How do viruses such as HIV or hepatitis C, manage to outsmart their hosts' immune systems?

McGill University

How viruses disarm the immune system
Discovery of molecular mechanism could point toward new targets for treating patients

How do viruses that cause chronic infections, such as HIV or hepatitis c virus, manage to outsmart their hosts’ immune systems?

The answer to that question has long eluded scientists, but new research from McGill University has uncovered a molecular mechanism that may be a key piece of the puzzle. The discovery could provide new targets for treating a wide range of diseases.

Fighting off infections depends largely on our bodies’ capacity to quickly recognize infected cells and destroy them, a job carried out by a class of immune cells known as CD8+ T cells. These soldiers get some of their orders from chemical mediators known as cytokines that make them more or less responsive to outside threats. In most cases, CD8+ T cells quickly recognize and destroy infected cells to prevent the infection from spreading.

“When it comes to viruses that lead to chronic infection, immune cells receive the wrong set of marching orders, which makes them less responsive,” says Martin Richer, an assistant professor at McGill’s Department of Microbiology & Immunology and senior author of the study, published recently in the journal Immunity.

The research, conducted in Richer’s lab by graduate student Logan Smith, revealed that certain viruses persist by driving the production of a cytokine that leads to modification of glycoproteins on the surface of the CD8+ T cells, making the cells less functional. That maneuver buys time for the pathogen to outpace the immune response and establish a chronic infection. Importantly, this pathway can be targeted to restore some functionality to the T cells and enhance the capacity to control infection.

The discovery of this regulatory pathway could help identify new therapeutic targets for a variety of diseases. “We might be able to take advantage of the pathways induced by these signals to fight chronic viral infections by making the immune system more responsive,” Richer says. “The findings might also prove useful for diseases like cancer and autoimmunity, where T cells function is poorly regulated.”

Interleukin-10 Directly Inhibits CD8+ T Cell Function by Enhancing N-Glycan Branching to Decrease Antigen Sensitivity was published in Immunity

Tapping the innate immune system’s infection response

Tapping the innate immune system’s infection response
Seán Duke | 18 May 2017

In Ireland, hundreds of rhesus negative women were infected with hepatitis C from contaminated anti-D blood products they received after they gave birth between 1977 and 1979.

Some readers will recall that 12 years passed before any of the women knew that the anti-D they had received was contaminated, when a major ‘look back’ exercise was initiated. This investigation found that over 600 women had evidence of having been infected; with half having antibodies and the hepatitis C virus (HCV) in their systems and half having antibodies against HCV but no virus. In the latter case, this indicated that the women’s adaptive immune systems had helped resolve their infection. However, some other women that received anti-D showed no sign of having been infected and scientists wondered why.

When scientists at Trinity, led by Prof O’Farrelly, investigated this group of people more closely, they found that many of the women had received anti-D from batches that had very low viral loads – too low to cause infection. The Trinity researchers also estimated that almost 400 women received anti-D that was contaminated with a significant viral load, but were not infected and there was no sign of a strong response by the adaptive immune system.

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Hepatitis C treatment: Genes found that calibrate how our immune system affects virus

Hepatitis C treatment: Genes found that calibrate how our immune system affects virus

A big data study of hepatitis C and more than 500 patients with the virus has opened the way for a better understanding of how the virus interacts with its human hosts.

Researchers at the University of Oxford have for the first time developed a method for analyzing and comparing the genetic makeup of the hepatitis C virus (HCV), as well as that of more than 500 patients with the virus.

Viral hepatitis is one of the leading causes of death and disability worldwide, with 2-3% of the world’s population thought to be infected with HCV, which left untreated can led to liver disease and cancer.

Professor Ellie Barnes from the Nuffield Department of Medicine, who led the study with Dr Chris Spencer, said: “We identified two places in the human genome where the genetic variation that calibrates our immune system affects the genetic diversity of the virus…Within 15 years, DNA sequencing of disease-causing bugs like HCV will become a routine part of healthcare.”

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Newly found tactics in offense-defense struggle with hepatitis C virus

 

This is a schematic on the window board of Dr. Ram Savan's lab at UW Medicine South Lake Union in Seattle. The schematic outlines how a genetic variant produces a...

Click here for more information.    Newly found tactics in offense-defense struggle with hepatitis C virus    Some people are genetically equipped to resist HCV's efforts to turn off a type interferon 
The hepatitis C virus (HCV) has a previously unrecognized tactic to outwit antiviral responses and sustain a long-term infection. It also turns out that some people are genetically equipped with a strong countermeasure to the virus' attempt to weaken the attack on it.

The details of these findings suggest potential targets for treating HCV, according to a research team led by Dr. Ram Savan, assistant professor of immunology at the University of Washington. The study was published in Nature Immunology.

HCV infects more than 150 million of the world's people. The virus is notorious for evading the body's immune system and establishing an infection that can continue for decades, despite treatment. A lasting infection can damage the liver, and in some cases produce liver cancer. HCV infection is a major cause of liver failure requiring an organ transplant.

The virus, hiding in other tissues, can return in the transplanted liver. HCV and the human immune system are engaged in a seemingly never-ending duel, each trying to overcome the others latest move. Several HCV mechanisms for defying the body's immune system have already been uncovered.

Present treatments are about 70 percent effective in curing the infection, Savan said. The triple combination treatments consist of interferon, ribavirin and direct-acting antiviral agents.

He added, however, that resistant strains of HCV are emerging in antiviral treated patients. Also troubling, he said, is that certain patients can undergo almost a year of treatment weeks – and still be infected. They've endured the unpleasant, flu-like side effects of the regimen with little benefit.
After observing that patients of Asian descent reacted better to HCV treatment than did those of African descent, other research teams searched entire human genomes to identify gene clusters associated with response to therapy.

On chromosome 19, the scientists found different, single-letter DNA code changes linked to treatment response and the natural ability to clear HCV infection.

These tiny genetic variations are located near an area that encodes for interferon-lamda3 (IFNL3), also called interleukin-28B. Viruses can trigger blood cells and other cells to produce this potent substance, which is released to protect against virus invasion.

The mechanism aligning this genetic finding with clearance of HCV had been elusive, Savan's group noted in their paper. His team discovered how the single-letter variation in the IFNL3 gene was responsible for the differences between those who could and those who could not effectively clear HCV.

Individuals who carry the T (for thymidine) variant have an unfavorable outcome in fighting HCV, while those who carry the G (for guanosine) variant have a favorable outcome.

Their data showed that HCV could induce liver cells to target the activities of the IFNL3 gene with two microRNAs. MicroRNAs are silencers: They stop the messengers who transmit information to produce a protein from a gene, in this case the production of the antiviral interferon lambda-3.
These two particular microRNAs are generally turned off in liver cells, until HCV coerces them to act on its behalf. Normally, these so called myomiRs are associated with myosin-encoding genes in skeletal and heart muscle.

"This is a previously unknown strategy by which HCV evades the immune system and suggests that these microRNAs could be therapeutic targets for restoring the host antiviral response," the researchers wrote in their paper. Adding support to this suggestion is the researchers' observation that the bad-acting microRNAs in question could not land on and repress interferon lambda-3, if the host carried the favorable "G" variant.

In those cases, the host is able to escape adverse regulation by HCV, the researchers observed. Savan pointed out that this particular escape variant has been found only in humans, and not in other primates. He said it is not yet known if the G variant arose in humans as a response to selective pressure by infection with HCV.

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Savan came to the University of Washington in late 2011 from the National Institutes of Health. The first author on the paper, Adelle McFarland, was a research scientist in Savan's lab and is now a graduate student in the Molecular and Cellular Biology Program at the UW.

Funding for this project came from a start-up grant from the UW Department of Immunology and from the National Institutes of Health (HHSN261200800001E, AI060389, AI88778, and CA148068)
Other researchers on the project, reported in the article "The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAS," were Stacy M. Horner, Abigail Jarret, Rochelle C. Joslyn, all at the UW Department of Immunology at the time of the study; Eckart Bindewald and Mary Carrington of the Frederick National Laboratory for Cancer Research, Bruce A. Shapiro of the National Cancer Institute, and Don A. Delker and Curt H. Hagedorn, both of the University of Utah. Michael Gale, Jr., a collaborator in this study, is from the UW department of Immunology.

A Nature Immunology News & Views commentary, "Outflanking HCV." by Zhigang Tian of the University Of Life Sciences Of China in Hefei, gives a perspective on the research findings.

CNIO scientists decipher how the immune system induces liver damage during hepatitis

CNIO scientists decipher how the immune system induces liver damage during hepatitis

Viral infections are the primary cause of liver inflammation or hepatitis, affecting hundreds of millions of people all over the world, and they represent a public health problem worldwide. The acute condition can cause irreversible damage to the liver, and if not cured can become chronic, leading to serious diseases such as cirrhosis or cancer.

A study published today in the online edition of The Journal of Clinical Investigation, and carried out by Erwin Wagner's team, Director of the BBVA Foundation-CNIO Cancer Cell Biology Programme and holder of an ERC Advanced Grant, shows how the immune system 'attacks' liver cells during hepatitis by using the AP-1 gene JunB.

Latifa Bakiri, one of the study's authors and a researcher in Wagner's laboratory details: "The activation of the JunB/AP-1 gene in a subset of immune cells, called NK cells, increases the production of interferon-gamma that attacks liver cells while the organ is suffering from hepatitis".

 

With this discovery, the study's authors propose a new mechanism by which AP-1 acts as a double-edged sword in the liver: it's a first line of defence against viruses that cause the disease, but also encourages liver damage depending on the diet or genetics of the patient.

"The balance of these signals is fundamental to the understanding of the pathogenesis of inflammatory liver disease and to design new therapeutic approaches to reverse this disease", says Wagner.

NK-type immune cells are also part of the micro-environment surrounding tumours. Researchers point out in the discussion of the article that a better knowledge of these cells may be vital for designing immune-therapies that specifically target tumour cells.

Source: Centro Nacional de Investigaciones Oncologicas (CNIO)

Why the immune system often makes us worse while trying to make us well

Interferon's used during hepatitis C standard therapy or newer triple therapy works by stimulating the body's immune response, often leading to side effects including flu-like symptoms, fever, and muscle aches.

Interferon was discovered in 1957 by Alick Isaacs and Jean Lindenmann, it wasn't until 1996 that the FDA approved alfa interferon for the treatment of hepatitis C. In a recent article published online last month by the journal PNAS researchers presented the first clinical assessment of how interferon works and fights HIV and Hepatitis infections, view the USCF article here.

The Immune System
When I was undergoing standard hepatitis C therapy I asked my physician why I ran a low-grade fever. He explained in simple terms, it went something like this - "Interferons (IFNS) are made naturally in the body as a response to the presence of viruses and "interfere" with viral replication, hence their name. The symptoms experienced during a fever are related to the production of IFNs during infection.  Because you're injecting the drug interferon you may experience the same symptoms. 

Interferon-Fever 
On a high note researchers presented a study last year at the 2011 AASLD meeting, which found people who experience a fever soon after starting interferon-based therapy are more likely to experience early virological response, view the abstract here.

This brings us to an article today in the news highlighting the immune system. When the immune system jumps start the host may feel the ill effects. This article answers the question - "Why the immune system often makes us worse while trying to make us well." 

Why getting healthy can seem worse than getting sick

A new article in The Quarterly Review of Biology helps explain why the immune system often makes us worse while trying to make us well.

The research offers a new perspective on a component of the immune system known as the acute-phase response, a series of systemic changes in blood protein levels, metabolic function, and physiology that sometimes occurs when bacteria, viruses, or other pathogens invade the body. This response puts healthy cells and tissue under serious stress, and is actually the cause of many of the symptoms we associate with being sick.

"The question is why would these harmful components evolve," asks Edmund LeGrand (University of Tennessee, Knoxville), who wrote the paper titled with Joe Alcock (University of New Mexico). The researchers contend that answer becomes clear when we view the acute-phase response in terms of what they call "immune brinksmanship."

The immune brinksmanship model "is the gamble that systemic stressors will harm the pathogens relatively more than the host," LeGrand said. The concept, he explains, is akin to what happens in international trade disputes. When one country places trade sanctions on another, both countries' economies take a hit, but the sanctioning country is betting that its opponent will be hurt more.
"One of our contributions here is to pull together the reasons why pathogens suffer more from systemic stress," LeGrand said.

The acute-phase response creates stress in several ways. It raises body temperature and causes loss of appetite and mild anemia. At the same time, certain vital nutrients like iron, zinc, and manganese are partially sequestered away from the bloodstream.

 Some of these components are quite puzzling. Why reduce food intake just when one would expect more energy would be needed to mount a strong immune response? Zinc is essential for healthy immune function. Why pull it out of the bloodstream when the immune system is active? The benefits of a stressor like fever are fairly well known; heat has been shown to inhibit bacterial growth and cause infected cells to self-destruct. But what hasn't been clear is why pathogens should be more susceptible to this stress than the host.

LeGrand and Alcock offer some answers. For an infection to spread, pathogens need to multiply, whereas host cells can defer replication. Replication makes DNA and newly forming proteins much more susceptible to damage. It also requires energy and nutrients—which helps explain the benefits of restricting food and sequestering nutrients.

The act of invading a body also requires bacteria to alter their metabolism, which can make them more vulnerable to all kinds of stress, including heat.
Another reason pathogens are more vulnerable to stress is that the immune system is already pummeling them with white blood cells and related stressors at the site of the infection. That means that pathogens are already under local stress when systemic stressors are piled on. "In many ways, the acute-phase response reinforces the stress inflicted on pathogens locally at the infection site," LeGrand said.

As the term "brinksmanship" implies, there's an inherent risk in a strategy that involves harming oneself to hurt the enemy within. This self-harm leaves the body more vulnerable to other dangers, including other infections. Additionally, it is possible for the immune stressors to do more damage than required to control the pathogens.

"But in general, systemic stressors when properly regulated do preferential harm to invaders," LeGrand said. Viewed this way, it's not surprising that natural selection has utilized the stressful parts of the acute-phase response in mammals, reptiles, fish, and even invertebrates.

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Edmund LeGrand and Joe Alcock, "Turning Up The Heat: Immune Brinksmanship In The Acute-phase Response." The Quarterly Review of Biology 87:1 (March 2012).
The premier review journal in biology since 1926, The Quarterly Review of Biology publishes articles in all areas of biology but with a traditional emphasis on evolution, ecology, and organismal biology. QRB papers do not merely summarize a topic, but offer important new ideas, concepts, and syntheses. They often shape the course of future research within a field. In addition, the book review section of the QRB is the most comprehensive in biology.
Source

'Pep talk' can revive immune cells exhausted by chronic viral infection

'Pep talk' can revive immune cells exhausted by chronic viral infection

Chronic infections by viruses such as HIV or hepatitis C eventually take hold because they wear the immune system out, a phenomenon immunologists describe as exhaustion.

Yet exhausted immune cells can be revived after the introduction of fresh cells that act like coaches giving a pep talk, researchers at Emory Vaccine Center have found. Their findings provide support for an emerging strategy for treating chronic infections: infusing immune cells back into patients after a period of conditioning.

The results are published this week in Proceedings of the National Academy of Sciences Early Edition.

The first author of the paper is Rachael Aubert, a student in Emory's Immunology and Molecular Pathogenesis program who completed her doctorate in 2009. Senior author Rafi Ahmed, PhD, is director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.

Ahmed's laboratory has extensive experience studying mice infected with lymphocytic choriomeningitis virus (LCMV). Immune responses against LCMV are driven by CD8 or "killer" T cells, which destroy virus-infected cells in the body. But a few weeks after exposure to LCMV, the mice develop a chronic infection that their immune systems cannot shake off, similar to when humans are infected by viruses like HIV and hepatitis C.

Aubert and her co-workers examined what happened to mice chronically infected with LCMV when they infused CD4 or "helper" T cells from uninfected mice. After the infusion, the CD8 cells in the infected mice revived and the levels of virus in their bodies decreased by a factor of four after a month. Like coaches encouraging a tired athlete, the helper cells drove the killer cells that were already in the infected mice to emerge from exhaustion and re-engage.

The cell-based treatment was especially effective when combined with an antibody that blocks the molecule PD-1, which appears on exhausted T cells and inhibits their functioning. The antibody against PD-1 helps the exhausted T cells to revive, and enhances the function of the helper cells as well: the combination reduced viral levels by roughly ten-fold, and made the virus undetectable in some mice.

"We have not seen this sharp of a reduction in viral levels in this system before," says co-author Alice Kamphorst, a postdoctoral fellow.

The helper cells were all genetically engineered to recognize LCMV, a difference between mouse experiments and potential clinical application. However, it may be possible to remove helper T cells from a human patient and stimulate them so that all the cells that recognize a given virus grow, Kamphorst says.

"This is an active area of research and several laboratories are looking at how best to stimulate T cells and re-introduce them," she says.

In addition, she and her co-workers are examining what types of hormones or signaling molecules the helper cells provide the killer cells. That way, that molecule could be provided directly, instead of cell therapy, she says.

The molecule PD-1 was previously identified by Ahmed and colleagues as a target for therapy designed to re-activate exhausted immune cells. Antibodies against PD-1 have been undergoing tests in clinical studies against hepatitis C and several forms of cancer.

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Collaborators from Harvard Medical School/Dana Farber Cancer Institute contributed to the paper. The research was supported by the National Institutes of Health and the Cancer Research Institute.

Reference: R.D. Aubert et al. Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection. PNAS Early Edition (2011).

Hepatitis C; Strengthening fragile immune memories to fight chronic infections

Strengthening fragile immune memories to fight chronic infections

After recovering from the flu or another acute infection, your immune system is ready to react quickly if you run into the same virus again. White blood cells called memory T cells develop during the infection and help the immune system remember the virus and attack it if it comes back.

But chronic infections such as those caused by viruses like HIV and hepatitis C are different. If the immune system can't clear the infection out of the body fast enough, the memory T cells that initially developed against the virus upon first encounter are lost. This poses a challenge for vaccine development.

Researchers at the Emory Vaccine Center have identified the conditions that make memory T cells slip away during persistent infections. They have also shown that a molecule called 2B4 on memory cells causes them to slow down during chronic infections. The results are published online this week in the journal Immunity.

The results have implications for vaccine design. The authors emphasize the importance of having vaccines that encourage the immune system to quickly control a potentially chronic infection or prevent it from gaining a foothold – a task that some experimental vaccines against HIV's cousin SIV have accomplished.

"In a chronic infection, the memory T cells become so tightly regulated that they eventually are ineffective," says first author Erin West, an Emory graduate student in immunology and molecular pathogenesis. "This is why it's so important to have that initial strength at the beginning."

West and most of the co-authors are in the laboratory of Rafi Ahmed, PhD, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar. Researchers from Harvard Medical School also contributed to the study, including W. Nicholas Haining and Cox Terhorst.

West and her colleagues studied mice infected by a meningitis virus which establishes a chronic infection. A weaker form of the virus can be cleared from the body in a couple weeks. They tracked naïve T cells as well as memory T cells' responses to infections that varied in dose and persistence.

A molecule called 2B4 appears on memory T cells that are activated during chronic infections and slows them down, the Emory team found. This level of regulation probably helps control the immune system and prevents it from developing dangerous over-inflammation, West says.

"Perhaps the body says 'I can't take care of this, so I will shut down,' before too much inflammation and damage occurs," she says.

Emory researchers have identified other molecules that produce "immune exhaustion" on T cells such as PD-1, but 2B4 is different because it seems to specifically regulate memory T cells. If memory T cells are engineered to lack 2B4, they are better able to persist during a chronic infection, although it's not clear whether the cells are then more effective at fighting the infection, West says. Blocking 2B4 might be a way to enhance immune responses against chronic infections, but more information is needed about how it works, she says.

The researchers also found that memory T cells need more "help," in the form of signals from other T cells, in the setting of chronic infection. This is a reversal of the situation in acute infections, where memory T cells are quicker to respond and need less help, she says.

In the paper, the Emory team cites a HIV vaccine tested in Thailand that was shown to have some ability to block initial infection, and an experimental hybrid vaccine against SIV designed by scientists in Oregon that has shown similar effects. They suggest that their results could be used to tune future vaccine design efforts and take advantage of these successes.

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The research was supported by the National Institutes of Health.
Reference: E.E. West et al. Tight Regulation of Memory CD8+ T cells Limits Their Effectiveness during Sustained High Viral Load. Immunity (posted online August 18, 2011).
The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service.

HIV; Forgiveness Can Improve Immune Function

May 5, 2011 (Washington, DC) — Could forgiveness lead to enough beneficial physiological change to improve immune function in people whose immune status is already compromised?

A new study conducted in people living with HIV shows individuals who truly forgave someone who had hurt them in the past showed positive changes in their immune status.

The study was presented here at the Society of Behavioral Medicine 32nd Annual Meeting and Scientific Sessions.

Amy Owen, PhD, Duke University Medical Center, Durham, North Carolina, found that greater forgiveness significantly correlated with higher CD4 cell percentages (P = .042). Unlike the CD4 cell count, which is a measure of how many functional CD4 T cells are circulating in the blood, the CD4 cell percentage represents the percentage of total lymphocytes that are CD4 cells.

In regression analyses, the relationship of forgiveness and CD4 cell percentages remained significant even when controlling for variables that could affect CD4 cell counts, including age, race, sex, level of education, years with HIV, adherence, substance use, and viral load (P = .034).

"We hypothesized that higher levels of forgiveness would be associated with higher CD4 cell percentages controlled for demographic and behavioral variables as well as viral load," Dr. Owen told Medscape Medical News. "And none of these variables accounted for the relationship between forgiveness and CD4 cell percentages. So there is something special going on between forgiveness and CD4 cell counts."

Beneficial Effect
The study involved 78 individuals living with HIV and receiving antiretroviral medications. Subjects had been taking anti-HIV medications for at least 1 year, and 67% of them had undetectable viral loads. Eighty-one percent were nonwhite. Medication adherence was assessed by calculating the mean number of missed doses during the past 4 days. Subjects were also asked about tobacco, alcohol, marijuana, and cocaine use.

Forgiveness was measured by the Enright Forgiveness Inventory, a tool that assesses positive and negative feelings, thoughts, behaviors, or imagined behaviors toward an individual who caused the subject hurt.

Dr. Owen also defined forgiveness strictly as being a freely made choice to move away from negative cognitive, emotional, and behavioral responses toward a person who caused a hurt and work towards developing positive cognitive emotional and behavioral responses toward that person.

"For my study, I compared the relationship of forgiveness of another person and CD4 cell percentages both without controlling for any other factors (using a bivariate correlation), and then I tested whether this relationship would hold up when I controlled for other possible factors linked to CD4 percentage levels that could account for an observed relationship between forgiveness and CD4 percentages (using a hierarchical linear regression)."

In bivariate correlations, results showed that greater forgiveness was significantly associated with higher CD4 percentages, whereas linear regression analyses found that this relationship remained significant after controlling for the potential influence of other factors.

"Results support our hypothesis and reflect previous findings on relationships of psychosocial factors with immune makers in people living with HIV/AIDS, and findings indicate that forgiveness of another person may be beneficial for their health," said Dr. Owen.

Understanding Forgiveness Key
She also noted that helping people who have been violated in the past come to a place of peace can be done, but it has to be done well.

"If psychiatrists want to counsel patients about forgiveness, they first need to understand very deeply what forgiveness is and what it is not," she said. "If there isn't a good therapeutic relationship between a physician and the patient, “what patients can hear from you when you are suggesting forgiveness is, 'I don't want to hear about it anymore and what's wrong with you that you are not just fine with it.' But that can be extremely violating and potentially retraumatize the person who has already been deeply hurt."

It's also very important to respect a patient's anger, she added, because sometimes that is all a person has.
"If you threaten that by suggesting that the patient shouldn't be so angry, it can be disrespectful, so if a psychiatrist wants to engage with a patient on the topic of forgiveness, it's essential they understand the definitions of forgiveness and be willing to journey with that person over time. Patients will struggle with it; it's not a linear process, but it is very transformative."

Emotional Pain Common
Reverend Michael Barry, PhD, Cancer Treatment Centers of America, Philadelphia, Pennsylvania, told Medscape Medical News that unforgiveness is a state where a person retains negative emotions, including anger and hatred, for a perpetrator of harm.

"This creates a state of chronic anxiety, and chronic anxiety has a predictable impact on a wide range of bodily functions, including the reproductive system, the digestive system, and the immune system," he said.

For example, stress hormones, including cortisol and adrenalin, have been shown to reduce the production of natural killer cells — the "foot soldiers" in the fight against cancer, he noted.
Dr. Barry's own research has shown that almost two-thirds of cancer patients identified forgiveness as a personal issue for them, and 1 in 3 of them indicated they had severe forgiveness issues, "so we are aware of the emotional pain that many of our patients are in.

"There is a direct correlation between unforgiveness and our immune system, which directly affects our healing processes. We teach people what we have learned about the process of forgiveness in a short-term forgiveness intervention program that works," he added.

Dr. Owen has disclosed no relevant financial relationships. Dr. Barry is the author of The Forgiveness Project. He also developed a forgiveness program, entitled Release! The Healing Power of Forgiveness.

Society of Behavioral Medicine (SBM) 32nd Annual Meeting and Scientific Sessions: Abstract 4010. Presented April 30, 2011.

Authors and Disclosures
Journalist
Pam Harrison

Pam Harrison is a freelance writer for Medscape.
Pam Harrison has disclosed no relevant financial relationships.

http://www.medscape.com/viewarticle/742198.

Hepatitis C; How interferon-induced genes launch antiviral defenses

Big picture of how interferon-induced genes launch antiviral defenses revealed

When viruses attack, one molecule more than any other fights back. Interferon triggers the activation of more than 350 genes, and despite the obvious connection, the vast majority have never been tested for antiviral properties. A team of researchers, led by scientists from Rockefeller University, for the first time has carried out a comprehensive, systematic evaluation of the antiviral activity of interferon-induced factors. The findings, published online today in the journal Nature, are a first step toward unraveling how these naturally occurring molecules work to inhibit viruses.

"We hope this study will open the door to future work on the mechanisms of antiviral molecules," says first author John Schoggins, a postdoctoral associate in Charles M. Rice's Laboratory of Virology and Infectious Disease at Rockefeller. "Such mechanistic studies may set the stage for the development of new and much needed drugs to combat a diverse array of viruses that pose significant health threats to people worldwide."

The researchers were interested in type I interferon, a cellular molecule that is made when a person becomes infected with certain viruses. Type I Interferon is used clinically in the treatment of some viral diseases, such as hepatitis C, and its presence has been shown to significantly limit the severity of certain viral infections.

Schoggins and his colleagues, including researchers from the Aaron Diamond AIDS Research Center and the Howard Hughes Medical Institute, systematically evaluated the majority of common interferon-induced genes, one by one, to determine which of them had antiviral activity against a panel of disease-causing viruses, including the hepatitis C virus, HIV, West Nile virus, the yellow fever virus and chikungunya virus.

The scientists used a cell-based "screen" to measure the ability of each gene to halt the growth of the viruses: One by one, genes were delivered into the cells that were then infected with virus. In cells that had no interferon-induced genes delivered, Schoggins and his team observed normal levels of virus replication. In cells that had interferon-induced genes delivered, they occasionally found "hits" that could significantly impair virus replication.

Overall, Schoggins and his colleagues found that each virus tested was susceptible to inhibition by a unique subset of these interferon-induced genes, with some genes having specific effects on only one virus, and other genes having more broad effects on multiple viruses.

The researchers also showed that two genes in combination were more potent than either gene alone, supporting the long-standing hypothesis that many interferon-induced factors work in a combinatorial fashion. A number of the factors, the researchers found, work by interfering with the process by which viral RNA is translated in protein.

"It's fascinating that evolution has provided us with an array of hundreds of molecules that can be summoned by the host upon viral infection," says Schoggins. "Even more interesting is that none of these factors on their own are 'magic bullets' that can eradicate the virus. Instead, the cell relies on the cooperative action of numerous factors to effectively shut down the virus."

Schoggins and his colleagues hope their work will ultimately help inform the design of new antiviral drugs.

"This study is a first step toward unraveling how these previously uncharacterized, naturally occurring interferon-induced factors inhibit viruses," says Rice, who is the Maurice R. and Corinne P. Greenberg Professor at Rockefeller and scientific director of the Center for the Study of Hepatitis C. "In future studies, we hope to reveal the exact mechanisms by which these molecules suppress viral replication. If this can be done, then we will have a platform for the development of novel drugs that may be beneficial for combating viral infections."

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http://www.eurekalert.org/pub_releases/2011-04/ru-bpo040811.php

Your immune system

From The UC Berkeley Wellness Letter

Answering Your Questions About Immunity

Your immune system is crucial in maintaining your health—so it's important to keep it in good order. But how do you do that? People talk about boosting immunity as if it were a task similar to building muscles or reducing blood cholesterol. Hundreds of ads for supplements and other products promise to boost immunity. But keeping your immune system in good shape is a complicated task. "How do I boost immunity?" is really the same question as "What can I do to stay well?"

How does the immune system fight disease?

Because war is a handy metaphor for the human body's reaction to disease, science writers like to describe the immune system in militaristic terms—the body's department of defense. But unlike the Armed Forces, the immune system has no headquarters or commander-in-chief. And its operations are usually swifter and more efficient than any army's could be.

Rather than "making war," your immune system is really more like an immigration service: a highly differentiated cellular bureaucracy that supervises your biological commerce with the outside world, sorts through billions of pieces of information about incoming materials, and takes routine action as required. Only occasionally does it declare an emergency.

The immune system's basic task is to recognize "self" (the body's own cells) and "nonself" (an antigen—a virus, fungus, bacterium, or any piece of foreign tissue, as well as some toxins). To deal with nonself or antigens, the system manufactures specialized cells—white blood cells—to recognize infiltrators and eliminate them. We all come into the world with some innate immunity. As we interact with our environment, the immune system becomes more adept at protecting us. This is called acquired immunity.

What are the parts of the system?

Among the primary components of the immune system are a variety of white blood cells. These constitute a communications network that helps organize the immune response.

Most people are surprised to learn that the skin, including the mucous membranes, is among the most vital components of immunity. The skin not only forms a wall against intruders, but actually alerts the white blood cells if the wall is breached by invading organisms (through a wound, for instance). The protection afforded by the intact skin is why it's nearly impossible to catch a disease from a toilet seat, for example.

Most infectious agents get inside the body when we inhale them or swallow them; a few can enter through the genitals. They make their way into the blood and move rapidly through the body. The immune system has its own circulatory system called lymphatic vessels, which allow white blood cells to catch intruders. Other important parts of the immune system include the tonsils and adenoids, thymus, spleen, lymph nodes, appendix, certain areas of the small intestine, and bone marrow.

What do the white cells do?

Many mature white blood cells are highly specialized. The so-called T lymphocytes (T stands for thymus-derived) have various functions, among them switching on various aspects of the immune response, and then (equally important) switching them off. Another lymphocyte, the B cell, manufactures antibodies. A larger kind of white cell, the scavenger called the phagocyte (most notably the macrophage), eats up all sorts of debris in tissue and the bloodstream, and alerts certain T cells to the presence of antigens.

In addition, there are killer, suppressor, and helper T cells. Killer T cells, stimulated by helper T cells, zero in on cells infected by antigens, or turn against the body's own cells when, as in the case of cancer, they begin to proliferate abnormally. Another class of lymphocyte killer cell is called "natural" because, unlike T and B cells, it doesn't need to recognize a specific antigen. Most healthy cells are of no interest to natural killer cells, but cancer cells and cells invaded by viruses may be vulnerable to their search-and-destroy missions.

What makes a person immune to various diseases?

Thanks to the lymphocytes, the immune system possesses a memory, or a sense of history. The lymphocytes manufacture antibodies (proteins circulating in the blood) that attack intruders. Once you have produced antibodies to a certain microbe—a specific flu virus, for example—that particular virus cannot make you sick again, because you have cells that immediately recognize it and produce the antibodies that destroy it. The immunity may last for years, sometimes for life. This is "acquired immunity."

Science has also developed vaccines. It all began in the late eighteenth century, when the English physician Edward Jenner observed that people who caught a mild disease called cowpox never got smallpox, which is related to it. Using a boy who had not had either disease, Jenner tried inoculation: he scraped the child's skin and applied secretions from cowpox sores, and the boy got cowpox. When Jenner later inoculated him with smallpox matter, the boy did not develop smallpox. (Such human experimentation would land Dr. Jenner in court today.)

Creating immunity by injecting healthy people with dead or altered disease-causing microbes has prevented millions of deaths from measles, polio, diphtheria, flu, smallpox, tetanus, yellow fever, and many other diseases. Vaccines truly are immune-system boosters.

Does loss of sleep depress immunity?

It can. But losing sleep for a few nights won't necessarily make you ill. Many things boost or depress immunity temporarily. The number of immune cells rises and falls naturally in healthy people.

What foods boost immunity?

An adequate diet helps maintain immunity and keeps you healthy. The immune system needs such nutrients as protein, fatty acids, vitamins, and minerals. Severely malnourished people are particularly vulnerable to immune dysfunction, and they get sick more easily than other people and stay sick longer. What most people want to know, though, is whether one specific food or kind of food will boost immunity in otherwise healthy people on an adequate diet. The answer is generally no.

What supplements boost it?

So far there's no reason to believe that supplements will boost immunity in healthy people, except in the malnourished and many of the elderly. Though severe malnutrition is rare in the U.S., some groups, particularly the elderly, may be deficient in such nutrients as vitamin C, certain B vitamins, and zinc. Studies suggest that raising nutrient intakes to adequate levels can enhance immunity, and there is some evidence that elderly people stay healthier if they take a multivitamin/mineral pill. In contrast, other research suggests that megadoses of certain nutrients can significantly suppress some immune responses.

Consider zinc, for instance, found in meat and grains, and often promoted as an ideal immune-system booster when taken as a supplement. While some studies show that zinc supplements can boost immunity and promote wound-healing in the elderly, high intakes can actually suppress the immune response.

A diet low in beta carotene can depress immunity, but it's not clear that beta carotene supplements can correct the situation, or what levels of supplementation would be helpful. Among the agents that have been shown to stimulate immunity in experiments are bacteria such as those in yogurt, but it's far from certain that consuming yogurt (with or without live cultures) will promote resistance to disease.

What about vitamin C?

This vitamin is necessary to good health and no doubt to immune function. But numerous studies have shown that vitamin C supplements have minimal or no effect on the immune response, unless you are deficient in C.

Does exercise boost immunity?

Some research shows that sedentary people don't have as vigorous an immune system as those who exercise. Moderate exercise (for example, a moderate walking program undertaken by previously sedentary people) seems to improve immune function. But there is also evidence that overdoing exercise may depress the immune system: high-intensity or prolonged endurance exercise steps up the output of two so-called stress hormones, adrenaline and cortisol, both of which can depress various components of the immune system.

Olympians and other highly trained athletes often report that after intense competition and training they are more susceptible to colds. Yet such news should not deter athletes from competing or exercisers from exercising.

The health benefits of exercise are clear. Regular aerobic exercise is good for the heart. Weight-bearing exercise builds bone and muscle. The idea that your immune cells might not show a response to your exercise program should not deter you from exercising or from beginning an exercise program if you are sedentary.

Can emotions affect the immune system?

States of mind surely affect health, and extreme emotional stress may damage immunity and bring on illness. But research into the link between mind and immunity is in its early stages and has produced very little solid evidence so far—and not much advice about how to protect the immune system from the ill effects of emotional stress. An experiment may show that extreme grief depresses human T cells, for instance, but we don't know if the rest of the system is harmed, or whether the fluctuation means much.

Still, reports of increased illness and even death among the recently bereaved are common. Cancer patients with a "fighting spirit" seem to live longer than those who are despondent, but this may or may not prove something about immune function. Good social support is thought to improve immunity in people under stress.

Immune cells and nerve cells do interact. For example, when fighting an infection, immune cells are able to stimulate the brain to transmit the impulses that produce fever. Receptors for many of the chemicals released during stress, such as epinephrine and norepinephrine, have been observed on the surface of lymphocytes found near nerve terminals in the lymph nodes and spleen. This suggests that what goes on in the brain can interact with the immune system to suppress or, conversely, enhance it.

What does smoking do to immunity?

Part of the reason smokers are at risk for lung cancer and respiratory diseases may be that smoking suppresses immune cells. When smokers quit, immune activity begins to improve within 30 days.

When and why does the immune system malfunction?

The immune system has so many built-in fail-safes that, in theory at least, we should rarely fall ill. But, in fact, we do. Harmful agents such as HIV can baffle our defenses. The system can simply be overwhelmed by the number and toxicity of viruses, bacteria, or other foreign cells and toxins.

Though the immune system defends us against cancer, it is subject to cancer. Leukemia is a cancer of the white blood cells; multiple myeloma affects certain lymphocytes that produce antibodies. Cancers of the lymph system include lymphoma and Hodgkin's disease. Some of these cancers can now be successfully treated.

Sometimes the gatekeepers of the system go crazy, mistaking a basically inoffensive intruder such as pollen, dust, or a bit of bee venom for an enemy and causing the body to go into the red alert known as an allergic reaction. In addition, the immune system can mistake the body's own cells and tissues for "nonself" and attack them, as in auto-immune diseases like rheumatoid arthritis and systemic lupus.

The immune system will also reject and kill potentially lifesaving organ and tissue transplants, unless some way can be found to circumvent the reaction. Though in theory a pregnant woman's immune system should attack the fetus—which is nonself—it doesn't. This is because the fetus itself produces a substance that shields it from the maternal defense system.

So how can I nurture my immune system?

Perhaps the most direct action you can take is to consume a varied, balanced diet of vegetables, fruits, whole and fortified grains, and dairy products, with small amounts of fish and meat if you wish. A basic daily multivitamin/mineral supplement is usually a good idea for older people. Beware of any supplement, however, that promises to boost immunity: protein supplements, enzyme supplements, and the whole range of specific vitamins and minerals, antioxidants, and nostrums that claim to boost immunity don't strengthen it.

Regular moderate exercise is associated with good health and longevity and will benefit your cardiovascular system, whether it boosts immunity or not. Getting adequate sleep is also helpful. And, of course, don't smoke.

3D Animation; The Immune System

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Amazing 3D Animation

The Immune System - Fighting Infection by Clonal Selection

The Immune System - Fighting Infection by Clonal Selection

'Fighting Infection by Clonal Selection' ; was created to commemorate the 50th anniversary of Burnet's Clonal Selection Theory.

The animation shows how clonal selection works during a bacterial infection of the throat. Frank Macfarlane Burnet was awarded the Nobel Prize in 1960 and is widely acknowledged as the founder of modern immunology.

http://www.wehi.edu.au/

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White Blood Cell Chases Bacteria - Video

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