to modern biology, specifically to develop a philosophical and social theory on global health.

First author Lekhika Pathak, PhD student at the KaviKrishna Lab, GBP, IIT-Guwahati, India, commented: “I joined the laboratory hoping to further ASC research exploiting the model of MHV-1-infected stem cell-mediated Mtb dormancy. Our research findings now may provide a novel approach to understand the interaction between two pathogens, coronavirus and M. tuberculosis, both of which are major threats to global health.”

Co-investigator Herman Yeger, PhD, of the Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada, added: “I commend Bikul Das for being innovative in transforming a piece of Indian philosophy into a testable biological experiment on altruism. Now that we have obtained convincing data on the identification of ASC and their defense against coronavirus, we hope to develop a novel approach to tackle this growing pandemic.”

https://www.elsevier.com/about/press-releases/research-and-journals/stem-cells-may-hold-a-key-to-developing-new-vaccines-against-covid-19

Source: https://bioengineer.org/stem-cells-may-hold-a-key-to-developing-new-vaccines-against-covid-19/

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$1 million grant to address cold storage logistics in vaccine delivery

Credit: Penn State College of Engineering COVID-19 vaccines have been tested, validated and administered to millions of people around the

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COVID-19 vaccines have been tested, validated and administered to millions of people around the world. But in some countries, the vaccines have yet to arrive in great enough numbers.

One significant hurdle is that the vaccines must be stored between 36 and 46 degrees Fahrenheit to retain their full efficacy, according to the Centers for Disease Control. To ensure the proper temperature, the vaccines need a refrigerated supply chain, also known as a cold chain, as they are distributed across the globe.

“If they are in warm temperatures, COVID vaccines and other medications are susceptible to degradation, which means they lose potency,” said Medina, who heads the Medina Group Precision Therapeutics and Bioresponsive Materials Lab at Penn State. “And the cold storage supply chain is expensive to maintain, with several transport steps necessary from the manufacturer to the distributer to the provider facility.”

To address that challenge, Medina and his team plan to develop fluorochemical dispersants, known as “FTags,” which coat the proteins within the vaccine liquids to stabilize them thermally.

“The FTags dissolve the proteins in a fluorine-based liquid, which yields proteins that we believe may be stable at elevated temperatures, without compromising their structure or function,” Medina said. “When dissolved in the fluorine-based liquid, the proteins also are immune to contamination by microorganisms and enzymes.”

Fluorochemicals are used in a range of applications, such as in making surfaces resistant to scratches and chemical degradation, as in the case of non-stick cookware.

Eventually, Medina plans to study the use of fluorochemical coatings in other biological products, with the goal of eliminating the need to move any pharmaceutical via a cold chain.

“This will allow access to medications in places where currently there is not,” Medina said. “For example, a soldier at war could be exposed to a harmful chemical agent. A fluorochemical-coated protein, which can be carried without refrigeration, could neutralize that agent immediately. This is part of DARPA’s interest in supplying this grant.”

The grant is part of DARPA’s Young Faculty Award program, which provides funding, mentoring and networking opportunities to faculty early in their careers who plan to focus their research on Department of Defense and national security interests.

In 2020, Medina published a study in ACS Nano on delivering therapeutic medications directly to a precise area of the body through an acoustically sensitive carrier, guided by ultrasound. The proposed DARPA-funded study is a spin-off of that study’s findings.

“Janna Sloand, my former grad student who recently defended her doctoral research, came up with the coating technology in our last study,” Medina said. “It dovetails nicely with our new study, which will use those same coatings to take on the limitations of the cold chain.”

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Source: https://bioengineer.org/1-million-grant-to-address-cold-storage-logistics-in-vaccine-delivery/

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