About two decades after first devising a new kind of vaccine, Oregon Health & Science University researchers are unlocking why it stops and ultimately clears the monkey form of HIV, called SIV, in about half of nonhuman primates — and why it’s a promising candidate to stop HIV in people.
In scientific papers that were simultaneously published today in the journals Science and Science Immunology, creators of the cytomegalovirus, or CMV, vaccine platform describe the unusual biological mechanisms through which it works.
The findings also helped fine-tune VIR-1111, the CMV-based experimental vaccine against HIV that was developed at OHSU and is now being evaluated in a Phase 1 clinical trial. The trial is being conducted by Vir Biotechnology, which licensed the CMV vaccine platform technology from OHSU.
“Knowing the mechanism that the CMV-based SIV vaccine uses to work in rhesus macaques gives us a way to judge the potential of a human vaccine very quickly,” said Louis Picker, M.D., the associate director of the OHSU Vaccine and Gene Therapy Institute and a professor of pathology/molecular microbiology and immunology in the OHSU School of Medicine. “If you have the wrong genes in the CMV vaccine, the critical immune response needed for efficacy won’t develop. You have to thread the CMV vaccine’s needle exactly if you want a high degree of protection, and you have to know what you’re looking for.”
Two of the papers describe that the cytomegalovirus vaccine needs to generate an unusual type of CD8-positive T cell response called MHC-E-restricted T cells to effectively fight off SIV in monkeys.
“We knew for a while that we have unusual T cell responses in monkeys that receive our CMV vaccine against SIV,” said Klaus Frueh, Ph.D., a professor of molecular microbiology and immunology in the OHSU School of Medicine and OHSU Vaccine and Gene Therapy Institute. “But we didn’t know if they were important for protection against SIV. This research shows clearly that, without this special MHC-E-restricted T cell response, we don’t have protection.”
The study published in Science Immunology shows that the vaccine was only able to generate these special T cells to fight off SIV if eight specific genes were missing or inactivated from the natural form of monkey CMV. And a corresponding paper published via Science’s First Release describes how a specific cytomegalovirus protein known as Rh67 is required to generate MHC-E-restricted T cells to protect against SIV. Together, these papers suggest how a CMV-based vaccine needs to be designed to create these unconventional T cell responses.
And, in a separate Science Immunology paper that was also published today, a research team led by Andrew J. McMichael, Ph.D., of Oxford University looked into whether what has been learned from nonhuman primate experiments could be transferrable to humans. These researchers showed that MHC-E-restricted CD8-positive T cells could be increased and suppress HIV in laboratory cell cultures.
This new research is being published as the OHSU Vaccine and Gene Therapy Institute celebrates the 20th anniversary of its first building opening for research in April 2001. Picker and Frueh moved to Oregon to help start the institute: Picker has led its vaccine program since its founding, and Frueh joined forces with Picker in 2006. Picker first received a $3.5 million grant from the National Institutes of Health in 2004 to develop a CMV-based HIV vaccine. Picker says the following in a May 25, 2004, OHSU announcement about the grant: “We believe a persistent viral vector could produce a superior and more durable anti-HIV immune response that would, in effect, hold the line against HIV.”
The following funding was awarded to OHSU in support of the research described in these three studies: the National Institute of Allergy and Infectious Diseases (grants P01 AI094417, U19 AI128741, UM1 AI124377, R37 AI054292, R01AI140888, R01 AI059457), National Institutes of Health Office of the Director (grant P51 OD011092); National Cancer Institute (contract HHSN261200800001E), and the Bill & Melinda Gates Foundation-supported Collaboration for AIDS Vaccine Discovery (OPP1033121).
In the interest of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regards to this research, OHSU and several individuals have a significant financial interest in Vir Biotechnology Inc., a company that may have a commercial interest in the results of this research and technology. These individuals include Picker, Frueh, Sacha, Malouli, Hansen and Hancock.

Researchers at the National Institutes of Health (NIH) have discovered specific regions within the DNA of neurons that accumulate a certain type of damage (called single-strand breaks or SSBs). This accumulation of SSBs appears to be unique to neurons, and it challenges what is generally understood about the cause of DNA damage and its potential implications in neurodegenerative diseases.
Because neurons require considerable amounts of oxygen to function properly, they are exposed to high levels of free radicals — toxic compounds that can damage DNA within cells. Normally, this damage occurs randomly. However, in this study, damage within neurons was often found within specific regions of DNA called “enhancers” that control the activity of nearby genes.
Fully mature cells like neurons do not need all of their genes to be active at any one time. One way that cells can control gene activity involves the presence or absence of a chemical tag called a methyl group on a specific building block of DNA. Closer inspection of the neurons revealed that a significant number of SSBs occurred when methyl groups were removed, which typically makes that gene available to be activated.
An explanation proposed by the researchers is that the removal of the methyl group from DNA itself creates an SSB, and neurons have multiple repair mechanisms at the ready to repair that damage as soon as it occurs. This challenges the common wisdom that DNA damage is inherently a process to be prevented. Instead, at least in neurons, it is part of the normal process of switching genes on and off. Furthermore, it implies that defects in the repair process, not the DNA damage itself, can potentially lead to developmental or neurodegenerative diseases.
This study was made possible through the collaboration between two labs at the NIH: one run by Michael E. Ward, M.D., Ph.D. at the National Institute of Neurological Disorders and Stroke (NINDS) and the other by Andre Nussenzweig, Ph.D. at the National Cancer Institute (NCI). Dr. Nussenzweig developed a method for mapping DNA errors within the genome. This highly sensitive technique requires a considerable number of cells in order to work effectively, and Dr. Ward’s lab provided the expertise in generating a large population of neurons using induced pluripotent stem cells (iPSCs) derived from one human donor. Keith Caldecott, Ph.D. at the University of Sussex also provided his expertise in single strand break repair pathways.
The two labs are now looking more closely at the repair mechanisms involved in reversing neuronal SSBs and the potential connection to neuronal dysfunction and degeneration.
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The evolving science of wisdom rests on the idea that wisdom’s defined traits correspond to distinct regions of the brain, and that greater wisdom translates into greater happiness and life satisfaction while being less wise results in opposite, negative consequences.
Scientists have found in multiple studies that persons deemed to be wiser are less prone to feel lonely while those who are lonelier also tend to be less wise. In a new study, published in the March 25, 2021 issue of the journal Frontiers in Psychiatry, researchers at University of California San Diego School of Medicine take the connection between wisdom, loneliness and biology further, reporting that wisdom and loneliness appear to influence — and/or be influenced by — microbial diversity of the gut.
The human gut microbiota is comprised of trillions of microbes — bacteria, viruses, fungi — that reside within the digestive tract. Researchers have known for a while about the “gut-brain axis,” which is a complex network that links intestinal function to the emotional and cognitive centers of the brain.
This two-way communication system is regulated by neural activity, hormones and the immune system; alterations can result in disruptions to stress response and behaviors, said the authors, from emotional arousal to higher-order cognitive abilities, such as decision-making.
Past studies have associated gut microbiota with mental health disorders including depression, bipolar disorder and schizophrenia, as well as personality and psychological traits regarded as key, biologically based components of wisdom. Recent research has connected the gut microbiome to social behavior, including findings that people with larger social networks tend to have more diverse gut microbiotas.
The new Frontiers in Psychiatry study involved 187 participants, ages 28 to 97, who completed validated self-report-based measures of loneliness, wisdom, compassion, social support and social engagement. The gut microbiota was analyzed using fecal samples. Microbial gut diversity was measured in two ways: alpha-diversity, referring to the ecological richness of microbial species within each individual and beta-diversity, referring to the differences in the microbial community composition between individuals.

Researchers from Charité — Universitätsmedizin Berlin and the Francis Crick Institute have developed a mass spectrometry-based technique capable of measuring samples containing thousands of proteins within just a few minutes. It is faster and cheaper than a conventional blood count. To demonstrate the technique’s potential, the researchers used blood plasma collected from COVID-19 patients. Using the new technology, they identified eleven previously unknown proteins which are markers of disease severity. The work has been published in Nature Biotechnology.
Thousands of proteins are active inside the human body at any given time, providing its structure and enabling reactions which are essential to life. The body raises and lowers the activity levels of specific proteins as required, including when responding to external factors such as pathogens and drugs. The detailed patterns of the proteins found inside cells, tissues and blood samples can therefore help researchers to better understand diseases or make diagnoses and prognoses. In order to obtain this ‘protein fingerprint’, researchers use mass spectrometry, a technology known to be both time-consuming and cost-intensive. ‘Scanning SWATH’, a new mass-spectrometry-based technology, promises to change this. Developed under the leadership of Prof. Dr. Markus Ralser, Director of Charité’s Institute of Biochemistry, this technology, which is much faster and cost-effective than previous methods, enables researchers to measure several hundred samples per day.
“In order to speed up this technology, we changed the mass spectrometer’s electric fields. The data produced are of such extreme complexity that humans can no longer analyze them,” explains Einstein Professor Prof. Ralser, who is also a Group Leader at the Francis Crick Institute in London. He adds: “We therefore developed computer algorithms that are based on neural networks and which use these data to extract the relevant biological information. This enables us to identify thousands of proteins in parallel and greatly reduces measuring timescales. Fortunately, this method is also more precise.”
This high-throughput technology has a broad range of potential applications, ranging from basic research and large-scale drug development to the identification of biological markers (biomarkers), which can be used to estimate an individual patient’s risk. The technology’s suitability for the latter was demonstrated by the researchers’ study on COVID-19. As part of this research, the team analyzed blood plasma samples from 30 Charité inpatients with COVID-19 of varying degrees of disease severity, comparing the protein patterns obtained with those of 15 healthy individuals. The actual measurements conducted on individual samples only took a few minutes.
The researchers were able to identify a total of 54 proteins whose serum levels varied according to the severity of COVID-19. While 43 of these proteins had already been linked to disease severity during earlier studies, no such relationship had been established for 11 of the proteins identified. Several of the previously unknown proteins associated with COVID-19 are involved in the body’s immune response to pathogens which increases clotting tendency. “In the shortest of timeframes, we discovered protein fingerprints in blood samples which we are now able to use to categorize COVID-19 patients according to severity of disease,” says one of the study’s lead authors, Dr. Christoph Messner, who is a researcher at Charité’s Institute of Biochemistry and the Francis Crick Institute. He continues: “This type of objective assessment can be extremely valuable, as patients will occasionally underestimate the severity of their disease. However, in order to be able to use mass spectrometry analysis for the routine categorization of COVID-19 patients, this technology will need to be refined further and turned into a diagnostic test. It may also become possible to use rapid protein pattern analysis to predict the likely course of a case of COVID-19. While the initial findings we have collected are promising, further studies will be needed before this can be used in routine practice.”
Prof. Ralser is convinced that mass spectrometry-based investigations of the blood could one day complement conventional blood count profiles. “Proteome analysis is now cheaper than a complete blood count. By identifying many thousands of proteins at the same time, proteomic analysis also produces far more information. I therefore see enormous potential for widespread use, for instance in the early detection of diseases. We will therefore continue to use our studies to develop proteome technology for this type of application.”
The study is the result of a collaboration with the University of Cambridge, United Kingdom, the Chalmers University of Technology, Sweden, the Bernhardt Nocht Institute for Tropical Medicine in Hamburg, Germany, and SCIEX, a Canadian manufacturer of mass spectrometers.
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Researchers at Baylor College of Medicine, Shandong University in China and other institutions may have found an explanation for dawn phenomenon, an abnormal increase of blood sugar only in the morning, observed in many patients with type 2 diabetes. They report in the journal Nature that mice lacking the circadian clock gene called Rev-erb in the brain show characteristics similar to those of dawn phenomenon.
The researchers then looked at Rev-erb gene expression in patients with type 2 diabetes comparing a group with dawn phenomenon to a group without it and found that the gene’s expression followed a different temporal pattern between these two groups. The findings support the idea that an altered daily rhythm of expression of the Rev-erb gene may underlie dawn phenomenon. Future investigations may lead to therapies.
“We began this study to investigate what was the function of Rev-erb in the brain,” said co-corresponding author Dr. Zheng Sun, associate professor of medicine-endocrinology, diabetes and metabolism at Baylor. “We are interested in this gene because it is a ‘druggable’ component of the circadian clock with potential applications in the clinic. Rev-erb is expressed only during the day but not at night. When we started, we did not know where this was going to lead us.”
The researchers first developed a mouse model by knocking out the Rev-erb gene in GABA neurons. They chose this approach because the gene’s expression is highly enriched in a particular brain area called the suprachiasmatic nucleus that is mainly composed of GABA neurons.
An unexpected finding
“We observed something very interesting in these mice,” Sun said. “They were glucose intolerant — that is they had high glucose levels — only in the evening. Mice are nocturnal, meaning that they become active in the evening as people do in the morning.”
When the body awakes and takes in food, insulin is secreted from the pancreas to signal the body to lower blood sugar. Insulin is more effective in doing this job upon waking than at other times of the day. This high insulin sensitivity is probably because the body is anticipating feeding behaviors upon waking up. In mice, high insulin sensitivity occurs in the evening, while in people it occurs in the morning.

Researchers at Lund University in Sweden have investigated how the X and Y chromosomes evolve and adapt to each other within a population. The results show that breaking up coevolved sets of sex chromosomes could lead to lower survival rates among the offspring — something that could be of importance in species conservation, for example. The study is published in the journal PNAS.
The results provide new clues on how species are formed, and suggest it could be harmful to bring together individuals from different populations that have been separated for a long time. The reason is that the offspring have lower survival rates.
“This is something worth keeping in mind in conservation biology, where you want to see a population grow,” says Jessica Abbott, researcher in evolutionary ecology at Lund University.
It is previously known that hybrids between different species often do better if they are female (two X chromosomes) rather than male (X and Y chromosome).
In the study, the researchers crossed fruit flies from five different populations from different continents in order to combine X and Y chromosomes with different origins. They then followed and studied the subsequent generations.
The results show that males with X and Y chromosomes that don’t match had higher reproductive success than males with matching X and Y chromosomes. However, the higher male fertility was paired with lower survival rates among their offspring.
“We were expecting the opposite, that males with different origin X and Y chromosomes would have lower reproductive success, so that was surprising,” says Jessica Abbott.
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Other drug makers have begun similar trials of their Covid-19 vaccines. If they work in children younger than 12 as expected, it will be easier for the U.S. to reach herd immunity.Pfizer has begun testing its Covid-19 vaccine in children under 12, a significant step in turning back the pandemic. The trial’s first participants, a pair of 9-year-old twin girls, were immunized at Duke University in North Carolina on Wednesday.Results from the trial are expected in the second half of the year, and the company hopes to vaccinate younger children early next year, said Sharon Castillo, a spokeswoman for the pharmaceutical company.Moderna also is beginning a trial of its vaccine in children six months to 12 years of age. Both companies have been testing their vaccines in children 12 and older, and expect those results in the next few weeks.AstraZeneca last month began testing its vaccine in children six months and older, and Johnson & Johnson has said it plans to extend trials of its vaccine to young children after assessing its performance in older children.Immunizing children will help schools to reopen as well as help to end the pandemic, said Dr. Emily Erbelding, an infectious diseases physician at the National Institutes of Health who oversees testing of Covid-19 vaccines in special populations.An estimated 80 percent of the population may need to be vaccinated for the United States to reach herd immunity, the threshold at which the coronavirus runs out of people to infect. Some adults may refuse to be vaccinated, and others may not produce a robust immune response.Children under 18 account for about 23 percent of the population in the United States, so even if a vast majority of adults opt for vaccines, “herd immunity might be hard to achieve without children being vaccinated,” Dr. Erbelding said.Pfizer had initially said it would wait for data from older children before starting trials of its vaccine in children under 12. But “we were encouraged by the data from the 12 to 15 group,” said Ms. Castillo, who did not elaborate on the results so far.Scientists will test three doses of the Pfizer vaccine — 10, 20 and 30 micrograms — in 144 children. Each dose will be assessed first in children 5 through 11 years of age, then in children ages 2 through 4 years, and finally in the youngest group, six months to 2 years.After determining the most effective dose, the company will test the vaccine in 4,500 children. About two-thirds of the participants will be randomly selected to receive two doses 21 days apart; the remaining will get two placebo shots of saline. The researchers will assess the children’s immune response in blood drawn seven days after the second dose.“It sounds like a good plan, and it’s exciting that another Covid-19 vaccine is moving forward with trials in children,” said Dr. Kristin Oliver, a pediatrician and vaccine expert at Mount Sinai Hospital in New York.Dr. Oliver said about half of the parents she sees in practice are eagerly waiting for vaccines, and even to volunteer their children for clinical trials, while the rest are skeptical because comparatively few children become seriously ill from coronavirus infection.Both groups of parents will benefit from knowing exactly how safe and effective the vaccines are in children, she said.Children represent 13 percent of all reported cases in the United States. More than 3.3 million children have tested positive for the virus, at least 13,000 have been hospitalized and at least 260 have died, noted Dr. Yvonne Maldonado, who represents the American Academy of Pediatrics on the federal Advisory Committee on Immunization Practices.The figures do not fully capture the damage to children’s health. “We don’t know what the long-term effects of Covid infection are going to be,” Dr. Maldonado said.Other vaccines have helped to control many horrific childhood diseases that can cause long-term complications, she added: “For some of us who’ve seen that, we don’t want to go back to those days.”Children often react more strongly to vaccines than adults do, and infants and toddlers in particular can experience high fevers. Any side effects are likely to appear soon after the shot, within the first week and certainly within the first few weeks, experts have said.Some vaccines are tested only in animals before being assessed in children, and have to be monitored carefully for side effects.“But this is a little different, because we’ve already had experience with tens of millions of people with these vaccines,” Dr. Maldonado said. “So there’s a higher degree of confidence now in giving this vaccine to kids.”Some experts suggested that the Food and Drug Administration may require up to six months of safety data from studies of children before authorizing the Covid-19 vaccines. But a spokeswoman said the agency did not expect six months of safety data to support the vaccines’ authorization.The Pfizer-BioNTech vaccine is authorized for children 16 through 18 years old, and the authorization for that age group was based on just two months of safety data, she said.Parents will want to know how the companies and the F.D.A. plan to monitor and disclose side effects from the vaccines, and how long they will continue to follow trial participants after the vaccines’ authorization, Dr. Oliver said.“I think everyone has learned throughout this,” she said. “The more transparent you can be, the better.”

A new study conducted at the Galveston National Laboratory at the The University of Texas Medical Branch at Galveston (UTMB) has shown substantial benefit to combining monoclonal antibodies and the antiviral remdesivir against advanced Marburg virus. The study was published today in Nature Communications.
“Marburg is a highly virulent disease in the same family as the virus that causes Ebola. In Africa, patients often arrive to a physician very ill. It was important to test whether a combination of therapies would work better with really sick people, said Tom Geisbert, a professor in the Department of Microbiology & Immunology at UTMB and the principal investigator for the study. “Our data suggests that this particular combination allowed for recovery when given at a very late stage of disease.”
Dr. Zachary A. Bornholdt, Senior Director of Antibody Discovery and Research for Mapp Biopharmaceutical and a co-author on the study, said, “Often small molecules and antibodies are positioned to compete with each other for a single therapeutic indication. Here we see the benefit of pursuing both treatment strategies in tandem and ultimately finding synergy upon combining both approaches together.”
Geisbert, Bornholdt and a large team at UTMB, Mapp Biopharmaceuticals and Gilead have been developing monoclonal antibody (mAbs) therapies to treat extremely dangerous viruses like Marburg and Ebola for several years. The treatments have proven to be highly effective in laboratory studies and emergency use, particularly when delivered early in the disease course.
In this study, using a rhesus model, treatment with monoclonal antibodies began six days post infection, a critical point in disease progression. The combination therapy with the antiviral remdesivir showed an 80 percent protection rate, indicating promise for treatment of advanced Marburg infections.
The study was supported by the Department of Health and Human Services, National Institutes of Health grant U19AI142785 and UC7AI094660 for BSL-4 operations support of the Galveston National Laboratory.
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Early screening can mean the difference between life and death in a cancer and disease diagnosis. That’s why University of Central Florida researchers are working to develop a new screening technique that’s more than 300 times as effective at detecting a biomarker for diseases like cancer than current methods.
The technique, which was detailed recently in the Journal of the American Chemical Society, uses nanoparticles with nickel-rich cores and platinum-rich shells to increase the sensitivity of an enzyme-linked immunosorbent assay (ELISA).
ELISA is a test that measures samples for biochemicals, such as antibodies and proteins, which can indicate the presence of cancer, HIV, pregnancy and more. When a biochemical is detected, the test generates a color output that can be used to quantify its concentration. The stronger the color is, the stronger the concentration. The tests must be sensitive to prevent false negatives that could delay treatment or interventions.
In the study, the researchers found that when the nanoparticles were used in place of the conventional enzyme used in an ELISA — peroxidase — that the test was 300 times more sensitive at detecting carcinoembryonic antigen, a biomarker sometimes used to detect colorectal cancers.
And while a biomarker for colorectal cancer was used in the study, the technique could be used to detect biomarkers for other types of cancers and diseases, says Xiaohu Xia, an assistant professor in UCF’s Department of Chemistry and study co-author.
Colorectal cancer is the third leading cause of cancer-related deaths in the U.S., not counting some kinds of skin cancer, and early detection helps improve treatment outcomes, according to the U.S. Centers for Disease Control and Prevention.

The glow of a panther’s eyes in the darkness. The zig-zagging of a shark’s dorsal fin above the water.
Humans are always scanning the world for threats. We want the chance to react, to move, to call for help, before danger strikes. Our cells do the same thing.
The innate immune system is the body’s early alert system. It scans cells constantly for signs that a pathogen or dangerous mutation could cause disease. And what does it like to look for? Misplaced genetic material.
The building blocks of DNA, called nucleic acids, are supposed to be hidden away in the cell nucleus. Diseases can change that. Viruses churn out genetic material in parts of the cell where it’s not supposed to be. Cancer cells do too.
“Cancer cells harbor damaged DNA,” says Sonia Sharma, Ph.D., an associate professor at the La Jolla Institute for Immunology (LJI). “Mislocated DNA or aberrant DNA is a danger signal to the cell. They tell the cell, ‘There’s a problem here.’ It’s like the first ringing of the alarm bell for the immune system.”
Now Sharma and her colleagues have published a new Nature Immunology study describing the process that triggers this alert system directly inside tumor cells. Their research shows that a tumor-suppressor enzyme called DAPK3 is an essential component of a multi-protein system that senses misplaced genetic material in tumor cells, and slows tumor growth by activating the fierce-sounding STING pathway.