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

'We may never get rid of our hospital superbugs'

Thursday August 21 2008

HOSPITAL bugs like MRSA and C Diff -- linked to dozens of deaths in Ireland -- may always be with us, a top consultant has warned.

C Diff infection contributed to 10 deaths at St Colmcille's Hospital, Loughlinstown last year, and to 13 deaths at Ennis General Hospital.

A new virulent strain of C Diff, called 027, has emerged recently and it has more toxins in it than in other types of C Diff, making it a more serious strain, consultant microbiologist with the Health Protection Surveillance Centre, Dr Fidelma Fitzpatrick said.

The priority was to minimise the incidence of Healthcare-Associated Infections (HCAIs) as much as possible and she believed hospitals have procedures in place to prevent them.

But eventually eliminating MRSA, C Diff and other infections in hospitals or the community is problematic because "as long as there is healthcare, there will be HCAIs," she said.

High risk patients include those who are older, have a damaged immune system due to cancer or other diseases, patients on antibiotics or those with breaks in their skin from insertion of drips, from wounds or burns or after surgery.

C Diff is a bug found in the bowel of about one in 20 healthy patients and is kept in check by the "good" bacteria in the bowel.

"If a patient takes an antibiotic, sometimes this can kill off the good bacteria in the bowel and that allows bugs such as C Diff to multiply and in some patients this can also lead to C Diff infection," Dr Fitzpatrick said.

The most common symptom of C Diff is diarrhoea, although some people complain of nausea, reduced appetite and crampy abdominal pain.

"It's important to remember that most patients recover completely from C Diff," she said.

"However, in a small percentage of patients, the infection causes an inflammation of the bowel (colitis) and that can be very serious. But again, it is more serious in the high risk groups of patients."

The most recent comprehensive study, in 2006, showed that approximately one in 20 Irish patients had a HCAI at the time of the study. The incidence was less than in England, where around one in 12 patients had a HCAI at the time.

- Source: - Harold.ie