Body's anti-HIV 'training manual' offers vaccine hopes

The body's own "training manual" for successfully attacking HIV has been recorded by scientists and it is hoped it can be used to design vaccines.

HIV mutates to survive the onslaught of a patient's immune system.

However, some patients develop highly effective antibodies that can neutralise huge swathes of HIV mutants.

An analysis of the arms race between body and virus, published in the journal Nature, has shown how these antibodies are made.

When someone is infected with HIV, their body produces antibodies to attack it. But the virus mutates and evades the offensive, so the body produces new antibodies that the virus then evades and the war goes on.

However, after about four years of this struggle some patients hit on to a winner by targeting something the virus finds harder to change - an Achilles heel.

Barton Haynes

"Even though the virus mutates and there are literally millions of quasi-species of virus because of all these mutations, but there are parts the virus can't change otherwise the virus cannot infect - these are the vulnerable sites," Prof Barton Haynes, of Duke University, in North Carolina, reported.

At this stage of the infection it is far too late to make a difference for the patient as the virus is hiding in untouchable reservoirs.

However, some researchers believe that vaccines that encourage the body to produce these "broadly neutralising antibodies" may give people immunity to the virus.

The research team's study is based on a patient in Africa who had a rapid diagnosis, about four weeks after being infected with the virus.

They were eventually able to produce an antibody named CH103 that could neutralise 55% of HIV samples.

It was not produced in one easy step. Rather it was the product of the war of the immune system and HIV trying to out-evolve each other.

However, through regular genetic analyses of both the immune system and virus, researchers could piece together each of the steps that culminated in the production of CH103.

It is like a training manual for the immune system.

Prof Haynes said: "What we were able to do was map out the arms race of both virus and antibody, and in doing so we have now a map.

"This is the first time we've been able to see the actual road map."

He said the challenge now was to see if re-creating those steps could lead to a viable vaccine.

Jane Anderson

However, he said it would almost certainly need to be a vaccine combining multiple "Achilles heels" - in the same way that HIV therapies are a combination of drug treatments.

Prof Jane Anderson, consultant at Homerton hospital in London and chair of the British HIV Association, said: "The study gives important insights into the ways in which the human immune system responds to HIV infection and increases our understanding about the relationships between the virus and the human host.

"This is another welcome step on the path to develop vaccines against HIV."

Sarah Joseph

Dr Sarah Joseph, who tests HIV vaccines at the Medical Research Council clinical trials unit, said: "This paper is really interesting. Some people do make antibodies that neutralise a lot of HIV virus, bit it is not of use to them as they produce it way too late."

She said harnessing these antibodies "could be a big deal" and there was "even talk about mass-producing antibodies and infusing people with them".

Key molecular events in the immune system contribute to Inflammatory Bowel Disease (IBD)

Scientists at the Virginia Bioinformatics Institute at Virginia Tech have discovered some of the key molecular events in the immune system that contribute to inflammatory bowel disease.

The results, which help researchers move one step further in their efforts to develop new drugs to treat inflammatory and immune-mediated diseases, are reported in the November 2010 edition (http://www.ncbi.nlm.nih.gov/pubmed/21068720) of the journal Mucosal Immunology from the Nature Publishing Group.

Inflammatory bowel disease starts when the gut initiates an abnormal immune response to some of the one hundred trillion or so bacteria that come into contact with the colon of the human body.

More than 1 million people are affected by inflammatory bowel disease in North America alone and direct healthcare expenses for inflammatory bowel disease in the United States are estimated at more than $15 billion annually.

Earlier mathematical and computational work (http://www.ncbi.nlm.nih.gov/pubmed/20362587) by the scientists pinpointed a special type of immune cell as a possible target for intervention strategies to fight inflammation-related disease in the gut.

The immune cells identified in the earlier work, which are known as M1 or classically activated macrophages, cause inflammation and possess a specific molecule, peroxisome proliferator-activated receptor-gamma, that, when activated, favors a switch to a type of macrophage that reduces the impact of inflammation (alternatively activated macrophage or M2) .

The activation of the receptor protein and the anti-inflammatory M2 macrophage switch plays a beneficial role in reducing the severity of the disease in the gut during experimentally induced inflammatory bowel disease.

“We have been able to validate experimentally some of the key events that take place in the regulation of the mucosal immune system when inflammatory bowel disease is triggered in mice,” said Josep Bassaganya-Riera, associate professor of immunology at the Virginia Bioinformatics Institute, leader of the Nutritional Immunology and Molecular Medicine Group in the institute’s CyberInfrastructure Division, and principal investigator.

“When we produce mice that lack the peroxisome proliferator-activated receptor-gamma specifically found in macrophages, the severity of inflammatory bowel disease increases significantly. In parallel, we are able to observe the impact of the onset of disease on key inflammation-related genes and other molecules involved in inflammation and metabolism.”

More on this article here Science blog website

NASA Shuttle Atlantis Astronauts Risk Damage to Immune system

Astronauts are known to have a higher risk of getting sick compared to their Earth-bound peers.

The stresses that go with weightlessness, confined crew quarters, being away from family and friends and a busy work schedule - all the while not getting enough sleep - are known to wreak havoc on the immune system.

A research group led by immunobiologist Ty Lebsack at the University of Arizona has discovered that spaceflight changes the activity of genes controlling immune and stress response, perhaps leading to more sickness.

Between spaceflight affecting a crew's susceptibility to infections and previous observations of sickness-causing microbes thriving in a near-zero gravity environment, long journeys to far-away destinations such as Mars pose a big challenge to manned space missions.

"Taken together, our results hint at the possibility that an astronaut's immune system might be compromised in space," said Lebsack of the UA's department of immunobiology in the College of Medicine.

Lebsack and his colleagues focused their study on the thymus gland, the organ that serves as a "factory" and "training academy" for T-cells that are key players of the immune system.

They compared gene-expression patterns in thymuses from four healthy mice that had spent 13 days aboard NASA's STS-118 Endeavor Space Shuttle to those from an equal number of control mice on the ground.

Their finding: 970 individual genes in the thymus of space-flown mice were up or down-regulated by a 1.5 fold change or greater. When these changes were averaged, 12 genes in the thymus tissue of all four space-flown mice were significantly up or down-regulated.

"The altered genes we observed were found to primarily affect signaling molecules that play roles in programmed cell death and regulate how the body responds to stress," Lebsack said.

Programmed cell death plays an important role in a functioning body, for example in the disposal of cells that are no longer needed or damaged beyond repair. However, cell death must be tightly regulated in the immune system to ensure the process does not get out of hand.

"Many of the genes whose activity was down-regulated in the space-flown mice play important roles in maintaining that balance," Lebsack said. "Potentially, you could get more cell death aboard a spacecraft because of these differences."

The results fit in with experiments carried out on the ground to study how microgravity affects immune cells. In these experiments, scientists mimicked weightlessness using clinostats - apparatuses that slowly rotate the study object so the Earth's gravitational pull is never perceived as coming from one consistent direction.

"Previous studies with cell cultures in clinostats showed increased cell death in T-cells when you take away the gravity stimulus," said Lebsack, "so it was a logical step to test whether we find the same effects in animals exposed to an actual lack of gravity."

"We observed an overall pattern about the genes whose expression was changed by space flight: All of them are involved, in one way or another, in the development, control and programmed cell death of immune cells."

This study represents the first use of microarray technology to investigate gene expression in thymus tissue of space-flown mice, according to the authors. Complex research undertakings like this require specialists combining their different areas of expertise.

The research was funded by NASA, and will be published in the May 15 issue of the Journal of Cellular Biochemistry.

Link: http://uanews.org

Tumours hide out from the immune system by mimicking lymph nodes

Tumours hide out from the immune system by mimicking lymph nodes

A new mechanism explaining how tumours escape the body's natural immune surveillance has recently been discovered at EPFL (Ecole Polytechnique Fédérale de Lausanne) in Switzerland. The study shows how tumours can create a tolerant microenviroment and avoid attack by the immune system by mimicking key features of lymph nodes.

The discovery, published in Science and in Science Express, underscores the role of the lymphatic system in cancer and may open up new possibilities for cancer treatment.

"The tumour tricks the body into thinking it is healthy tissue," says lead author Melody Swartz, head of the Laboratory of Lymphatic and Cancer Bioengineering (LLCB) and EPFL professor. Swartz and her team set out to understand how immune tolerance is induced by tumours, allowing them to progress and spread.

The researchers from EPFL concentrated their efforts on a certain protein that is normally present in healthy lymph nodes to attract T cells and program them to perform vital immune functions. They found that some tumours can secrete this protein to transform the outer layer of the tumour into lymphoid-like tissue.

This outer layer then attracts and effectively re-programs the T cells to recognise the tumour as friend not foe, resulting in a tumour that goes undetected by the immune system.

Since most tumours progress only if they have escaped the immune system, this new understanding of one mechanism by which the tumour can bypasses or hides from immune defenses is an important step towards future cancer therapies.

US Scientists ID key Ebola virus structure

Scripps Research Institute scientists say they've identified the structure of a key Ebola virus protein -- a major step that might help lead to a treatment.

The Ebola virus, although rare, is one of the deadliest viruses on Earth, killing 50 percent to 90 percent of those infected, scientists said.

There is currently no cure for Ebola hemorrhagic fever, no vaccine and no drug therapy. But the researchers said their finding of how a key component of the Ebola virus, called VP35, blocks the human immune system, allowing the virus uncontrolled replication, is an important advancement in understanding how the deadly virus works.

"After infection, the virus and immune system are in a race," said Associate Professor Erica Ollmann Saphire, who led the three-year study. "If the virus can hide its molecular signatures, it can suppress immune responses and replicate unchecked. This new understanding of the mechanism that Ebola virus uses to evade the immune system opens the door for developing drug therapies."

A signature of Ebola virus infection is its double-stranded RNA, which, when detected by immune system proteins, triggers a full immune response. The new research describes how the VP35 protein of the Ebola virus masks the double-stranded RNA to prevent the immune response.

The study is detailed in the early online edition of the Proceedings of the National Academy of Sciences. Read More.....

HIV Vaccine still a Fantasy? Research continues

FEARS that HIV vaccines may encourage infection with the virus have largely been laid to rest. This could revive the search for a vaccine.

In September 2007, pharmaceutical company Merck halted its STEP trial of an HIV vaccine because it appeared to work no better than a placebo.

The Cold Virus

Then it emerged that recipients of the vaccine who had previously caught the cold virus were more likely than those who hadn't to be infected with HIV, sparking fears that the vaccine made HIV infection more likely.

Loaded with HIV Genes

The vaccine consisted of a deactivated cold virus loaded with three HIV genes that were supposed to stimulate immunity. The fear was that participants with immune systems primed to fight the cold virus produced a surge of CD4 cells following injection with the vaccine, and that these cells provided ideal targets for HIV if the recipient was subsequently infected by the virus. "The vaccine may have added fuel to the fire," says Dan Barouch of the Beth Israel Deaconess Medical Center in Boston.

It Didn't Provoke Strong Immunity

Neither research team can explain why people with the cold virus antibodies were more likely to be infected with HIV. But Adrian Hill, a virologist at the University of Oxford, thinks this arose by chance, and that the vaccine failed simply because it didn't provoke strong enough immunity to HIV. The work should ease fears over other HIV vaccines, says Barouch.

Drug-trial cancer patients recover: Magic Bullet found! Ipilimumab

Two men with advanced and inoperable prostate cancer have staged dramatic recoveries after being treated with an experimental antibody drug.

Both are now cancer-free and have returned to normal life after they took part in a trial of a drug called ipilimumab that boosts the immune system.

Before treatment at the Mayo Clinic in Rochester, Minnesota, US, each of them had aggressive tumours that had grown well beyond the prostate gland into abdominal areas.

Trial leader Dr Eugene Kwon said: "The goal of the study was to see if we could modestly improve upon current treatments for advanced prostate cancer.

"The candidates for this study were people who didn't have a lot of other options. However, we were startled to see responses that far exceeded any of our expectations."

First, the patients received traditional hormone therapy to remove testosterone, which fuels prostate cancer. Researchers then introduced a single dose of ipilimumab. The drug is an antibody which builds on the hormone therapy and boosts the immune system's response to the cancer.

Both patients saw their prostate specific antigen (PSA) levels drop to the point where they became eligible for surgery. PSA is a protein in the blood that allows doctors to monitor prostate cancer.

When the surgeons made their incisions, they had a surprise. Mayo clinic urologist Dr Michael Blute said: "The tumours had shrunk dramatically. I had never seen anything like this before. I had a hard time finding the cancer. At one point the pathologist asked if we were sending him samples from the same patient."

Further research is now planned to understand more about the mechanisms of the antibody and how best to use it on patients, but Dr Kwon added: "This is one of the holy grails of prostate cancer research. We've been looking for this for years."