A viral cloaking device

Viruses achieve their definition of success when they can thrive without killing their host. Now, biologists Pamela Bjorkman and Zhiru Yang of the California Institute of Technology have uncovered how one such virus, prevalent in humans, evolved over time to hide from the immune system.

The human immune system and the viruses hosted by our bodies are in a continual dance for survival--viruses ever seek new ways to evade detection, and our immune system devises new methods to hunt them down. Human Cytomegalovirus (HCMV), says Bjorkman, Caltech's Delbrück Professor of Biology and a Howard Hughes Medical Institute (HHMI) Investigator, "is the definition of a successful virus--it thrives but it doesn't affect the host."

HCMV is carried by eight in 10 people. Although it generally harms only those who are immunocompromised, it has also been linked with brain tumors like the one for which Ted Kennedy recently had surgery. Understanding how HCMV survives may help in the development of a vaccine, as well as in the fight against other viruses with similar evasive tactics.

"We are interested in mechanisms taken by viruses to escape our immune system," says Caltech biology postdoc and HHMI associate Zhiru Yang. She and Bjorkman published their findings on HCMV survival mechanisms in the July 15 edition of Proceedings of the National Academy of Sciences. They describe the underpinnings of a viral cloaking device, partly made of stolen goods from healthy cells, that helps HCMV to move undetected through the body.

For 20 years, Bjorkman's lab has been dedicated to understanding class 1 major histocompatibility complex (MHC) proteins and the immune response, most recently related to AIDS research. MHC proteins carry peptides, small pieces that are chopped up from the cell's internal proteins, to the cell's surface. If a cell has been infected, MHC presents viral peptides to signal T cells to kill it. So some viruses evolved to evade T cells by keeping MHC from reaching the cell surface. In turn, the immune system recruited other hunters to search for cells that don't show MHC proteins.

Sometime along its treacherous evolutionary path, HCMV stole a class 1 MHC molecule from its host and modified it for supreme stealth. "This is a decoy," Bjorkman says. She and Yang analyzed the structure of the mimic, called UL18, to compare how similar it is to the real thing. They found that despite a mere 23 percent match in genetic sequences, UL18 looks almost exactly the same as a true class 1 MHC.

The same immune cells that search for missing MHC proteins are designed to bind to them when they find them, thereby inhibiting an immune response. Yang and Bjorkman found that UL18 happens to bind 1,000 times tighter to these inhibitory receptors than real MHC molecules do. "This is exactly what the virus wants--to avoid being recognized by T cells, but to engage inhibitory receptors to turn off immune cells," Yang notes. "Only a small number of UL18 molecules are required to have the same inhibitory effect as a large number of MHC class I molecules."

"What I find astounding is that the virus stole this gene and kept it almost identical but improved upon its binding," Bjorkman says.

UL18 didn't stop there. "It also binds peptides--that's unique to this MHC mimic. We don't know why," Bjorkman adds. The peptide is obscured from killer cells by yet another shield, Yang says. In a trait it shares with HIV proteins, HCMV's UL18 covers itself with carbohydrates, which are unrecognizable to the immune system. A real class 1 MHC molecule has one site for adding carbohydrates; the fake has 13, Bjorkman notes. The only place where it's not covered is where it binds to the inhibitory receptor.

All its efforts have made UL18 virtually undetectable. "It's a good example of a viral protein that evolved from its host ancestor to block unwanted interactions," Yang says. "The more we understand that, the more effectively we can fight viruses that hide out," Bjorkman adds.

Source : California Institute of Technology

New evidence of battle between humans and ancient virus

For millennia, humans and viruses have been locked in an evolutionary back-and-forth -- one changes to outsmart the other, prompting the second to change and outsmart the first. With retroviruses, which work by inserting themselves into their host's DNA, the evidence remains in our genes. Last year, researchers at Rockefeller University and the Aaron Diamond AIDS Research Center brought an ancient retrovirus back to life and showed it could reproduce and infect human cells. Now, the same scientists have looked at the human side of the story and found evidence that our ancestors fought back against that virus with a defense mechanism our bodies still use today.

"This is the first time that we've been able to take an ancient retrovirus and analyze how it interacts with host defense mechanisms in the laboratory in the present day," says Paul Bieniasz, who is an associate professor and head of the Laboratory of Retrovirology at Rockefeller and a scientist at the Aaron Diamond AIDS Research Center. Bieniasz and graduate student Youngnam Lee took their resurrected virus, called HERV-K, tested its strength against molecules involved in human antiviral defense and published their results in the Journal of Virology (online ahead of print, June 18).

Bieniasz, who also is an investigator at the Howard Hughes Medical Institute, and Lee found that, at least in the laboratory, human cells infected with HERV-K fought back with several antiviral proteins. One of those proteins, called APOBEC3G, leaves a tell-tale signature behind: It mutates virus DNA in a recognizable pattern and is one our cells use to attack modern retroviruses. "But this is the first time it's been shown for this ancient retrovirus," Bieniasz says.

Once the scientists found that modern human cells attacked HERV-K with this molecule, they went back to look at the "fossil evidence," remnants of the virus that still remain in our genes and that the researchers had previously used to reconstruct it. What emerged were two copies of HERV-K that had clearly been mutated, and thus inactivated, by the APOBEC3G protein. "We're looking at things that happened millions and millions of years ago," says Lee. "But these sorts of ancient interactions may have influenced how humans are able to combat these retroviruses today. These proteins help protect us against current retroviruses." Indeed, HERV-K may well have helped to shape the modern APOBEC3G defense.

The earlier study and this one provide two sides of the evolutionary coin: the infectious agent, and the host defense. "Retroviruses are able to infect us and leave remnants in our DNA, and our DNA also holds evidence of what we've done to them in return," Lee says. "It's an illustration of the fight between host and virus."

Source : Rockefeller University

Lyme Arthritis Study Sheds Light On Antibiotic Resistance And Persistent Joint Inflammation

Lyme disease in the U.S. is caused by a form of bacteria, the spirochete Borrelia burgdorferi, infecting humans by tick bites. It typically begins with a bull's-eye skin rash, accompanied by fever, muscle aches, or other flu-like symptoms. If diagnosed early, Lyme can be treated successfully within a month with either oral or intravenous antibiotics. Nearly 60 percent of patients who do not receive antibiotic therapy early in the illness develop intermittent or persistent arthritis, particularly affecting the knees. Moreover, a small percentage of Lyme patients who do receive antibiotic therapy suffer from persistent arthritis for months or even several years after 2-3 months of oral and intravenous antibiotic therapy. This confounding condition has been termed antibiotic-refractory, or slowly resolving, Lyme arthritis.

To gain insights into the survival of spirochetes following antibiotic therapy, researchers at the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital, Harvard Medical School, and the National Center for Infectious Diseases at the Centers for Disease Control and Prevention teamed up to study antibody responses to Borrelia burgdorferi in patients with antibiotic-refractory or antibiotic-responsive Lyme arthritis. Presented in the December 2007 issue of Arthritis & Rheumatism , their findings indicate that joint inflammation persists in patients with antibiotic-refractory Lyme arthritis after the disease-spreading spirochetes have been killed.

To compare antibody responses and determine their effect on Lyme arthritis, the team tested at least 3 blood serum samples each from 41 patients with antibiotic-refractory arthritis, 23 patients with antibiotic-responsive arthritis, and 10 non-antibiotic-treated controls - arthritis patients who had contracted Lyme disease during the late 1970s before the cause of the disease was known. Samples were obtained during the period of arthritis and sometimes after several months of remission for all patient groups. The patients with antibiotic-refractory and antibiotic-responsive arthritis had a similar age range, sex distribution, and duration of arthritis prior to antibiotic therapy.

All samples were tested for IgG reactivity with Borrelia burgdorferi bacteria and 4 outer surface lipoproteins of the spirochete. Among non-antibiotic-treated patients, antibody titers to Borrelia burgdorferi remained high throughout a prolonged period of persistent arthritis, 2 to 5 years. In contrast, in patients with antibiotic-responsive arthritis, the level of antibody titers to Borrelia burgdorferi and most outer-surface proteins remained steady or decreased within the first 3 months of starting antibiotic therapy. Consistent with this finding, these patients usually experienced relief from joint swelling during a 1-month course of oral antibiotics. In patients afflicted with antibiotic-refractory arthritis, the level of antibody titers to Borrelia burgdorferi and most outer-surface antigens increased slightly during the first 1 to 3 months of treatment. These patients suffered from persistent joint swelling for a median duration of 10 months, despite 2 to 3 months of oral or intravenous antibiotics. However, by 4 to 6 months after starting antibiotic therapy, antibody titers declined to similar levels in both antibiotic-treated groups, regardless of their differences in arthritis symptoms.

"In Lyme disease, there is a great need for a test that could be used in clinical practice as a marker for spirochetal eradication," observes Dr. Allen C. Steere, the senior author of the study. Yet, as he acknowledges, ridding the body of the Borrelia burgdorferi bacteria and its surface antigens does not always bring relief from arthritis. "Increasing antibody titers in patients usually suggested the presence of live spirochetes, whereas declining titers suggested that they had been killed," he notes. "Thus, patients with Lyme arthritis who have a sustained, gradual decline in antibody reactivity probably have the nearly complete or total eradication of spirochetes from the joint as a result of antibiotic therapy, even if joint inflammation persists after the period of infection."

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Article adapted by Medical News Today from original press release.
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Article: "Antibody Responses to Borrelia burgdorferi in Patients With Antiobiotic-Refractory, Antibiotic-Responsive, or Non-Antibiotic-Treated Lyme Disease," Priya Kannian, Gail McHugh, Barbara J.B. Johnson, Rendi M. Bacon, Lisa J. Glickstein, and Allen C. Steere, Arthritis & Rheumatism, December 2007.

Source: Amy Molnar
Wiley-Blackwell

Study Finds Pomegranate Effective In Fighting Bacteria, Viruses

A Pace University Study has found that pure pomegranate juice and pomegranate liquid extract are effective in fighting viruses and bacteria. According to their findings, 100% Pomegranate juice and POMx liquid extract could significantly reduce microbes found in the mouth that commonly cause cavities, staph infections and food poisoning

If the answer to improved health through protection against common germs and pathogens was as simple as drinking pomegranate juice, it seems everyone would be a lot healthier.

Recent preliminary research by Milton Schiffenbauer, Ph.D., a biology professor at Pace University in New York, indicates it just might be that simple. The research revealed that 100% pomegranate juice and POMx liquid extract (pomegranate polyphenol extract), made from the Wonderful variety of pomegranate grown in California, have antiviral and antibiotic effects. His findings will be introduced May 22 at the American Society for Microbiology's annual meeting in Toronto in a presentation entitled: "The Inactivation of Virus and Destruction of Bacteria by Pomegranate Juice."

In this exploratory study, Schiffenbauer tested 100% pomegranate juice and POMx liquid extract and the effect each had on a bacterial virus T1 and several bacteria over various periods of time, in various conditions and with the addition of other ingredients. The titer of T1 virus,(a model system) which infects E.coli B decreased up to 100% within 10 minutes of the addition of 100% pomegranate juice or POMx liquid extract. The research was funded by Pace University and POM Wonderful LLC and was conducted using POM Wonderful pomegranate products.

Both were also found to be effective in the destruction of bacteria S. mutans, known to cause cavities, S. aureus, the most common cause of staph infections, and B. cereus, a common cause of food poisoning. Schiffenbauer's findings also indicate that 100% pomegranate juice and POMx liquid extract inhibit the spread of Methicillin-resistant Staphylococcus aureus (MRSA), having widespread implications in the treatment of these potentially pathogenic microorganisms.

The addition of the POM products to various oral agents, including toothpaste and mouthwash, gave these agents an antimicrobial effect.

This work comes on the heels of earlier studies conducted by Schiffenbauer that found that white tea and green tea extracts also have antimicrobial effects. According to Schiffenbauer, pomegranate has gotten even better results than the teas.

Source: postchronicle.com