Vaccination campaign doubles HBV mutations

Contact: Garth Hogan ghogan@asmusa.org 202-942-9389 American Society for Microbiology

WASHINGTON, DC – October 7, 2013 – A universal infant vaccination campaign in China has led the Hepatitis B virus (HBV) to more than double its rate of “breakout” mutations. These mutations may enable the virus to elude the vaccine, necessitating new vaccination strategies. Researchers at the Chinese Centers for Disease Control and Prevention and University of North Carolina, Chapel Hill, report their findings in an article published ahead of print in the Journal of Virology.

Until a universal vaccination program for infants was implemented in 1992, nearly ten percent of Chinese—children included—were infected with HBV. The vaccination campaign has protected an estimated 80 million children, dramatically reducing the percentage of children under 5 who are infected, from nearly 10 percent in 1992 to less than one percent in 2005. But these gains are in danger of being eroded as the virus develops surface mutations.

Taking advantage of 1992 and 2005 survey, investigators found that the prevalence of HBV escape mutants in children rose from 6.5 percent in 1992, before the start of the universal vaccination program, to nearly 15 percent in 2005. Among the control group of adults unaffected by the universal vaccination campaign, the rate of break-out mutants was virtually unchanged.

Hepatitis B is an infectious illness of the liver which can cause vomiting, inflammation, jaundice, and, rarely, death. About a third of the world’s population has been infected at some point in their lives. Transmission of hepatitis B virus results from exposure to infectious blood or bodily fluids containing blood. The infection is preventable by vaccination, which has been routinely used since the 1980s.

Researcher Tao Bian of Chapel Hill says that the vaccine remains quite effective, but that because escape mutants are likely to increase, public health officials need to track the rise of escape mutants, in order to know when it becomes time to consider new vaccination strategies. Measures that might be taken include boosting doses, adjusting the timing of vaccinations, or improving the vaccine. A next generation HBV vaccine has been invented, containing a second antigen in addition to the virus’ surface antigen. That means that both antigens would have to develop breakout mutations in order to elude the vaccine.

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A copy of the manuscript can be found online at http://bit.ly/asmtip0913e.  Formal publication is scheduled for the November 2013 issue of the Journal of Virology.

The Journal of Virology is a publication of the American Society for Microbiology (ASM). The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM’s mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Virus kills melanoma in animal model, spares normal cells

Contact: Jim Sliwa jsliwa@asmusa.org 202-942-9297 American Society for Microbiology

Researchers from Yale University School of Medicine have demonstrated that vesicular stomatitis virus (VSV) is highly competent at finding, infecting, and killing  human melanoma cells, both in vitro and in animal models, while having little propensity to infect non-cancerous cells.

“If it works as well in humans, this could confer a substantial benefit on patients afflicted with this deadly disease,” says Anthony van den Pol, a researcher on the study. The research was published online ahead of print in the Journal of Virology.

Most normal cells resist virus infection by activating antiviral processes that protect nearby cells. “The working hypothesis was that since many cancer cells show a deficient ability to withstand virus infection, maybe a fast-acting virus such as VSV would be able to infect and kill cancer cells before the virus was eliminated by the immune system,” says van den Pol. And indeed, the virus was able to selectively infect multiple deadly human melanomas that had been implanted in a mouse model, yet showed little infectivity towards normal mouse cells, he says.

Many different mechanisms are involved in innate immunity, the type of immunity that combats viral infection. van den Pol plans to investigate which specific mechanisms are malfunctioning in cancer cells, knowledge that would be hugely beneficial both in understanding how cancer affects immunity, and in enhancing a virus’ ability to target cancer cells, he says.

Melanoma is the most deadly skin cancer. Most melanomas are incurable once they have metastasized into the body. The incidence of melanoma has tripled over the last three decades, and it accounts for approximately 75 percent of skin cancer-related deaths.

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A copy of the manuscript can be found online at http://bit.ly/asmtip0413b.  Formal publication is scheduled for the June 2013 issue of the Journal of Virology.

(G. Wollmann, J.N. Davis, M.W. Bosenberg, and A.N. van den Pol, 2013. Vesicular stomatitis virus variants selectively infect and kill human melanomas but not normal melanocytes. J. Virol.  Published ahead of print 3 April 2013 , doi:10.1128/JVI.03311-12)

Journal of Virology is a publication of the American Society for Microbiology (ASM).  The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. Its mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Mutation altering stability of surface molecule in acid enables H5N1 infection of mammals

Contact: Jim Sliwa jsliwa@asmusa.org 202-942-9297 American Society for Microbiology

A single mutation in the H5N1 avian influenza virus that affects the pH at which the hemagglutinin surface protein is activated simultaneously reduces its capacity to infect ducks and enhances its capacity to grow in mice according to research published ahead of print today in the Journal of Virology.

“Knowing the factors and markers that govern the efficient growth of a virus in one host species, tissue, or cell culture versus another is of fundamental importance in viral infectious disease,” says Charles J. Russell of St. Jude Children’s Research Hospital, Memphis, TN, an author on the study. “It is essential for us to identify influenza viruses that have increased potential to jump species, to help us make decisions to cull animals, or quarantine humans.” The same knowledge “will help us identify targets to make new drugs that stop the virus… [and] engineer vaccines.”

Various influenza viruses are spreading around the globe among wild birds, but fortunately, few gain the ability to jump to humans. However, those that do, and are able to then spread efficiently from person to person, cause global epidemics, such as the infamous pandemic of 1918, which infected one fifth and killed an estimated 2.7 percent of the world’s population. Occasionally, one of these viruses is exceptionally lethal. For example, H5N1 has killed more than half of the humans it has infected. The specter of such a virus becoming easily transmissible among humans truly frightens public health officials. But understanding the mechanisms of transmission could help microbiologists find ways to mitigate major epidemics.

When influenza viruses infect birds, the hemagglutinin surface protein of the virus is activated by acid in the entry pathway inside the host cell, enabling it to invade that cell. In earlier work, Russell and collaborators showed that a mutant version of the influenza H5N1 virus called K58I that resists acid activation, loses its capacity to infect ducks. Noting that the upper airways of mammals are more acidic than infected tissues of birds, they hypothesized, correctly, that a mutation rendering the hemagglutinin protein resistant to acid might render the virus more infective in mammals.

In this study the investigators found that K58I grows 100-fold better than the wild-type in the nasal cavities of mice, and is 50 percent more lethal. Conversely, the mutant K58I virus failed completely to kill ducks the investigators infected, while the wild-type killed 66 percent of ducks, says Russell. “A single mutation that eliminates H5N1 growth in ducks simultaneously enhances the capacity of H5N1 to grow in mice. We conclude that enhanced resistance to acid inactivation helps adapt H5N1 influenza virus from an avian to a mammalian host.”

“These data contribute new information about viral determinants of influenza virus virulence and provide additional evidence to support the idea that H5N1 influenza virus pathogenesis in birds and mammals is linked to the pH of [hemagglutinin] activation in an opposing fashion,” Terence S. Dermody of Vanderbilt University et al. write in an editorial in the journal accompanying the paper. “A higher pH optimum of [hemagglutinin] activation favors virulence in birds, whereas a lower pH optimum… favors virulence in mammals.”

Based on this and another study, “…surveillance should include phenotypic assessment of the [hemagglutinin] activation pH in addition to sequence analysis,” Dermody writes.

The journal carefully considered whether to publish the paper, because it raised issues of “dual use research of concern” (DURC), writes Dermody. DURC is defined as “Life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security,” according to a US government policy document. However, both the National Institute of Allergy and Infectious Diseases and the St. Jude Institutional Biosafety Committee concluded that the study failed to meet the definition of DURC. Clinching the case, “the addition of the key mutation in the Russell paper to other previously reported mutations would not result in an even more virulent H5N1 influenza virus,” says Dermody.

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A copy of the research manuscript can be found online at http://bit.ly/asmpr0213b.  The manuscript of the accompanying editorial can be accessed at http://bit.ly/asmpr0213c. Both are scheduled to be formally published in the May 2013 issue of the Journal of Virology.

(H. Zaraket, O.A. Bridges, and C.J. Russell, 2013. The pH of activation of the hemagglutinin protein regulates H5N1 influenza virus replication and pathogenesis in mice. J. Virol. online ahead of print February 28, 2013, doi:10.1128/JVI.03110-12.)

The Journal of Virology is a publication of the American Society for Microbiology (ASM).  The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. Its mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Diabetes linked to flu

The flu virus has another trick up its sleeve – it may trigger diabetes. The good news is that this discovery may give us a way to prevent some forms of the disease.

In diabetes, cells do not take up sugar from the blood. This can happen because cells have lost sensitivity to the hormone insulin, leading to what is called type 2 diabetes. Linked to diet and lifestyle, this form of the disease is rapidly becoming more common worldwide. Another cause of diabetes happens when the immune system destroys the pancreatic cells that produce insulin. People inherit a genetic predisposition for this condition, called type 1 diabetes, but an environmental trigger is also needed for it to appear.

Since the 1970s, researchers have suspected that viruses may provide this trigger, as type 1 diabetes often sets in suddenly after an infection. Enteroviruses and rotaviruses were both implicated; something about these infections confuses the immune system enough to make it attack the pancreas. But the picture remained unclear.

Then Ilaria Capua, of the World Organisation for Animal Health reference lab for bird flu in Legnaro, Italy, and her team decided to infect turkeys with flu. They did this because they knew birds with flu often have an inflamed pancreas, even when they have strains of the virus that do not normally spread outside the lungs. The team found that many of the turkeys developed severe pancreatic damage and diabetes.

Next, the researchers infected human pancreatic tissue with two common flu viruses. Both “grew really well” in the tissue, including in insulin-producing cells, says Capua.

Inflammatory response

Crucially, the presence of flu in the pancreatic cells triggered production of a set of inflammatory chemicals that have been shown to be central to the autoimmune reactions that lead to type 1 diabetes. One theory is that immune cells present bits of the infected tissue to destructive T-cells, to teach them to recognise the virus. But in the process the T-cells also learn to recognise the cells that make insulin, and to destroy them.

Can flu reach the pancreas? In humans, the virus is normally restricted to the lungs and gut, but can sometimes get into the blood. The virus might also travel up the duct that links the small intestine to the pancreas, Capua suspects. “Either way, when it gets to the pancreas it finds a good place to replicate.”

Capua is now testing the effects of flu on mouse models of type 1 diabetes. She is also looking for signs of recent flu infection in people with newly diagnosed diabetes. She suspects the H1N1 swine flu virus that caused the pandemic of 2009, and is still circulating, could be a particularly good trigger. Doctors in Japan and Italy have reported many newly diagnosed cases of type 1 diabetes in people who had recently had flu, and an upsurge in type 1 diabetes after the 2009 pandemic.

Real impact

“The great thing is that even if flu only causes a few per cent of type 1 diabetes cases, we can vaccinate and prevent flu in people who are genetically predisposed, and that can have a real impact,” says Capua. There are 65,000 new cases of type 1 diabetes worldwide annually, and that figure is growing by 3 to 5 per cent each year.

The link between diabetes and flu adds to growing evidence that many diseases considered non-infectious are actually caused by infection – and can therefore spread.

There is also new evidence that flu can cause heart attacks. Previously, this was suspected, because of the surge in heart attacks that regularly follows the annual flu season. But researchers at the University of Toronto, Canada, have  now demonstrated the effect in individual patients. They reported this week that vaccinating adults for flu, whether they already have cardiac problems or not, makes them half as likely to have a heart attack or stroke in the following year (Canadian Journal of Cardiology, doi.org/jnr).

Journal reference: Journal of Virology, doi.org/jnp

http://www.newscientist.com/article/dn22456-diabetes-linked-to-flu.html?full=true&print=true

Researchers Map Molecular Details That Encourage H1N1 Transmission To Humans

The 2009 H1N1 pandemic influenza virus appears to have required certain mutations in order to be transmitted to humans, according to a paper in the September Journal of Virology. The research could prove extremely valuable for efforts to predict human outbreaks.

The 2009 influenza pandemic was caused by a swine influenza virus that mutated in a way that made it transmissible among humans. The researchers, led by Hualan Chen of the Harbin Veterinary Research Institute, Harbin, China, have determined the probable details of the mutations that led to human transmission.

In this study, Chen, who is director of the National Avian Influenza Reference Laboratory at the Institute, and her collaborators have shown that two specific mutations in each of two proteins appear to be critical to transmission to, and among humans. One of those mutations, of a single amino acid in the virus’ hemagglutinin protein, gives the virus the ability to bind to human receptors, and enables transmission in mammals via droplets of respiratory fluids.

That amino acid, in the 226th slot in the protein, is glutamine. The researchers showed its importance by causing a mutation from glutamine, the amino acid in that position seen in viruses from infected humans, to argenine, as seen in swine. Working in cell cultures, the researchers showed that the switch dampened the virus’ ability to bind the human receptor, while boosting its ability to bind to the avian receptor. They showed further that the change rendered the virus non-transmissible via respiratory droplets in guinea pig models, and unable to replicate in the lungs of ferrets—results that suggest, but do not prove that the same may happen in humans.

Also in guinea pigs, changing an amino acid in the virus’ PB2 protein abolished transmission in guinea pigs via respiratory droplets, while that change, plus another single amino acid change in the hemagglutinin protein, killed such transmission in ferrets.

It gets still more convoluted. The same amino acid in the PB2 protein that enables virus transmission via respiratory droplets, which is located at position 271 in that protein, can also encourage the afore-mentioned mutation in hemagglutinin position 226 to glutamine, which enables the virus to cleave to the human receptor.

The value of all this information, says Chen, is that it provides a means for predicting outbreaks of human-transmissible H1N1.

(Y. Zhang, Q. Zhang, Y. Gao, X. He, H. Kong, Y. Jiang, Y. Guan, X. Xia, Y. Shu, Y. Kawaoka, Z. Bu, and H. Chen, 2012. Key molecular factors in hemagglutinin and PB2 contribute to efficient transmission of the 2009 H1N1 pandemic influenza virus. J. Virol. 86:9666-9674.)

Download a copy of the article at http://bit.ly/asmtip0912b