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Scooped by
Juan Lama
November 18, 2019 8:48 PM
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Children born to women on HIV therapy containing the drug efavirenz were 2 to 2.5 times more likely to have microcephaly, or small head size, compared to children born to women on regimens of other antiretroviral drugs, according to an analysis funded by the National Institutes of Health. The children with microcephaly also had a higher risk for developmental delays, compared to children with normal head size. The study was conducted by Paige L. Williams, Ph.D., of the Harvard T.H. Chan School of Public Health, and colleagues. It appears in The Lancet. "Our findings underlie the importance of having alternatives to combination therapy with efavirenz for pregnant women with HIV," said study author Rohan Hazra, M.D., chief of the Maternal and Pediatric Infectious Disease Branch of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, which provided funding for the study. Researchers analyzed data from a follow-up study of more than 3,000 infants born to women on HIV therapy during pregnancy. In this earlier study, the children's head circumferences were measured periodically from 6 months of age through 5 to 7 years of age. For the current study, investigators used two classification systems to rank the children's head growth. The first classification system combined standards developed by the U.S. Centers for Disease Control and Prevention for children under 3 years of age with Nellhaus Charts, an older set of standards for children over 3 years of age. For the second classification system, the researchers consulted Nellhaus Charts from birth to age 18. Based on Nellhaus standards, children whose mothers were on regimens containing the drug efavirenz were more than twice as likely to have microcephaly, compared to children whose mothers were on other regimens. According to the combined Nellhaus-CDC standards, children exposed to efavirenz in the womb were around 2.5 times as likely to have microcephaly. Children with microcephaly according to Nellhaus standards also scored lower on standardized tests of child development at ages 1 and 5 years. Of the 141 children exposed to efavirenz in the womb, 14 (9.9%) had microcephaly, compared to 142 of 2,842 who were not exposed to efavirenz (5%). The researchers noted that exposure to all other types of HIV therapies was not associated with a higher risk of microcephaly. Published in The Lancet (November 15, 2019): https://doi.org/10.1016/S2352-3018(19)30340-6
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Juan Lama
November 17, 2019 11:05 AM
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Using a relevant animal model (pigs), University of Saskatchewan researchers have shown that mild Zika virus infection in fetuses can cause abnormal brain development in apparently healthy young animals. The study, published Nov. 14 in PLOS Pathogens, provides new insights into the potential outcomes of Zika virus infection and could point to new prevention and treatment strategies to alleviate the long-term effects of Zika virus infection. Spread by the bite of an infected Aedes species mosquito, Zika infection of pregnant mothers can lead to death and decreased brain size (microcephaly) in fetuses, leading to life-long developmental and cognitive impairment. However, there is growing concern that sub-clinical infections (showing no symptoms) in pregnant mothers can result in brain disorders and delayed neurodevelopmental abnormalities in offspring after birth. Using the pig as a model, new research at USask's Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac) has provided direct evidence to support this concern. "We have demonstrated in a relevant animal model that mild infection in fetuses results in abnormal brain development and impaired immunity in young pigs," said VIDO-InterVac Director Dr. Volker Gerdts who also participated in the study. Some of the affected offspring also showed altered behaviour during stress. In 2016, the World Health Organization declared Zika virus a public health emergency. While this emergency declaration has been lifted, Zika infection remains a public health concern. There is currently no approved vaccine or therapy available to combat the infection. Karniychuk said a next step is to develop an animal model for the study of how to treat and cure infections such as Zika virus in utero. There are currently no in utero therapies for congenital viral infections. Earlier this year, Karniychuk was awarded $250,000 over two years by the federal New Frontiers in Research Fund to undertake this work aimed at reducing the long-term consequences of abnormalities in developing fetuses and the treatment required after birth. For almost 45 years, VIDO-InterVac has used large animal models to help understand how pathogens cause disease. Published in PLOS Pathigens (November 14, 2019): https://doi.org/10.1371/journal.ppat.1008038
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Juan Lama
November 14, 2019 8:03 PM
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A new study led by researchers at Baylor College of Medicine revealed how in utero Zika virus infection can lead to microcephaly in newborns. The team discovered that the Zika virus protein NS4A disrupts brain growth by hijacking a pathway that regulates the generation of new neurons. The findings point at the possibility of developing therapeutic strategies to prevent microcephaly linked to Zika virus infection. The study appears today in the journal Developmental Cell. Patients with rare genetic mutations shed light on how Zika virus causes microcephaly "The current study was initiated when a patient presented with a small brain size at birth and severe abnormalities in brain structures at the Baylor Hopkins Center for Mendelian Genomics (CMG), a center directed by Dr. Jim Lupski, professor of pediatrics, molecular and human genetics at Baylor College of Medicine and attending physician at Texas Children's Hospital," said Dr. Hugo J. Bellen, professor at Baylor, investigator at the Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital. This patient and others in a cohort at CMG had not been infected by Zika virus in utero. They had a genetic defect that caused microcephaly. CMG scientists determined that the ANKLE2 gene was associated with the condition. Interestingly, a few years back the Bellen lab had discovered in the fruit fly model that ANKLE2 gene was associated with neurodevelopmental disorders. Knowing that Zika virus infection in utero can cause microcephaly in newborns, the team explored the possibility that Zika virus was mediating its effects in the brain via ANKLE2. In a subsequent fruit fly study, the researchers demonstrated that overexpression of Zika protein NS4A causes microcephaly in the flies by inhibiting the function of ANKLE2, a cell cycle regulator that acts by suppressing the activity of VRK1 protein. The fruit fly helps clarify the mystery The team found that fruit fly larvae with mutations in ANKLE2 gene had small brains with dramatically fewer neuroblasts—brain cell precursors—and could not survive into adulthood. Experimental expression of the normal human version of ANKLE2 gene in mutant larvae restored all the defects, establishing the loss of Ankle2 function as the underlying cause. "To understand why ANKLE2 mutants have fewer neuroblasts and significantly smaller brains, we probed deeper into asymmetric cell divisions, a fundamental process that produces and maintains neuroblasts, also called neural stem cells, in the developing brains of flies and humans," said first author Dr. Nichole Link, postdoctoral associate in the Bellen lab. Asymmetric cell division is an exquisitely regulated process by which neuroblasts produce two different cell types. One is a copy of the neuroblast and the other is a cell programmed to become a different type of cell, such as a neuron or glia. Proper asymmetric distribution and division of these cells is crucial to normal brain development, as they need to generate a correct number of neurons, produce diverse neuronal lineages and replenish the pool of neuroblasts for further rounds of division. "When flies had reduced levels of Ankle2, key proteins, such as Par complex proteins and Miranda, were misplaced in the neuroblasts of Ankle2 larvae. Moreover, live imaging analysis of these neuroblasts showed many obvious signs of defective or incomplete cell divisions. These observations indicated that Ankle2 is a critical regulator of asymmetric cell divisions," said Link.... Published on Developmental Cell (November 14, 2019): https://doi.org/10.1016/j.devcel.2019.10.009
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Scooped by
Juan Lama
November 14, 2019 10:08 AM
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Large-scale study to identify human adenovirus genotypes in Singapore leads to discovery of four new adenovirus strains and increase in strains linked to severe diseases. Researchers suggest use of antiviral therapies and adenovirus vaccines, and routine monitoring of adenovirus strains. Human adenovirus (HAdV) infections in Singapore and Malaysia have caused severe respiratory disease among children and adults in recent years, but scientists still don't know whether these outbreaks are due to new or re-emerging virus strains. In the first large-scale study to systematically identify HAdV strains in Singapore, scientists led by Duke-NUS Medical School have discovered four new strains and found an increase in two strains linked to severe diseases. Using a genotyping algorithm to study HAdV infections among patients from two large public hospitals in Singapore, the researchers tested over 500 clinical samples from paediatric and adult patients. "We detected four new HAdV strains closely related to a strain isolated from an infant in Beijing during an epidemic in 2012-2013," said the study's lead author, Dr Kristen Coleman, from the Emerging Infectious Diseases (EID) Programme at Duke-NUS Medical School. "Our results also highlight an increase in HAdV types 4 and 7 among the paediatric population over time. Importantly, patients with weakened immune systems and those with HAdV types 2, 4 or 7 were more likely to experience severe disease." Adenoviruses are a family of viruses with over 50 known strains that can infect people of all ages and most commonly infect the respiratory system. The sore throat and fever associated with the common cold are among the symptoms brought about by different adenovirus strains. In some cases, particularly in patients with weakened immune systems, adenoviruses can cause severe respiratory symptoms, including pneumonia, or more life-threatening conditions like organ failure. "The high prevalence and severity of HAdV type 4 infections identified in our study is intriguing," stated Dr Gregory Gray, senior and corresponding author of the study, who is a professor in the EID Programme at Duke-NUS and member of the Duke Global Health Institute at Duke University, USA. "Upon its discovery in the 1950s, HAdV type 4 was largely considered restricted to and controlled by vaccine in the US military population, with rare detections among civilians. Singapore would benefit from more frequent studies of clinical HAdV genotypes to identify patients at risk for severe disease and help guide the use of new antiviral therapies." Given the study results, the authors suggest public health officials and clinicians in Singapore consider using antiviral therapies and adenovirus vaccines. Furthermore, they recommend Singapore and other countries considering new HAdV treatment and control measures conduct periodic and routine adenoviral genotype surveillance to collect the data needed to make informed, evidence-based decisions. Published in J. Infectious Disease (Sept. 30, 2019): https://doi.org/10.1093/infdis/jiz489
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Scooped by
Juan Lama
November 12, 2019 10:44 AM
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Current virus detection methods often take significant time or can be limited in sensitivity and specificity. The increasing frequency and magnitude of viral outbreaks in recent decades has resulted in an urgent need for diagnostic methods that are facile, sensitive, rapid and inexpensive. Here, we describe and characterise a novel, calcium-mediated interaction of the surface of enveloped viruses with DNA, that can be used for the functionalisation of intact virus particles via chemical groups attached to the DNA. Using DNA modified with fluorophores, we have demonstrated the rapid and sensitive labelling and detection of influenza and other viruses using single-particle tracking and particle-size determination. With this method, we have detected clinical isolates of influenza in just one minute, significantly faster than existing rapid diagnostic tests. This powerful technique is easily extendable to a wide range of other enveloped pathogenic viruses and holds significant promise as a future diagnostic tool. Compared with antibody staining of virus particles, the calcium labelling method is significantly faster, doesn’t necessitate sample preparation, requires cheaper reagents, and can be combined with alternative detection methods should specific identification of virus particles be required. Thus, we envisage that our assay has potential as a standalone technique, for example, as a rapid way of immobilizing and visualizing virus particles at the same time, by using biotinylated fluorescent DNA to pull down virus particles onto a microscope slide for observation. However, a further major advantage of the method is its compatibility with other techniques, such as existing virus purification or quantification assays. The method could feasibly be used as a rapid initial test to confirm the presence of a virus in a sample, which could then be followed up using antibody-specific labelling or RT-PCR if virus was detected. Published in Nature Scientific Reports (November 7, 2019): https://doi.org/10.1038/s41598-019-52759-5
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Scooped by
Juan Lama
November 8, 2019 6:59 PM
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A collaborative team of scientists has made a successful proof-of-principle demonstration of an advanced HIV vaccine strategy--an approach that may also work in protecting people from an array of other deadly infectious diseases. The team, led by scientists at Scripps Research, also included the Ragon Institute of Massachusetts General Hospital, MIT and Harvard University; the La Jolla Institute for Immunology; and IAVI, a scientific research organization focused on HIV and other global health challenges. Their research appears in Science. The new vaccine strategy centers on stimulating the immune system to produce broadly neutralizing antibodies (bnAbs) against HIV. These special antibodies are capable of neutralizing many different strains of the fast-mutating virus by binding to important yet difficult-to-access regions of the virus surface that don't vary much from strain to strain. The new vaccine strategy centers on stimulating the immune system to produce broadly neutralizing antibodies (bnAbs) against HIV. These special antibodies are capable of neutralizing many different strains of the fast-mutating virus by binding to important yet difficult-to-access regions of the virus surface that don't vary much from strain to strain. A vaccine that elicits such antibodies could save many millions of lives and billions of dollars--and ultimately, may help eliminate HIV as a significant public health problem. Based on a concept called "germline targeting," this novel strategy could potentially provide protection against the millions of different strains of the virus circulating globally. Achieving this goal has so far been elusive; no HIV vaccine candidate has ever been shown to induce a protective bnAb response in humans. "I believe that we need a germline-targeting strategy to develop an effective vaccine against HIV, and the same type of strategy may be helpful for making vaccines against many other difficult pathogens," says the study's co-senior author William Schief, PhD, a professor in the Department of Immunology and Microbiology at Scripps Research. "Here, with a great collaborative effort among multiple labs, we've shown the feasibility of a general germline-targeting approach." This study drew scientists from diverse backgrounds and areas of expertise: co-senior authors are Scripps Research's Schief, Facundo Batista, PhD, chief scientific officer at the Ragon Institute, and Shane Crotty, PhD, a professor in the Vaccine Discovery Division at La Jolla Institute for Immunology. The germline-targeting approach is meant to launch the production of a desired bnAb by stimulating the right antibody-producing cells. Antibodies are produced by immune cells called B cells, which start out in a "naïve" or "germline" state. A large repertoire of these germline B cells circulates in the blood and other tissues. In a viral infection--or after immunization with a vaccine that mimics an infecting virus--some germline B cells will bind at least weakly to structures on the surface of the virus. That will stimulate the cells to begin a weeks-long maturation process, in which the antibodies continuously improve in their ability to bind to the surface, thereby neutralizing the virus. The germline-targeting strategy for an HIV vaccine aims to stimulate the small number of germline B cells that are capable of maturing into cells that make bnAbs. Researchers suspect that other attempts to create an HIV vaccine that elicits bnAbs have failed because they haven't stimulated a sufficient number of these "bnAb precursor" germline B cells. Schief and colleagues previously demonstrated a germline-targeting strategy for one special case: a bnAb that grabs hold of HIV in an unusual way. The new approach is more powerful because it works for antibodies that grip their targets via a much more common mechanism. Furthermore, analyses performed in the study indicate that the approach can likely also be applied to vaccines for many other difficult pathogens such as influenza, dengue virus, Zika virus, hepatitis C and malaria. To demonstrate the feasibility of their strategy, Schief and Jon Steichen, PhD, a study co-first author and senior scientist in the Schief lab, started by choosing a known HIV bnAb called BG18 as the test case. Informed by structural studies of BG18 bound to its target on the virus--including structures determined for this study in the lab of Andrew Ward, PhD, professor of Integrative Structural and Computational Biology at Scripps Research, and published structures from the lab of Pamela Bjorkman, PhD, at Caltech--Steichen and Schief identified key features of this antibody's HIV-gripping ability. Next, they searched a large database of human antibody genes in order to find B cells making antibodies that naturally share BG18's key features. Then they used a sophisticated strategy to select and evolve a set of virus-mimicking proteins that could potentially activate multiple BG18-like B cells. These proteins would eventually serve as "immunogens" to stimulate BG18-like B cells in human vaccination. "As the repertoire of B cells differs from person to person, and in the same person over time, we believe that you need to target more than a few of these cells to have a reasonable chance of activating one of them in any given vaccine recipient," Steichen says. In the lab of Shane Crotty at the La Jolla Institute for Immunology, tests of blood samples from HIV-negative human donors confirmed that the team's immunogens bound well to normal circulating B cells that have the desired BG18-like features..... Published in Science (October 31, 2019): https://doi.org/10.1126/science.aax4380
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Juan Lama
November 6, 2019 10:39 AM
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A protein that is critical in controlling replication of West Nile and Zika viruses—and could be important for developing therapies to prevent and treat those viruses—has been identified by a Georgia State University biologist and his research group. The researchers found Z-DNA binding protein 1 (ZBP1) is a sensor that plays a significant role in triggering a robust immune response when it detects a viral infection within cells. The Georgia State study, published in the journal Frontiers in Microbiology, found ZBP1 is essential for restricting both West Nile and Zika virus replication, and that it prevents West Nile-associated encephalitis (inflammation of the brain) in mice. The absence of ZBP1 in mice leads to 100 percent mortality when infected with even a non-disease-producing strain of West Nile Virus, the study found. "It's significant because you take a virus that has never been shown to kill anything and if you block this protein the virus will just kill everything," said Mukesh Kumar, assistant professor of biology and senior author of the study. "We discovered that when cells are infected with viruses such as Zika and West Nile, they respond by triggering necroptosis, a form of programmed cell death, via ZBP1 signaling. This inhibits viral replication and spread, allowing the immune system to clear the virus." Kumar said the findings could present new treatment strategies for viruses that can infect the central nervous system by modulating ZBP1 expression. Subsequent research by Kumar's team will explore effectiveness against similar viruses such as Eastern Equine Encephalitis and Powassan virus. West Nile Virus is the leading mosquito-born disease and cause of viral encephalitis in the United States, with more than 50,000 people affected, including 480 cases reported in Georgia, according to the Centers for Disease Control and Prevention. There have been 2,330 associated deaths since it first reached the country in 1999. The Culex species of mosquito responsible for spreading it is common throughout the world. Zika, which is spread by the Aedes mosquito that has been found as far north as Florida and Texas, can cause serious neurological diseases such as Guillain-Barre syndrome, which causes the body's immune system to attack the nervous system. Birth defects such as microcephaly, an abnormally small head and brain can result. Most people who get Zika or West Nile don't get sick thanks to the body's natural immune response and may not know they've been infected, meaning their cases probably don't get reported. Of the West Nile cases reported in the U.S., nearly 50 percent invade the nervous system leading to life-threatening or -altering consequences such as encephalitis. Drug treatments are often ineffective once a virus reaches the brain, but Kumar hopes enhancing host ZBP1 expression within the central nervous system could clear the virus from the brain and prevent severe disease associated with neuroinvasive viral infections such as West Nile and Zika.... Study Published in Frontiers in Microbiology (Sept. 11, 2019): https://doi.org/10.3389/fmicb.2019.02089
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Juan Lama
November 4, 2019 6:30 PM
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As people age, they tend to develop diseases such as heart failure, kidney failure, diabetes, and obesity, and the presence of any one disease increases the risk of developing others. Traditional drug treatments, however, each target one condition. That means patients often have to take multiple medications, increasing both the risk of negative side effects and the likelihood of forgetting one. New research from the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School (HMS) suggests that it may be possible someday to tend to multiple ailments with one treatment. In the Wyss study, a single administration of an adeno-associated virus (AAV)-based gene therapy, which delivered combinations of three longevity-associated genes to mice, dramatically improved or completely reversed multiple age-related diseases, suggesting that a systems-level approach to treating such diseases could improve overall health and lifespan. The research is reported in PNAS. “The results we saw were stunning and suggest that holistically addressing aging via gene therapy could be more effective than the piecemeal approach that currently exists,” said first author Noah Davidsohn, a former research scientist at the Wyss Institute and HMS who is now chief technology officer of Rejuvenate Bio. “Everyone wants to stay as healthy as possible for as long as possible, and this study is a first step toward reducing the suffering caused by debilitating diseases.” The study was conducted in the lab of Wyss core faculty member George Church as part of Davidsohn’s postdoctoral research into the genetics of aging. Davidsohn, Church, and their co-authors homed in on three genes that had been shown to confer increased health and lifespan benefits in mice that were genetically engineered to overexpress them: FGF21, sTGFβR2, and αKlotho. They hypothesized that providing extra copies of those genes to nonengineered mice via gene therapy would similarly combat age-related diseases and bring health benefits. The team created separate gene therapy constructs for each gene using the AAV8 serotype as a delivery vehicle, and injected them into mouse models of obesity, Type 2 diabetes, heart failure, and renal failure both individually and in combination with the other genes to see whether there was a positive synergistic effect. FGF21 caused complete reversal of weight gain and Type 2 diabetes in obese, diabetic mice following a single gene therapy administration, and its combination with sTGFβR2 reduced kidney atrophy by 75 percent in mice with renal fibrosis. Heart function in mice with heart failure improved by 58 percent when they were given sTGFβR2 alone or in combination with either of the other two genes, showing that a combined therapeutic treatment of FGF21 and sTGFβR2 could successfully treat all four age-related conditions, therefore improving health and survival. Administering all three genes together resulted in slightly worse outcomes, likely from an adverse interaction between FGF21 and αKlotho, which remains to be studied. Importantly, the injected genes remained separate from the animals’ native genomes, did not modify their DNA, and could not be passed to future generations or between living animals. “Achieving these results in nontransgenic mice is a major step toward being able to develop this treatment into a therapy, and co-administering multiple disease-addressing genes could help alleviate the immune issues that could arise from the alternative of delivering multiple, separate gene therapies for each disease,” said Church, who is also a professor of genetics at HMS and professor of health sciences and technology at Harvard and MIT. “This research marks a milestone in being able to effectively treat the many diseases associated with aging, and perhaps could lead to a means of addressing aging itself.” Published in P.N.A.S. (November 4, 2019): https://doi.org/10.1073/pnas.1910073116
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Juan Lama
November 2, 2019 1:00 PM
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Dengue infection (DI) is the most important arboviral infection in the world. The majority of immunocompetent patients will have asymptomatic or mild infections, but the degree of dengue severity in kidney transplant recipients (KTx) is unknown. In recent decades, the growing number of organ transplant recipients in developing countries, living in or traveling to an endemic area of dengue, is at risk of developing this infection. Additionally, in kidney transplant recipients (KTx), DI may be associated with other viral infections, such as cytomegalovirus (CMV), increasing the risk for the recipients after renal transplantation (Tx). Because CMV remains one of the most important viruses affecting KTx, it is not clear whether the CMV coinfection may modify the outcome of DI as it usually does in other viral coinfections In this study, we report the clinical profile and outcomes of 39 dengue cases in KTx. From a total of 1,186 KTx outpatients in follow-up we reviewed clinical and laboratory records of 60 (5%) patients admitted with suspected DI initially screened by NS-1, IgM, and when possible, multiplex nested PCR. The prevalence of DI in KTx was 3% (39/1,118), with symptoms leading to hospital admission being fever, myalgia, malaise, and headache. Laboratory tests showed leucopenia, thrombocytopenia, and liver enzyme elevation. DI was confirmed by positivity of NS-1 (33%), IgM (69%), and/or RT-PCR (59%). Twenty-three patients (59%) had dengue with warning signs, and 15% had severe dengue, 2 of them with a fatal course. Acute graft dysfunction occurred in 59% (mean nadir serum creatinine: 2.9 ± 2.6mg/dL), 4 of them requiring dialysis. CMV coinfection diagnosed in 19% of the cases and patients was associated with worse clinical presentation. Our results suggest that KTx with DI presented initial physical and laboratorial profile similar to the general population. However, DI in KTx seems to have a higher risk for graft dysfunction, severe dengue, and death. Because CMV coinfection aggravates the DI clinical presentation and recovery, it must be evaluated in all cases. Published in PLOS One (October 30, 2019): https://doi.org/10.1371/journal.pone.0219117
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Juan Lama
November 1, 2019 8:42 PM
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Like an adjustable wrench that becomes the "go-to" tool because it is effective and can be used for a variety of purposes, an existing drug that can be adapted to halt the replication of different viruses would greatly expedite the treatment of different infectious diseases. Such a strategy would prevent thousands of deaths each year from diseases like dengue and Ebola, but whether it can be done has been unclear. Now, in new work, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) show that repurposing an existing drug to treat viral diseases is in fact possible - potentially bypassing the decades needed to develop such a broad-spectrum drug from scratch. In a new study published in the journal Molecular Therapy, the Temple researchers report that a drug used in the treatment of HIV also suppresses Zika virus infection. In cell and animal models, they show that the drug, called rilpivirine, stops Zika virus by targeting enzymes that both HIV and Zika virus depend on for their replication. These enzymes occur in other viruses closely related to Zika, including the viruses that cause dengue, yellow fever, West Nile fever, and hepatitis C. Dr. Khalili, a senior investigator on the new study, attributed the breakthrough work to a productive collaboration with Temple University colleagues, including Dr. Michael L. Klein, FRS, Laura H. Carnell Professor of Science and Dean of the College of Science and Technology at Temple; and Ilker K. Sariyer, DVM, PhD, and Jennifer Gordon, PhD, Associate Professors of Neuroscience at Temple's Center for Neurovirology. Historically rare and isolated to parts of Africa and Asia, Zika virus is now present throughout the Americas and occurs in multiple other regions of the world. It has attracted increasing attention in recent years, owing to its damaging effects to the brain and nervous system. The virus is transmitted to humans by mosquitoes. Once in the body, it infects cells and replicates, typically taking up residence in cells in neural tissues. In severe cases, Zika virus infection can cause an autoimmune condition known as Guillain-Barré syndrome, which culminates in muscle paralysis. Infants born to mothers infected during pregnancy may experience delays in neurological development and may be affected by microcephaly (abnormal smallness of the head). To replicate inside cells, Zika virus requires an enzyme called non-structural protein 5 RNA-dependent RNA polymerase (NS5 RdRp). In the new study, Dr. Sariyer showed that rilpivirine suppresses Zika virus infection in cells by blocking viral replication. Using structural biology and computational studies, Eleonora Gianti, PhD, a research assistant professor in Dr. Klein's laboratory, was able to show that rilpivirine prevents viral replication by binding specifically to the NS5 domain. Dr. Gordon's team carried out experiments in mice, in which animals were infected with Zika virus through their footpads, similar to the way a person becomes infected through a mosquito bite. Mice that become infected with Zika virus normally become very sick within about a week and eventually die. "We found, however, that when treated with rilpivirine, the animals survived," Dr. Gordon said. "Our conclusion is that rilpivirine disrupted the virus's usual course of infection." Rilpivirine is one of several non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs that have been developed for the treatment of HIV infection. Experiments in which the Temple researchers tested two other NNRTIs in Zika-infected cells revealed similar effects on viral replication, with the drugs specifically inhibiting NS5 activity. Published on Molecular Therapy (October 11, 2019): https://doi.org/10.1016/j.ymthe.2019.10.006
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Juan Lama
November 1, 2019 8:27 PM
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The USAID’s Predict program, which conducted animal virus surveillance and disease outbreak prevention training, is ending after its 10-year funding run according to The New York Times. Launched after an H5N1 bird flu outbreak, Predict was part of an effort to search for previously undiscovered zoonotic diseases, which are passed from animals to humans. Viruses such as AIDS, SARS, MERS, Ebola, and certain influenza strains originally came from animals. Researchers found more than 1,000 new viruses from animal samples collected during the program’s run, including a new Ebola strain. In addition, it provided disease outbreak prevention training for thousands of people and strengthened medical laboratories in developing countries. The program, which partnered with universities, conservation groups, and nonprofits to track, monitor, and prevent disease, was shut down at the end of its 10-year funding cycle [did the article explain why it wasn’t continued?]. Some public health officials worry that its end could leave the world more vulnerable to dangerous epidemics. “Predict needed to go on for 20 years, not 10,” says Jonathan Epstein, a veterinarian with the nonprofit EcoHealth Alliance, a Predict partner organization, to the Times. Some projects will be continued by other government agencies, but the focus on training health workers abroad will be reduced. The end of Predict “is really unfortunate, and the opposite of what we’d like to see happening,” Gro Harlem Brundtland, the former prime minister of Norway and the former World Health Organization director-general, tells the Times. “Americans need to understand how much their health security depends on that of other countries, often countries that have no capacity to do this themselves,” she adds.
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Juan Lama
October 31, 2019 7:44 PM
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A virus which commonly lives on human skin (so-called ‘low-risk’ human papillomaviruses) appears to play a role in protecting against skin cancer. They suggest this could be used within a therapeutic strategy. Patients who have immune systemsthat are suppressed from diseases or medical therapy are at an increased risk for cancers linked to viral infections, particularly squamous cell carcinoma (SCC) of the skin. Although multiple studies have tried to show a link between human papillomavirus (HPV) infections and SCC, none have been able to show that HPVs drive the development of the skin cancers, said Shawn Demehri, MD, PhD investigator in the Center for Cancer Immunology at Massachusetts General Hospital (MGH) department of Dermatology. Instead, working with experimental models and tissue samples from human skin cancer, Demehri and his colleagues found that the presence of ‘commensal’ papillomaviruses (low-risk forms of HPV that live on the skin of the majority of people) appears to have an indirect protective rather than harmful effects against SCC. “This is the first evidence that commensal viruses could have beneficial health effects both in experimental models and also in humans and it turns out that this beneficial effect has to do with cancer protection. The role of these commensal viruses, in this case papillomaviruses, is to induce immunity that then is protecting patients from skin cancers,” he said. Their findings suggest a novel method for preventing skin cancer using a vaccine based on T cells. “T cell-based vaccines against commensal HPVs may provide an innovative approach to boost this antiviral immunity in the skin and help prevent warts and skin cancers in high-risk populations,” the researchers write. They note that augmenting natural immunity against HPV immunity may further improve the effectiveness of immunotherapy against SCC using immune checkpoint inhibitors. Demehri and colleagues conducted experiments with mouse models showing that those with intact immune systems and natural immunity against papillomaviruses, as well as mice that had adaptive immunity from transfer of T cells, were protected when exposed to ultraviolet light or chemicals known to cause skin cancer. They also tested human skin cancer samples for the presence and activity of 25 known commensal low-risk HPVs and found that viral activity and viral load were significantly reduced in the skin cancers compared with adjacent normal skin, “suggesting a strong immune selection against virus-positive malignant cells.” Published in Nature (October 30, 2019): https://doi.org/10.1038/s41586-019-1719-9
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Juan Lama
October 30, 2019 3:46 PM
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Teams of researchers from Charité – Universitätsmedizin Berlin and the Medical University of Innsbruck have developed a new therapeutic concept for the treatment of temporal lobe epilepsy. It represents a gene therapy capable of suppressing seizures at their site of origin on demand. Having been shown to be effective in an animal model, the new method will now be optimized for clinical use. Results from this research have been published in EMBO Molecular Medicine. Epilepsy affects approximately 5 million people in Europe. The disorder is characterized by the recurrent and synchronized firing of groups of nerve cells. The propagation of these electrical discharges interrupts normal brain function and produces an epileptic seizure. The most common form of epilepsy is known as temporal lobe epilepsy (TLE), which is characterized by seizures originating in the temporal lobes. Long-term consequences of TLE can include memory problems as well as impaired learning and emotional control. Additionally, TLE patients’ quality of life is severely affected by restrictions on their ability to work, drive a car or do sports. This is further compounded by the fact that the drugs used to treat TLE patients are often unable to adequately control the disorder yet are still associated with severe side effects. For this particular group of patients, surgical removal of the temporal lobe frequently remains the only treatment alternative. However, this treatment is associated with adverse cognitive outcomes and does not guarantee that patients will remain free from seizures. Working alongside Prof. Dr. Christoph Schwarzer (Medical University of Innsbruck’s Department of Pharmacology), Prof. Dr. Regine Heilbronn (Director of the Institute of Virology on Charité’s Campus Benjamin Franklin) developed a new therapeutic concept for drug-resistant TLE. The new treatment method is based on targeted gene therapy. This technique involves the selective delivery of a specific gene to nerve cells within the area of the brain from which the epileptic seizures originate. The gene provides the cells with the information needed to synthesize dynorphins. These are naturally produced peptides which modulate neural activity. Once the gene has been delivered into the nerve cells, it remains there permanently. The cells then start to produce and store dynorphins. Explaining the new technique’s mechanism of action, Prof. Schwarzer says: “High-frequency stimulation of the nerve cells, such as that seen at the beginning of a seizure, results in the release of stored dynorphins. Dynorphin dampens signal transduction and, as a result, the epileptic seizure doesn’t spread.” The neurobiologist and epilepsy expert goes on to add: “As the cells will only release this substance when needed, this type of gene therapy is referred to as ‘release-on-demand’.” Using an animal model, the researchers were able to show that this gene therapy is capable of suppressing epileptic seizures for several months. Reduction of seizures also meant relief from their adverse effects on memory and learning. Moreover, no side effects have been observed so far. This is most probably due to the site-specific release of dynorphin and its short duration of action. Thanks to the substance’s on-demand delivery, there was also no evidence of drug tolerance. The researchers then went on to test their new treatment concept using tissue samples obtained from epilepsy patients. They did so with great success, as dynorphin was shown to significantly reduce the severity and frequency of synchronized nerve cell activity in human epileptic tissue... Published on EMBO Mol. Medicine (October 30, 2019): https://doi.org/10.15252/emmm.201809963
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Juan Lama
November 17, 2019 11:35 AM
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Adolescents and young adults who were born to mothers with HIV but remained uninfected themselves still face a greatly heightened risk of obesity and asthma-like symptoms, researchers from Massachusetts General Hospital (MGH) have found. In a study published in Journal of Acquired Immune Deficiency Syndromes (JAIDS), the team revealed for the first time that HIV-negative teens and young adults with a history of in utero HIV exposure showed more than fourfold increased odds of obesity and asthma-like symptoms compared to their unexposed peers. "Our study found that there are metabolic and immune consequences to being exposed to HIV in utero," says Lindsay Fourman, MD, of the Metabolism Unit, Department of Medicine, MGH, and lead author of the study. "These results underscore the need for all children of mothers with HIV—even those who are HIV-negative—to be screened and continually monitored over their lifetimes by clinicians attuned to their health risks. Too often, their exposure to HIV is lost from their medical records after they are found to be HIV-negative." Globally, more than one million babies are born each year to mothers with HIV. With the scale-up of prenatal antiretroviral therapy to prevent maternal transmission during pregnancy, up to 98 percent of these infants may be HIV-exposed but uninfected (HEU). While understanding the short-term health consequences of intrauterine HIV exposure has been actively investigated, the long-term health outcomes of uninfected individuals into adolescence and adulthood remain largely unknown. The MGH researchers shed light on the subject by looking at the mother's level of immune cells—known as CD4 T cells—during the last trimester of pregnancy. They found that lower maternal CD4 T cell count was strongly associated with increased body mass index (BMI), a measure of body fat based on height and weight, in their uninfected, adolescent offspring. Lower CD4 T cell count is also associated with more severe HIV infection during pregnancy. "These linkages suggest the need for good immune system control during the mother's pregnancy," emphasizes Steven Grinspoon, MD, chief, Metabolism Unit at MGH and study co-author. "Improved immune regulation may not only be good for the mother during pregnancy, but for her child over the long-term." The comprehensive study drew on a cohort of 50 adolescents and young adults (ages 13 to 28 years old) who were HIV-exposed but uninfected (HEU), and 141 of their peers not exposed to HIV during pregnancy. All were part of the Research Patient Data Registry that includes patients from MGH, Brigham & Women's Hospital, and other affiliated hospitals. The researchers found that obesity was present in 42 percent of the HEU adolescents and young adults compared to 22 percent of their unexposed counterparts.... Published in Journal of AIDS (November 14, 2019): https://doi.org/10.1097/QAI.0000000000002235
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Juan Lama
November 16, 2019 11:27 AM
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As the global effort to eradicate polio gets tantalizing close to its goal, the program is running in to new challenges. One of the biggest obstacles this year is the proliferation of so-called "vaccine-derived" polio outbreaks. Conventional polio caused by the traditional form of the disease is now only occurring in two countries in the world — Afghanistan and Pakistan. The World Health Organization calls this form "wild" polio and there've been roughly 100 cases so far this year. This is a tiny number compared to the 350,000 cases that occurred globally before the Global Polio Eradication Initiative was launched in 1988. But what's troubling now is that there are currently more kids being paralyzed by cases of vaccine-derived polio than by the original "wild" variety. "We have seen a lot more countries impacted this year than last year," says Dr. John Vertefeuille, the head of polio eradication at the U.S. Centers for Disease Control and Prevention. There've been outbreaks this year in the Philippines, China, Myanmar, Pakistan and a half a dozen African countries. "Because of the rising number of individual outbreaks," Vertefeuille says. "The CDC has taken a decision to do a surge staffing effort focusing on Africa." He says the CDC is in the midst of sending up to 100 additional personnel to Africa to help track, manage and wipeout vaccine-derived polio outbreaks over a six-month period. Currently around the world, all children are supposed to get vaccinated against polio. In the U.S. and other wealthy nations, kids get 4 injections of inactivated polio vaccine spread out over their first 7 years of life. This injectable vaccine does not contain live virus, so it does not and cannot cause vaccine-derived polio. In lower income countries with weaker health systems, an oral vaccine containing a live but weakened version of the polio virus is used. It's cheap and easy to administer through a few drops in a child's mouth. In the early days of polio eradication, this live oral vaccine also had the added benefit that it could circulate in a community just like the real, wild virus. In places with poor sanitation, wild polio and the virus in the oral vaccine can spread from sewage to drinking water. At first this was great. Kids who hadn't been vaccinated by health workers ended up getting exposed to the oral vaccine and protected against wild polio because of their lousy drinking water supplies. But over time the virus from the oral vaccine starts to regain strength and if it's allowed to circulate long enough, it reverts back to the point that it can cause paralysis just like the original virus. "We actually do genetic analysis so that we can understand the closest relative of each (virus) detection that we see globally," says Vertefeuille at the CDC. And in these vaccine-derived outbreaks, they can see that the virus that's paralyzing kids is directly linked to the vaccine that was distributed earlier. "You have to keep vaccinating all the children so you won't have any paralyzed children," Noymer says, "But the more you vaccinate, the more live virus continues to circulate. And the minute you step off the treadmill, you get some paralyzed kids." One way to get off that treadmill would be to get rid of the live oral vaccine and switch to the not-live, injectable vaccine used in the United States. The Global Polio Eradication Initiative has tried to move in that direction but there are several challenges. First there just isn't enough supply globally of the injectable vaccine to cover the hundreds of millions of kids in low income countries. Training vaccinators to give injections is much harder than training them to give two drops in to a child's mouth. Also the vaccines work slightly differently — with the oral version doing a better job of breaking chains of transmission and stopping outbreaks....
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Juan Lama
November 14, 2019 7:51 PM
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Mosquitoes zapped with radiation to make them sterile are set to be released into the wild in a bid to fight outbreaks of dengue fever. The World Health Organization has announced that from next year it will start large-scale studies of what is known as the sterile insect technique. This involves irradiating male Aedes mosquitoes, the species responsible for the spread of diseases such as dengue, Zika and chikungunya. The scientists hope that the sterile males will be released in such large numbers that they will overwhelm the native male population and then go on to mate with females. But they will produce no offspring so the insect population will reduce over time, alongside the number of cases of the disease. The technique has been used for about 50 years in the management of agricultural pests, such as the Mediterranean fruit fly, and experts are confident that it poses no risk to either human health or the environment. WHO has been working with organisations including the International Atomic Energy Agency (IAEA) and the Food and Agriculture Organisation on preliminary studies in countries including Bangladesh, Cuba, Brazil and Mauritius. Dengue fever has become a major health threat with 110 countries around the world suffering outbreaks this year. WHO believes that as many as five million cases may be reported by the end of 2019 - up from an average of three million in previous years. Urbanisation and climate change are expected to see the mosquito responsible for transmitting the disease spread to new areas. Raman Velayudhan, coordinator of WHO’s department of neglected tropical diseases, said there was a desperate need for new tools to control the Aedes mosquito which lives in urban areas, bites during the day and whose eggs are able to survive for long periods. “It’s a unique mosquito which has silently expanded and today is present in over 130 countries,” he told a press conference, where the trial was announced. Experts insist the technique is safe - the mosquitoes are not “radioactive” and there is no genetic mutation. WHO also stresses that the technique will not harm the wider eco-system. There are more than 3,500 different types of mosquito that serve as food for animals so removing one species will have little impact. The IAEA is looking at refining the technique for malaria-carrying mosquitoes, although Dr Velayudhan said there were already control tools for this mosquito, such as bed nets and indoor residual spraying.
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Juan Lama
November 12, 2019 8:56 PM
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The US Food and Drug Administration halts a study by Solid Biosciences after a patient experiences severe side effects following treatment. A clinical trial of a gene therapy for Duchenne muscular dystrophy has been halted after a patient suffered serious side effects following treatment, Reuters reports today (November 12). After receiving Solid Biosciences’s experimental therapy, SGT-001, the patient experienced kidney injury and drops in red blood cell count, leading the US Food and Drug Administration (FDA) to place the study on hold. “We are encouraged that this patient is recovering,” Ilan Ganot, Solid Biosciences’s CEO, president, and cofounder, says in a statement. “In the coming weeks, we anticipate that we will have a better understanding of the biological activity and potential benefit of SGT-001. We look forward to sharing this additional data and working with the FDA to resolve the clinical hold and determining next steps for the program.” SGT-001 has been administered to six people so far, and involves the transfer of an engineered version of the dystrophin gene DMD, which is dysfunctional in people with Duchenne muscular dystrophy, using an adeno-associated virus (AAV) as a vector. Sarepta Therapeutics, Pfizer, and other biopharmaceutical companies are investigating similar approaches to treat the condition, although the choice of AAV varies. This isn’t the first time Solid Biosciences’s trial of SGT-001 has been put on hold. Early last year, the FDA halted the same study after a patient receiving a low dose of the therapy experienced a drop in red blood cell count and had to be hospitalized. The company was allowed to resume the trial last June after making changes to the study design. In February, the company reported disappointing interim results from the first stage of the trial, which administered a low dose of the therapy to the first three patients in the study. The patient mentioned in today’s announcement was one of three patients subsequently given a higher dose. Shares in the company dropped 71 percent following today’s announcement, according to Reuters.
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Juan Lama
November 11, 2019 10:23 AM
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The gene-editing tool CRISPR has been heralded as a scientific miracle destined to eradicate diseases from sickle-cell anemia to cancer, or decried as "the genetic scissors that tailor the human gene pool," an ethically risky technology driving us toward a designer babies. Case Western Reserve University researchers see a different opportunity in the CRISPR technique: A new "universal biosensing" point-of-care medical device--similar to the existing commercial blood-glucose sensor--that rapidly and accurately detects troublesome viruses like human papillomavirus (HPV) or parvovirus B19 (PB-19). To do that, researchers converted the CRISPR "recognition induced enzymatic signal" to an electrical signal, which was then used to detect the biomarkers for those viruses. Dai is the lead author on a paper about the process which landed the cover story for Angewandte Chemie, a journal of the German Chemical Society. Dai said existing tests for those viruses take three to five days for an accurate result and can be expensive, while the biosensor envisioned by Case Western Reserve researchers would provide accurate results in under an hour. According to the U.S. Centers for Disease Control, HPV is a common virus that can lead to six types of cancers later in life. Nearly 80 million Americans are infected with some type of HPV, spread through intimate skin-to-skin contact. Parvovirus B19, or parvo, spreads through respiratory secretions, such as saliva or nasal mucus, when an infected person coughs or sneezes. The virus can present a range of symptoms, depending on a person's age and overall health. About two out of 10 people infected with this virus will have no symptoms. Others may have only a mild rash..... E-CRISPR is the name Dai and co-authors gives to what they call an "electrochemical platform" that relies on the precision of the CRISPR technique to identify and quantify viruses in the blood. What sounds complex is actually quite simple, Dai said, "The CRISPR technique works so that it cuts all of the nonspecified single-strand DNA around it once the target is recognized, so we program to electrochemically probe this activity," he said. "No virus--no cutting, it's that simple. And the opposite is true: If CRISPR starts to cut, we know the virus is present." Published in the J. Angewandte Chemie (September 30, 2019).: https://doi.org/10.1002/anie.201910772
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Juan Lama
November 8, 2019 12:33 PM
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The vaccine provided protection from Ebola virus, Sudan virus, Marburg virus and Lassa virus. Scientists funded by the National Institutes of Health have developed an investigational vaccine that protected cynomolgus macaques against four types of hemorrhagic fever viruses endemic to overlapping regions in Africa. The University of Texas Medical Branch in Galveston and Profectus BioSciences of New York are developing and testing the candidate quadrivalent VesiculoVax vaccine, with support from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Redeemer’s University in Nigeria. The newly published study in the Journal of Clinical Investigation describes how the vaccine was created using a live-attenuated (weakened) vesicular stomatitis virus to deliver proteins that elicit protective immune responses. The proteins are from Ebola virus (Kikwit strain), Sudan virus (Boniface strain, which also causes Ebola virus disease), Marburg virus (Angola strain) and Lassa virus (Josiah strain). There are no licensed vaccines to provide protection from any of those viruses — all of which can cause severe disease and death — although the European Medicines Agency has recommended licensing a VSV-Ebola vaccine. Importantly, the monkeys infected in the study were exposed to different strains of Sudan virus (Gulu) and Lassa virus (0043/LV/14) than those in the candidate vaccine to help the researchers determine whether the vaccine would be cross-protective. Lassa 0043/LV/14 is circulating in an outbreak in Nigeria that began in 2018. Previous studies indicate that the investigational Ebola virus (Kikwit) vaccine will protect against other strains of Ebola virus. The scientists inoculated 20 macaques with a primary and booster dose of quadrivalent VesiculoVax. The animals had five blood draws to check for an immune response, including on the day of initial vaccination and on days 10 and 28, then on day 56 when they received a booster inoculation, and again on day 66. On day 84 scientists infected the macaques with the four different hemorrhagic fever viruses and monitored them to day 112. Twelve additional macaques in the study who were infected with the four viruses but not vaccinated all became sick, but none of the vaccinated animals did. Only one of the 20 vaccinated animals had any of the four hemorrhagic fever viruses detectible (Lassa) following the study. The scientists state that the addition of the Lassa virus component to their multivalent vaccine is an exciting research advance as they already had developed an investigational trivalent vaccine that provided protection against Ebola, Sudan and Marburg viruses. The researchers now plan further vaccine tests against other strains of Lassa virus, and they want to further evaluate whether a single-dose quadrivalent vaccine appears safe and effective. Published in the Journal of Clinical Investigation (October 22, 2019): https://doi.org/10.1172/JCI131958
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Juan Lama
November 5, 2019 2:55 PM
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Genes from a virus that was stitched into the human genome thousands of years ago are active, producing proteins in the human brain and other tissues, according to researchers at the University of Washington School of Medicine and the Laval University School of Medicine in Quebec, Canada. Their finding might help explain why people who inherit this “fossil virus” appear to have a higher risk of developing neurodegenerative diseases such as multiple sclerosis and Alzheimer’s. “There have been some reports that the virus, called human herpesvirus-6, can reactivate, but if it does, it’s rare,” said Dr. Alex Greninger, UW assistant professor of laboratory medicine. “What we wanted to know whether some of the virus’ individual genes were being turned on without full reactivation of the virus.” The Journal of Virology published the article recently. Its lead authors were Vikas Peddu, a bioinformatician in the Greninger lab, and Isabelle Dubuc of Laval University. The project was led by Greninger and Louis Flamand, professor in the microbiology and immunology at Laval. The researchers were interested in two versions of human herpesvirus-6 (HHV-6) that can integrate into chromosomes and be inherited like any other human gene. HHV-6B causes the common childhood illness, roseola. This infection affects about 90 percent of children early in life, causing high fevers and rash. However, relatively little is known about the second virus, HHV-6A. After infection, both viruses can remain dormant in the body and reactivate later, particularly in people whose immune systems are suppressed. In the new study, the researchers looked at a form of the virus that is not acquired by infection but which about one in a hundred people inherit as part of their genome. About 8 percent of human DNA comes from viruses inserted into our genomes in the distant past, in many cases into the genomes of our pre-human ancestors millions of years ago. Most of these viral genes come from retroviruses, RNA viruses that insert DNA copies of their own genes into our genomes when they infect cells. HHV-6 is unique because it is the only known human DNA herpesvirus that integrates into the human genome and can be routinely inherited. HHV-6’s genome may have been accidentally copied into the human genome because it has repeating DNA sequences that resemble those found in human chromosomes. In conducting the study, the investigators analyzed a database of genome sequences of 650 people who gave consent before they died for their DNA genomes to be researched. The scientists also had access to cellular RNA in up to 40 tissue samples. “A lot of human genomicists have overlooked these integrated HHV-6 sequences in human genomes. They’re not in the human reference sequences and they’re not common enough to rise on the radar,” Greninger said. The researchers identified six individuals who had HHV-6 integrated in their genomes: two with HHV-6A and four with HHV-6B. The RNA sequences revealed that in these individuals, a number of viral genes were being actively expressed, in particular one gene called U90 and another called U100. In most tissues, the level of expression was low and sporadic, but the highest expressions were found in the esophagus, testes, adrenal gland and brain. The gene U100 codes for a viral protein that is part of the viral outer shell, or envelope. U90 codes for a protein known as a transactivator, which means it promotes the expression of other genes.... Published in Journal of Virology (Open Access)(Oct. 9, 2019) https://doi.org/10.1128/JVI.01418-19
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Juan Lama
November 4, 2019 11:30 AM
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ETH researchers are using synthetic biology to reprogram bacterial viruses—commonly known as bacteriophages—to expand their natural host range. This technology paves the way for the therapeutic use of standardized, synthetic bacteriophages to treat bacterial infections. Bacteriophages ("phages" for short) are viruses that infect bacteria. Phages are highly host-specific and will typically only infect and kill an individual species or even subspecies of bacteria. Compared to conventional antibiotics, phages do not indiscriminately kill bacteria. Therefore when used as a therapeutic, phages do not cause collateral damage to beneficial "good" bacteria living in the gut. This ability to target only disease-causing bacteria has led to phages being seen as potential "magic bullets" in the fight against bacterial infections, especially against bacteria that have developed antibiotic resistance. However, the high specificity of phages is also a disadvantage: Clinicians have to administer different combinations of phages to be sure the right phage is present to target a single bacterial infection. Not only does this approach limit the chances of phage therapy becoming a standardized treatment option, but also finding a phage, or combination of phages, for every infection becomes a time-consuming and labor-intensive task. Until now, phages had to be first isolated from their natural environment, tested against the bacterial strain(s) in question, and—most importantly—have their genomes sequenced to ensure they are safe for use in humans. Genetically modified phages Under the direction of Samuel Kilcher, an "Ambizione" fellow funded by the Swiss National Science Foundation, researchers from the Institute of Food, Nutrition and Health (IFNH) at ETH Zurich have genetically reprogrammed phages to produce synthetic phages that recognize and attack a broader range of bacterial strains beyond their natural host. The researchers reported their findings in the journal Cell Reports. On the bottoms of phage tails are specialized receptor binding proteins that recognize specific receptors on the exposed cell walls of a target bacterium. "Using X-ray crystallography, we cracked the atomic structure of the first receptor binding protein from a Listeria phage, providing the structural blueprint for re-engineering our phages," says lead author Matthew Dunne. Akin to building with Lego blocks, the researchers assembled new receptor binding proteins by fitting together protein components derived from different phages to provide different host specificities. Finally, the researchers genetically modified Listeria phages with their designer receptor binding proteins, resulting in phages that recognize and kill new strains of the target bacterium. Although these designer phages attack different new hosts, they all share the same genome, except for the gene encoding their receptor binding proteins. Phage cocktail as a form of therapy A mixture of such phage variants could now be used to treat patients. "We could cover a broad range of hosts by administering several synthetically produced phages in a single cocktail," Kilcher explains. The difference to a wild-type phage cocktail is that the synthetic ones could be developed, produced and adapted in a much more targeted fashion. Cultivating artificial phages in pure culture is neither expensive nor labor-intensive. "We can program them accordingly for almost every specific purpose," he adds. Alongside therapeutic applications, the researchers could also use the synthetic phages as diagnostic markers of specific molecular structures, such as for detecting pathogenic strains among a mixed bacterial population... Studies published in Cell Reports (October 29, 2019): https://doi.org/10.1016/j.celrep.2019.09.062
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Juan Lama
November 2, 2019 12:41 PM
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Immune responses that are associated with a decreased risk of infection are called correlates of protection (CoP). Clinical trials that measure vaccine-induced antibody and cell-mediated immune responses help to define CoP to HIV, which are necessary to assess the efficacy of a promising HIV vaccine candidate.A pilot study led by senior authors Georgia Tomaras and Peter Gilbert and first authors Scott Neidich, Youyi Fong and Shuying Li of the NIAID-funded HIV Vaccine Trials Network (HVTN) demonstrated that an increase in three antibody-mediated immune responses (antibody-mediated Fcƴ receptor [FcƴR] recruitment, antibody-dependent cellular phagocytosis [ADCP], and anti-Env IgG3) correlated with a decrease in HIV transmission. To date, only the RV144/Thai trial has demonstrated moderate efficacy for an experimental HIV vaccine. RV144 identified two primary immune correlates—IgG antibodies to the variable regions of HIV Env correlated with decreased risk of HIV transmission, and plasma IgA to Env correlated with decreased vaccine efficacy. As only one HIV vaccine trial has shown efficacy thus far, the RV144 immune correlates should be corroborated in an independent study to confirm the CoP are true surrogate markers for protection from HIV acquisition. To date, only the RV144/Thai trial has demonstrated moderate efficacy for an experimental HIV vaccine. RV144 identified two primary immune correlates—IgG antibodies to the variable regions of HIV Env correlated with decreased risk of HIV transmission, and plasma IgA to Env correlated with decreased vaccine efficacy. As only one HIV vaccine trial has shown efficacy thus far, the RV144 immune correlates should be corroborated in an independent study to confirm the CoP are true surrogate markers for protection from HIV acquisition. To test whether the antibody functions were independent correlates of HIV risk, ADCP and antibody-mediated FcƴR recruitment (antibody-mediated immune responses) were statistically assessed and the polyfunctionality score for CD4+ and CD8+ T cells (cellular-mediated immune responses) were measured. The authors found that both the antibody- and cellular-mediated immune responses significantly correlated with the decreased transmission of HIV. Individual Env IgG3 (subclass of antibody) measurements significantly correlated with reduced risk of HIV transmission. Env IgA responses modulated antibody Fc effector functions supporting the previously identified RV144 IgA CoR. To best predict the transmission of HIV, this study demonstrated that measuring both antibody and cellular mediated immune responses are necessary. The antibody and cellular mediated immune responses at four weeks after the final vaccination (month 7) were determined in a blinded case control study of 125 HVTN 505 participants who did not acquire HIV and 25 participants who acquired HIV. Previous studies confirmed that vaccine-induced CD8+ T cells impact viral load; however it is not known if antibody Fc effector functions can play a protective role after HIV infection in humans. The researchers examined the relationship between the strength of antibody Fc effector functions with viral load (VL) set point in those vaccinees who acquired HIV. The pilot study confirmed that antibody effector function significantly correlated with lower VL set point in those vaccinees who acquired HIV. Notably, of the antibody responses, ADCP and IgG3 were among the strongest correlates associated with the decrease in HIV transmission; however, Fc?RIIa engagement was the only correlate of decreased VL in infected vaccinees. ADCP, IgG3 and FcR engagement are emerging hypotheses that can be tested as a CoP upon completion of the HVTN 702, HVTN 705, and HVTN 706 large-scale HIV vaccine efficacy trials underway globally. Published in J. Clinical Investigation (October 7, 2019): https://doi.org/10.1172/JCI126391
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Juan Lama
November 1, 2019 8:33 PM
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The FDA has imposed a partial hold on clinical trials for intrathecal administration of the Novartis gene therapy AVXS-101, which won the FDA's first approval for treating some forms of spinal muscular atrophy (SMA) in May under the name Zolgensma® (onasemnogene abeparvovec-xioi). The partial hold does not affect the marketing of Zolgensma or clinical trials assessing intravenous (IV) delivery of AVXS-101, Novartis emphasized. However, the hold affects studies assessing AVXS-101 administered as an injection into the spinal canal in patients with SMA Type 2. As a result of the hold, enrollment in the high dose cohort has been stopped in the Phase I STRONG trial (NCT03381729), an ongoing, open-label, dose-comparison, multi-center trial designed to evaluate the efficacy, safety, and tolerability of one-time intrathecal administration of AVXS-101. The low- and mid-dose cohort enrollment has previously been completed and interim results have been presented. The pharma giant said the partial hold followed AveXis, A Novartis Company, alerting authorities and clinical trial investigators about animal findings from a small, AveXis-launched preclinical study showing dorsal root ganglia (DRG) mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss. “The clinical significance of the DRG inflammation observed in this preclinical animal study is not known and was not seen in prior animal studies with AVXS-101,” Novartis said in a statement, adding that DRG inflammation can be associated with sensory effects. “We have completed a thorough review of human safety data from all available sources to date and no adverse effects related to sensory changes have been seen in AVXS-101 intrathecal or Zolgensma. We are working with health authorities to confirm further guidance to clinical investigators.” Novartis also said it will continue to closely monitor for any reports of related safety events in patients, adding: “We remain confident that the overall benefit-risk profile for patients on treatment is favorable.” The partial clinical hold comes a month after another safety issue related to the gene therapy. Last month, Novartis acknowledged the death of a six-month-old patient treated with Zolgensma in the European Phase III clinical trial STRIVE-EU (NCT03461289)—but insisted that the death was not the result of toxicity within the gene therapy. “According to the coroner’s report, the immediate cause of death was hypoxic-ischemic brain damage with respiratory tract infection as the underlying cause,” AveXis stated on September 19. “SMA Type 1 was indicated as the underlying cause for the respiratory tract infection. In addition, there was no evidence of an inflammatory CNS process or a toxic or a treatment-related brain damage.” Zolgensma is an adeno-associated virus vector-based gene therapy that won FDA approval on May 24. Zolgensma is indicated for the treatment of SMA in pediatric patients less than two years of age with SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.....
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Juan Lama
November 1, 2019 11:28 AM
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New research shows the virus can have devastating effects on the immune system that persist much longer than the illness itself. Measles is far more dangerous than most people realize, new research shows. The disease itself can cause a severe and sometimes deadly illness, but two new studies published on Thursday found that even when patients recover, the virus can inflict lasting harm on their immune systems. The weakened immunity leaves a child vulnerable for several years to other dangerous infections like flu and pneumonia. The damage occurs because the virus kills cells that make antibodies, which are crucial to fighting off infections. Scientists call the effect “immune amnesia.” During childhood, as colds, flu, stomach bugs and other illnesses come and go, the immune system forms something akin to a memory that it uses to attack those germs if they try to invade again. The measles virus erases that memory, leaving the patient prone to catching the diseases all over again. The findings make the need for measles vaccination even more urgent, because it protects children against much more than measles, the researchers said. “When parents say no to getting a measles vaccine, you’re not just taking a risk of your kid getting measles, you’re causing them to lose this amazing resource of defenses they’ve built up over the years before measles, and that puts them at risk of catching other infections,” said Dr. Michael J. Mina of the Harvard Medical School and Brigham and Women’s Hospital, the lead author of one of the new studies, published in the journal Science. “You’ve got to watch your kid’s back for a few more years.” In fact if a person who has received vaccinations for other diseases contracts measles, it may wipe out the protection those vaccines had provided. Revaccination could help restore the child’s immunity, the researchers said. The second study, by a different team, was published in Science Immunology. “This is wonderful science,” said Dr. William Schaffner, an infectious disease expert at Vanderbilt University, who was not involved in the research. “These are two wonderfully complementary studies that have provided a basic immunologic understanding of a phenomenon that has been recognized for a long time, mainly that measles infection causes immune suppression.” The studies arrive at a time of heightened concern about measles, as outbreaks flare up in the United States and other developed countries where vaccines had largely eradicated the disease, but where a growing number of parents have begun to refuse vaccination. Some claim religious reasons, and some mistakenly fear a link to autism, based on research that has been discredited as fraudulent. Globally, the measles vaccine is estimated to have saved 21 million lives between 2000 and 2017. But there are still more than 7 million cases and 100,000 deaths a year, many in developing countries where people lack access to the vaccine. Most who die are children younger than five years. Vaccination involves two injections, usually given when children are one year old and then four years old. The same shots (commonly referred to as MMR) include vaccines against mumps and rubella, and a newer version also protects against chickenpox. Findings reported in two studies published on November 1, 2019: https://doi.org/10.1126/science.aay6485 https://doi.org/10.1126/science.aay6125
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Juan Lama
October 31, 2019 11:18 AM
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Previous studies have documented how infection during pregnancy can increase the risk of ASD and a range of psychiatric disorders in the offspring. A new study reveals how maternal infections can affect neural development and how the timing of infection plays a critical role in elevating the risks of mental health conditions. It has been observed in both humans and animals that severe infections in the pregnant mother are a risk factor for developing psychiatric disorders such as schizophrenia and autism spectrum disorders later in life for the offspring. Now, researchers from Copenhagen have shown in mice how infections in the mother can cause the stem and precursor cells to neuronal cells in the brain to have their development impaired. The new study is published in the scientific journal Molecular Psychiatry. “The connection has been made in animal studies and clinical observation studies. However, this is the first time that we show how infections during pregnancy affect brain development and can lead to cognitive impairment. While many factors have been hypothesised or indicated, it is important that we show the steps of neuronal development that are actually affected,” says Konstantin Khodosevich, Associate Professor in the Biotech Research and Innovation Centre (BRIC). Immediate and long-lasting effect The researchers studied the development of neurons in mice. The mother’s immune response to infection had an effect stretching from stem cells and precursor cells to neuronal cells leading to profound disruption in their development in the brain. More specifically, the development of cortical GABAergic interneurons – the key neuronal class that provides inhibition in the brain – was impaired. The effect was immediate and cascaded to dramatic long-lasting impairments, thus resulting in multiple “hits” during the process of neuronal development – from the time neurons are born to the time they mature. Furthermore, the researchers also concluded that the newborn mice showed symptoms resembling those from human psychiatric disorders including decreased prepulse inhibition, altered social interactions and cognitive decline. “There are big technological and ethical issues about studying this in humans because of the vulnerability of pregnant women. That is why we study how the mechanisms work in mice. Psychiatric disorders are really complex and for some of them, we are still only guessing how they arise. We really want to contribute to the scientific understanding of these diseases,” says Konstantin Khodosevich. Deep-dive into molecular mechanisms One of the major findings of the study was showing the effects of having the infections at different times during the pregnancy. Depending on the time of infection, different precursor cells, and as a result different neurons, were affected. This means that the timing of infection is very important and can lead to varying outcomes based on which stage of brain development is affected. This can potentially underlie the complexity of psychiatric disorders. The researchers are now looking forward to dive deeper into the molecular mechanisms and signaling pathways behind the impairment of the interneuron development. Published on Molecular Pshychiatry (October 8, 2019): https://doi.org/10.1038/s41380-019-0539-5
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