Long-acting drug effectively prevents HIV-like infection in monkeys

The new drug cabotegravir (in vials above) has been shown to protect monkeys from infection by an HIV-like virus, and a clinical trial testing cabotegravir's safety and acceptability has begun. Unlike other preventive treatments, it would require only one injection every three months.
Credit: Zach Veilleux / The Rockefeller University

A regime of anti-HIV drugs -- components of regimens to treat established HIV infection -- has the potential to protect against infection in the first place. But real life can interfere; the effectiveness of this prophylactic approach declines if the medications aren't taken as prescribed.

HIV researchers hope a new compound, known as cabotegravir, could make dosing easier for some because the drug would be administered by injection once every three months. A clinical trial testing long-acting cabotegravir's safety and acceptability has already begun at multiple U.S. sites including The Rockefeller University Hospital. Meanwhile two new studies, including one conducted by researchers at the Aaron Diamond AIDS Research Center (ADARC) and Rockefeller University, published today (January 15) in Science Translational Medicine, show that long-acting cabotegravir injections are highly protective in a monkey model of vaginal transmission of a virus similar to HIV.

"Clinical trial results have demonstrated that the effectiveness of preventive oral medications can range with results as high as 75 percent effective to as low as ineffective, and a lot of that variability appears to hinge on the patient's ability to take the pills as prescribed," says study researcher Martin Markowitz, a professor at Rockefeller University and ADARC. "Long acting cabotegravir has the potential to create an option that could improve adherence by making it possible to receive the drug by injection once every three months."

Developed by ViiV Healthcare and GlaxoSmithKline, and previously known as GSK744 LA, cabotegravir is an antiretroviral drug. Antiretrovirals interfere with HIV's ability to replicate itself using a host cell and they are used to treat an HIV infection or to prevent those at high risk from acquiring it in the first place.

Cabotegravir belongs to a group of antiretrovirals that target integrase, an enzyme the virus uses to integrate itself into the cell's genome. This compound is a relative of an already FDA-approved integrase inhibitor, dolutegravir, but with chemical properties that allow it to be formulated into a long-acting suspension for injection.

A previous study by the ADARC and Rockefeller team in collaboration with ViiV Healthcare and GSK found long-acting cabotegravir could protect male rhesus macaque monkeys from exposure to a virus related to HIV. Following up on these results, a phase 2 clinical trial is now underway in a group of 120 men at low risk of infection. Before cabotegravir's effectiveness in high risk individuals can be tested, trials must show that study participants tolerate the drug well and find the quarterly injections, which are a novel approach to HIV prevention, acceptable.

Both new animal studies were conducted with women in mind; in 2013 women accounted for 47 percent of new HIV infections worldwide according to the Joint United Nations Programme on HIV and AIDS. Working separately, two teams tested the drug's ability to block vaginal transmission in two species of monkeys with different breeding cycles and susceptibility to infection.

First author Chasity Andrews, a postdoctoral fellow at ADARC and Rockefeller, and colleagues at ADARC, the Tulane Regional Primate Center and ViiV/GSK, studied female rhesus macaques treated with progesterone to increase their susceptibility to the virus. They found injections of long acting cabotegravir were 90 percent effective at protecting the monkeys from repeated high-dose exposures to the virus.

Meanwhile, the complementary study conducted by researchers at the CDC and ViiV/GSK found female pigtail macaques injected with cabotegravir were completely protected against multiple exposures to the virus.

"While we are still a long way off from showing that this drug works for HIV prevention in humans, our hope is that it may one day offer high risk women, as well as men, an additional option for HIV prevention," Markowitz says. "One of the lessons we have learned from contraception is the more options available, the better. We are hoping for the same in HIV prevention -- more options and better results."

Source: Rockefeller University

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What bank voles can teach us about prion disease transmission and neurodegeneration

This image shows accumulation of misfolded, toxic prion protein (brown staining) in the brain of a transgenic mouse expressing bank vole PrP and challenged with human variant Creutzfeldt-Jakob disease (vCJD) prions. Credit: Image courtesy of Dr. Joel Watts

When cannibals ate brains of people who died from prion disease, many of them fell ill with the fatal neurodegenerative disease as well. Likewise, when cows were fed protein contaminated with bovine prions, many of them developed mad cow disease. On the other hand, transmission of prions between species, for example from cows, sheep, or deer to humans, is -- fortunately -- inefficient, and only a small proportion of exposed recipients become sick within their lifetimes.

A study published on April 3rd in PLOS Pathogens takes a close look at one exception to this rule: bank voles appear to lack a species barrier for prion transmission, and their universal susceptibility turns out to be both informative and useful for the development of strategies to prevent prion transmission.
Prions are misfolded, toxic versions of a protein called PrP, which in its normal form is present in all mammalian species that have been examined. Toxic prions are "infectious"; they can induce existing, properly folded PrP proteins to convert into the disease-associated prion form. Prion diseases are rare, but they share features with more common neurodegenerative diseases like Alzheimer's disease.

Trying to understand the unusual susceptibility of bank voles to prions from other species, Stanley Prusiner, Joel Watts, Kurt Giles and colleagues, from the University of California in San Francisco, USA, first tested whether the susceptibility is an intrinsic property of the voles' PrP, or whether other factors present in these rodents make them vulnerable.

The scientists introduced into mice the gene that codes for the normal bank vole prion protein, thereby generating mice that express bank vole PrP, but not mouse PrP. When these mice get older, some of them spontaneously develop neurologic illness, but in the younger ones the bank vole PrP is in its normal, benign folded state. The scientists then exposed young mice to toxic misfolded prions from 8 different species, including human, cattle, elk, sheep, and hamster.

They found that all of these foreign-species prions can cause prion disease in the transgenic mice, and that the disease develops often more rapidly than it does in bank voles. The latter is likely because the transgenic mice express higher levels of bank vole PrP than are naturally present in the voles.

The results show that the universal susceptibility of bank voles to cross-species prion transmission is an intrinsic property of bank vole PrP. Because the transgenic mice develop prion disease rapidly, the scientists propose that the mice will be useful tools in studying the processes by which toxic prions "convert" healthy PrP and thereby destroy the brain. And because that process is similar across many neurodegenerative diseases, better understanding prion disease development might have broader implications.

Source:  PLOS

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Microbiologists discover how gut bacterial resources are hijacked to promote intestinal, foodborne illnesses

Dr. Vanessa Sperandio. Credit: Image courtesy of UT Southwestern Medical Center

UT Southwestern Medical Center microbiologists have identified key bacteria in the gut whose resources are hijacked to spread harmful foodborne E. coli infections and other intestinal illnesses.

Though many E. coli bacteria are harmless and critical to gut health, some E. coli species are harmful and can be spread through contaminated food and water, causing diarrhea and other intestinal illnesses. Among them is enterohemorrhagic E. coli or EHEC, one of the most common foodborne pathogens linked with outbreaks featured in the news, including the multistate outbreaks tied to raw sprouts and ground beef in 2014.

The UT Southwestern team discovered that EHEC uses a common gut bacterium called Bacteroides thetaiotaomicron to worsen EHEC infection. B. thetaiotaomicron is a predominant species in the gut's microbiota, which consists of tens of trillions of microorganisms used to digest food, produce vitamins, and provide a barrier against harmful microorganisms.

"EHEC has learned to how to steal scarce resources that are made by other species in the microbiota for its own survival in the gut," said lead author Dr. Meredith Curtis, Postdoctoral Researcher at UT Southwestern.

The research team found that B. thetaiotaomicron causes changes in the environment that promote EHEC infection, in part by enhancing EHEC colonization, according to the paper, appearing in the journal Cell Host Microbe.

"We usually think of our microbiota as a resistance barrier for pathogen colonization, but some crafty pathogens have learned how to capitalize on this role," said Dr. Vanessa Sperandio, Professor of Microbiology and Biochemistry at UT Southwestern and senior author.

EHEC senses changes in sugar concentrations brought about by B. thetaiotaomicron and uses this information to turn on virulence genes that help the infection colonize the gut, thwart recognition and killing by the host immune system, and obtain enough nutrients to survive. The group observed a similar pattern when mice were infected with their equivalent of EHEC, the gut bacterium Citrobacter rodentium. Mice whose gut microbiota consisted solely of B. thetaiotaomicron were more susceptible to infection than those that had no gut microbiota. Once again, the research group saw that B. thetaiotaomicron caused changes in the environment that promoted C. rodentium infection.

"This study opens up the door to understand how different microbiota composition among hosts may impact the course and outcome of an infection," said Dr. Sperandio, whose lab studies how bacteria recognize the host and how this recognition might be exploited to interfere with bacterial infections. "We are testing the idea that differential gastrointestinal microbiota compositions play an important role in determining why, in an EHEC outbreak, some people only have mild diarrhea, others have bloody diarrhea and some progress to hemolytic uremic syndrome, even though all are infected with the same strain of the pathogen."

The Centers for Diseases Control and Prevention (CDC) estimates that each year roughly 1 in 6 Americans (or 48 million people) gets food poisoning; 128,000 are hospitalized;, and 3,000 die of their food-borne disease. EHEC, which also caused a widespread outbreak in Europe in 2011, can lead to bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome, which in turn can lead to kidney disease and failure. EHEC is among the top five pathogens contributing to domestically acquired foodborne illnesses resulting in hospitalization, according to the CDC. Outbreaks in 2014 were reported in California, Idaho, Massachusetts, Michigan, Missouri, Ohio, Montana, Utah, and Washington.

Source: UT Southwestern Medical Center

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Natural substance in red wine has an anti-inflammatory effect in cardiovascular diseases

Researchers see great therapeutic potential in the natural substance resveratrol, particularly in connection with prevention of the synthesis of inflammatory factors in cardiovascular diseases. Credit: photo/©: Peter Pulkowski, Mainz University Medical Center

A natural substance present in red wine, resveratrol, inhibits the formation of inflammatory factors that trigger cardiovascular diseases. This has been established by a research team at the Department of Pharmacology of the University Medical Center of Johannes Gutenberg University of Mainz (JGU) working in collaboration with researchers of the Friedrich Schiller University in Jena and the University of Vienna. Their results have recently been published in the scientific journal Nucleic Acids Research.

Despite the fact that they eat more fatty foods, the French tend to less frequently develop cardiac diseases than Germans. This so-called French Paradox is attributed to the higher consumption of red wine in France and it has already been the subject of various studies in the past. A number of research projects have actually demonstrated that the natural product resveratrol, present in red wine, has a protective effect against cardiovascular diseases. But what exactly is the reason for this? It seems that at least part of the protective effect can be explained by the fact that resveratrol inhibits the formation of inflammatory factors, a conclusion reached by the research team of Junior Professor Andrea Pautz and Professor Hartmut Kleinert of the Mainz University Medical Center following collaboration in a joint project with Professor Oliver Werz of the Friedrich Schiller University in Jena and Professor Verena Dirsch of the University of Vienna. In fact, the researchers discovered that the natural substance binds to the regulator protein KSRP and activates it. KSRP reduces the stability of messenger RNA (mRNA) in connection with a number of inflammatory mediators and thus inhibits their synthesis.

"We now know more precisely how resveratrol inhibits the formation of the inflammatory factors that trigger cardiovascular diseases. This is an important finding in view of the fact that more recent research has shown that cardiovascular diseases are significantly promoted by inflammatory processes in the body," said Pautz. Cardiovascular disorders, such as myocardial infarction and strokes, frequently occur in association with chronic inflammatory diseases, such as arthritis. The natural substance resveratrol thus has major therapeutic potential, particularly when it comes to the treatment of inflammatory diseases that can cause serious damage to the cardiovascular system.

Source: Universität Mainz

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