Herpes linked to Alzheimer's: Antivirals may help

A new commentary by scientists at the Universities of Manchester and Edinburgh on a study by Taiwanese epidemiologists supports the viability of a potential way to reduce the risk of Alzheimer's disease.

When the Taiwanese authors looked at subjects who suffered severe herpes infection and who were treated aggressively with antiviral drugs, the relative risk of dementia was reduced by a factor of 10.

Manchester's Professor Ruth Itzhaki and Edinburgh's Professor Richard Lathe say the paper, by Tzeng et al. and published in Neurotherapeutics in February 2018, also shows that herpes simplex virus type 1 (HSV1) leads to an increased risk of developing the disease.

"This article and two others by different research groups in Taiwan provide the first population evidence for a causal link between herpes virus infection and Alzheimer's disease, a hugely important finding," said Professor Itzhaki.

They publish a commentary in the Journal of Alzheimer's Disease on the three articles, arguing that they provide the strongest evidence yet for a causal link between herpes infection and Alzheimer's disease, backing 30 years of research by Professor Itzhaki.

Professor Itzhaki said: "I believe we are the first to realise the implications of these striking data on this devastating condition which principally affects the elderly. No effective treatments are yet available.

"Almost 30 million people worldwide suffer from it and sadly, this figure will rise as longevity increases.

"But we believe that these safe and easily available antivirals may have a strong part to play in combating the disease in these patients.

"It also raises the future possibility of preventing the disease by vaccination against the virus in infancy.

"Successful treatment by a specific drug, or successful vaccination against the putative microbe, are the only ways to prove that a microbe is the cause of a non- infectious human disease."

Most Alzheimer's disease researchers investigate its main characteristics -- amyloid plaques and neurofibrillary tangles; however, despite the vast amount of research, the causes of their formation are unknown.

HSV1 infects most humans in youth or later and remains lifelong in the body in dormant form within the peripheral nervous system.

From time to time the virus becomes activated and, in some people, it then causes visible damage in the form of cold sores.

The Taiwanese study identified 8,362 subjects aged 50 or more during the period January to December 2000 who were newly diagnosed with severe HSV infection.

The study group was compared to a control group of 25,086 people with no evidence of HSV infection.

The authors then monitored the development of dementia in these individuals over a follow-up period of 10 years between 2001 and 2010.

The risk of developing dementia in the HSV group was increased by a factor of 2.542. But, when the authors compared those among the HSV cohort who were treated with antiviral therapy versus those who did not receive it, there was a dramatic tenfold reduction in the later incidence of dementia over 10 years.

Professor Richard Lathe added: "Not only is the magnitude of the antiviral effect remarkable, but also the fact that -- despite the relatively brief duration and the timing of treatment -- in most patients severely affected by HSV1 it appeared to prevent the long-term damage in brain that results in Alzheimer's.

Professor Itzhaki said: "It was as long ago as 1991 when we discovered that, in many elderly people infected with HSV1, the virus is present also in the brain, and then in 1997 that it confers a strong risk of Alzheimer's disease in the brain of people who have a specific genetic factor.

"In 2009, we went on to show that HSV DNA is inside amyloid plaques in Alzheimer's patients' brains.

"We suggested that the virus in brain is reactivated by certain events such as stress, immunosuppression, and infection/inflammation elsewhere.

"So we believe the cycle of HSV1 reactivation in the brain eventually causes Alzheimer's in at least some patients."

Source: https://www.sciencedaily.com/releases/2018/07/180712100515.htm

DNA Vaccine Protects Against AIDS, Not HIV

While a new DNA vaccine may not be able to prevent HIV infection, it could protect against progression to full-blown AIDS. Researchers from Kansas report their findings in the March 2005 issue of the Journal of Virology.

Developing a vaccine to protect against HIV in attempt to gain control of the AIDS pandemic is a top priority for researchers throughout the world. Extensive testing has been conducted with live vaccines to determine if immunization would be effective at prevention, but they are not suitable for human use due to the potential that the vaccine viruses could mutate and reacquire the ability to cause disease.

DNA vaccines offer a new possibility for treatment. The have the advantages of safety, low cost of production, and ease of use in field conditions due to their minimal need for refrigeration.

In the study the DNA of a simian/human immunodeficiency virus (SHIV) was made non-infectious by removing the gene that makes reverse transciptase (a protein the virus requires to replicate). Four macaques were injected with the non-infectious vaccine, while two control animals remained unvaccinated. Both groups were challenged with SHIV. All four of the immunized macaques became infected with the challenge virus, but three survived. The two control subjects died.

“The results showed strong evidence that this type of vaccine could prevent AIDS and established that a DNA vaccine, such as this one, could be used alone, without the need for booster doses with viral proteins, for large-scale immunization programs,” say the researchers.

(D.K. Singh, Z. Liu, D. Sheffer, G.A. Mackay, M. Smith, S. Dhillon, R. Hegde, F. Jia, I. Adany, O. Narayan. 2005. A noninfectious simian/human immunodeficiency virus DNA vaccine that protects macaques against AIDS. Journal of Virology, 79. 6: 3419-3428.)

Source: https://www.sciencedaily.com/releases/2005/04/050419105400.htm

Progress in fighting cancer and infections with T cell therapy

The quest to bring immunotherapy into widespread clinical use against cancer and infectious diseases has made great strides in recent years. For example, clinical trials of adoptive T cell therapy are yielding highly promising results. The latest progress is being reported at the Annual Meeting of the American Association for the Advancement of Science (AAAS 2016) by three international leaders in the field: Prof. Dirk Busch of the Technical University of Munich (TUM), Prof. Chiara Bonini of the San Raffaele Scientific Institute, and Prof. Stanley Riddell of the Fred Hutchinson Cancer Research Center and the University of Washington.

 T cell immunity has evolved to recognize and respond to health threats and provide a lifelong memory that prevents recurrent disease. However, with chronic diseases, reactive T cells often become inactive or even disappear. Recent advances have brought the idea of fighting chronic infections, and even cancers, by restoring protective T cell responses much closer to reality.

The main focus of the AAAS 2016 session "Fighting Cancer and Chronic Infections with T Cell Therapy: Promise and Progress" is on adoptive T cell therapy, in which a patient receives "killer" immune cells that target a disease-associated molecule. Several obstacles have stood in the way of widespread clinical use: identifying or generating T cells that will be most effective for each individual case, whether from the patient or from a suitable donor; avoiding or countering potential side-effects; and finding ways to shorten the path from bench to bedside. Progress is being reported on all three fronts, including data from the first clinical trials.

Potent cells, with a safety mechanism

"There is a lot of scientific competition, of course, as well as growing industry interest," says Prof. Dirk Busch. "What we bring into the game is, first, the conviction that you have to select the right cells to generate optimal cell products for therapy, together with superior techniques to do it. Over the past years, we at TUM as well as Stan Riddell and Chiara Bonini have worked on providing cell products that will upon tranfer to patients expand to large numbers and stay active for a long time, potentially life-long. We identified a subset of T cells with high regenerative potential, where even low numbers of transferred cells -- in the extreme a single T cell -- can confer therapeutic immune responses." The use of such potent cells, he adds, requires the implementation of safety mechanisms, and that too has now been demonstrated.

Within the TUM Institute for Advanced Study (TUM-IAS) Focus Group on Clinical Cell Processing and Purification, Busch, Riddell, and colleagues have pioneered methods to rapidly select defined T cell subsets for clinical applications. Central memory T cells (TCMs) are of special interest: TCMs can engraft, expand, and persist long-term, even at very low numbers of transferred cells. Also, they can be genetically engineered to express novel antigen-targeting receptors without affecting their in vivo behavior. The first clinical trials using engineered T cells expressing so-called chimeric antigen receptors that recognize an antigen on B cell leukemia (anti-CD19-CARs) have provided outstanding results -- including cases of complete remission of end-stage, blood-borne malignancies. Encouraging results have also been seen in clinical trials of adoptive T cell therapy against chronic infections.

At the same time, the researchers are exploring safeguards that would allow, in the event of side-effects, selective elimination of the genetically modified T cells used for therapy. One such safety mechanism has been tested successfully in pre-clinical animal models and has already been transferred to human patients. "We put a marker into the T cells, so that we can give an antibody that binds to the cells that we have engineered but no others," Busch explains. "If an antibody binds to a cell, then other immune mechanisms get activated that eliminate it. We call this antibody-mediated cell toxicity."

The broader goal is to make sure the therapeutic cell products are so well understood and defined -- and backed up by safety mechanisms -- that the same approach can be confidently used to treat different patients, on an individualized basis. "We believe the more defined our cell products are, the more predictable the clinical outcome will be," Busch says.

Technology developed at TUM helped to launch a spin-off company called STAGE Cell Therapeutics, which has merged with Seattle-based Juno Therapeutics. The Munich-based Juno Therapeutics GmbH is the company's European arm.

Source: https://www.sciencedaily.com/releases/2016/02/160214201151.htm

The 'bad apples' of the immune system are also its secret weapon, according to major Australian research published today in the world-leading journal Science.

In a world first, scientists from Sydney's Garvan Institute of Medical Research have revealed how a population of 'bad' antibodies in the immune system -- which are usually 'silenced' because they can harm the body -- can provide crucial protection against invading microbes. The research was carried out in mice.

The 'bad' antibodies are known to react against the body's own tissues and can cause autoimmune disease. For this reason, it was once thought that they were discarded by the immune system or that they were made inactive in the long term. However, the new findings show for the first time that 'bad' antibodies go through a rapid 'redemption' process and are activated when the body is faced with a disease threat that other antibodies cannot tackle.

As a result, the 'redeemed' antibodies no longer threaten the body, but instead become powerful weapons to fight disease -- and particularly diseases that evade the immune system by disguising themselves to look like normal body tissue.

Professor Chris Goodnow, who co-led the new research with A/Prof Daniel Christ (both Immunology Division, Garvan), says the new findings will fundamentally change thinking about how the immune system protects us.

"We once thought that harmful antibodies were discarded by the body -- like a few bad apples in the barrel -- and no one had any idea that you could start with a 'bad' antibody and make it good.

"From these new findings, we now know that every antibody is precious when it comes to fighting invading microbes -- and this new understanding means that 'bad' antibodies are a valuable resource for the development of vaccines for HIV, and for other diseases that go undercover in the body."
This study was made possible by the generosity of The Bill and Patricia Ritchie Foundation, and through funding from the National Health and Medical Research Council (Australia).

Carrying out the immune system's toughest task

The new research appears to solve an enduring mystery that has puzzled scientists for decades: How does the immune system attack invading microbes that look almost identical to the body's own molecules, without mounting an attack on the body at the same time?

Campylobacter, HIV and others are particularly problematic targets for the immune system because they have evolved to appear almost identical to the body's own molecules; they are 'wolves in sheep's clothing'. This makes it difficult for the immune system to attack them, because it systematically avoids using antibodies that can attack 'self'.

To understand how the immune system recognises these 'wolves in sheep's clothing', scientists from the Garvan Institute zeroed in on a mysterious army of immune cells in the bloodstream.

'Bad' antibodies are hiding inside silenced B cells

The silenced cell army contains millions of immune cells known as B cells -- which produce antibodies to fight diseases. Unlike other B cells, though, the cells of this army pose a danger to the body. This is because they can make 'bad' antibodies, which can attack 'self' and cause autoimmune disease. For this reason, they are kept in a long-term silenced state (known as anergy).
Professor Chris Goodnow discovered the silenced cells 30 years ago -- and has been working to understand their function ever since.

"The big question about these cells has been why they are there at all, and in such large numbers," says Prof Goodnow. "Why does the body keep these cells, whose antibodies pose a genuine risk to health, instead of destroying them completely, as we once thought?"

The new findings appear to answer that question, showing that selected cells in the army can be reawakened to fight invaders -- but only once their 'bad' antibodies are made good.

"We've shown that these silenced cells do have a crucial purpose, says Deborah Burnett, a PhD student at Garvan whose work forms the basis of the study. "Far from 'clogging up' the immune system for no good reason, they're providing weapons -- bad apples made good -- to fight off invaders whose 'wolf in sheep's clothing tactics make it almost impossible for the other cells of the immune system to fight them."

Three tiny DNA changes turn bad into brilliant

Working with a sophisticated preclinical mouse model, which was developed at Garvan by Prof Rob Brink (Immunology Division) and his team, the researchers showed that the silenced cells can produce antibodies when they encounter an invader that appears highly similar to 'self'.

Crucially, before the cells attack, the antibodies they make are first redeemed through tiny alterations to their DNA sequence. This ensures the antibody that each cell makes no longer attacks 'self', but rapidly becomes a 5000 times more potent weapon against the invading foreigner.

Remarkably, in the model system tested, only three DNA changes were needed to transform antibodies from dangerous cells to effective weapons against disease: a first change to stop the antibody from binding to 'self', and a further two changes to increase their ability to specifically bind the invader.

At the atomic level, a dimple makes the difference

In experiments conducted at the Australian Synchrotron, the research team showed how the three DNA changes rearrange the tips of the antibody in defined ways, so that it becomes much better at recognising the foreign molecule and worse at recognising 'self'. In particular, the redeemed antibody fits neatly around a nanoscale 'dimple' that is present on the foreign molecule but is absent on self.

"This research has taken us on an exciting journey," says A/Prof Christ. "Not only have we uncovered a new kind of immunity, we've been able to confirm precisely how a bad antibody can be made good.
"Crucially, these redeemed antibodies are by no means a fall-back option. In fact, our findings show the opposite -- that antibodies made by tweaking 'bad' antibodies can be even better than those developed through established pathways."

Towards better vaccines

Our findings indicate that theres a whole class of B cells out there -- the silenced B cells -- that might be accessible for vaccine development, and that we have so far largely ignored, A/Prof Christ says.
Dr Burnett adds, "We're hoping that, instead of ignoring this population of silenced B cells, researchers will in the future consider targeting these cells when they're developing vaccines, particularly against targets such as HIV, which disguise themselves as 'self'."



Source: https://www.sciencedaily.com/releases/2018/04/180412141052.htm