Early intervention with new treatment enables durable control of HIV-like virus in monkeys

There are more than 25 drugs to control HIV, yet the virus remains one of the world’s biggest health problems. One of the many challenges with existing therapies is that a dormant version of the virus is always lurking in the background, ready to attack the immune system as soon as treatment is interrupted.

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From Rockefeller University:

Now, new research from The Rockefeller University and the National Institutes of Health suggests that treatment with two anti-HIV antibodies immediately after infection enables the immune system to effectively control the virus, preventing its return for an extended period.

“This form of therapy can induce potent immunity to HIV, allowing the host to control the infection,” says Michel Nussenzweig, head of the Laboratory of Molecular Immunology and an Investigator with the Howard Hughes Medical Institute. “It works by taking advantage of the immune system’s natural defenses, similar to what happens in some forms of cancer immunotherapy.”

The research was conducted in macaque monkeys, using a model of HIV infection called simian-human immunodeficiency virus (SHIV). Although this model does not precisely mimic human HIV infection, the findings suggest that immunotherapy should be explored as a way of controlling the virus and boosting an immune response that might be capable of controlling the infection in people. The study publishes on March 13 in Nature.

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Viral suppression: Working in a monkey model of HIV, scientists discovered that a dual-antibody therapy can boost the immune system to control the infection and prevent the virus from returning.
Credit: Image courtesy of Rockefeller University

Long-term control

The two drugs used in the study, 3BNC117 and 10-1074, belong to a class of molecules called broadly neutralizing antibodies. They were discovered by the Nussenzweig laboratory in studies of “elite controllers,” people whose immune systems have a rare ability to fight off the virus. Each antibody binds to a different site of the virus, preventing its damaging effects from different angles.

13 monkeys were inoculated with the SHIV virus, and then given three intravenous infusions of the two antibodies over a two-week period. The treatment suppressed the virus to levels near or below the limit of detection, and its effect lasted for as long as six months. After the antibodies had cleared out of the monkeys’ bodies, the virus rebounded in all but one animal.

But then, 5 to 22 months later, something remarkable happened: six of the monkeys spontaneously regained control of the virus. Their virus levels once again plummeted to undetectable levels and remained suppressed for another 5 to 13 months.

These six monkeys were also able to maintain healthy levels of key immune cells after receiving the antibody infusions.

In addition, four other monkeys that did not regain complete control of the virus nevertheless showed promising responses to the treatment: they maintained extremely low viral loads and healthy levels of key immune cells for two to three years after infection. In total, 10 of the 13 monkeys benefitted from antibody immunotherapy.

Feasibility in humans

Nussenzweig and colleagues also investigated what aspect of the immune system was helping the monkeys ward off the virus’s return. They gave the six controller monkeys an antibody that targets and depletes a type of immune cell called cytotoxic T cells. Infusion of this antibody immediately increased the amount of SHIV in the monkeys’ blood and decreased cytotoxic T cell levels, indicating that these cells play a key role in preventing SHIV replication after therapeutic antibody infusion.

The researchers are now repeating this experiment after a longer exposure to the virus, waiting two to six weeks after SHIV infection before administering the therapeutic antibody infusions. This is how long it usually takes for an HIV-infected person to be diagnosed and able to receive treatment.

Clinical trials testing the antibody combination in humans are also underway at The Rockefeller University Hospital.

Read article here.

If you have been diagnosed with HIV Group O, HIV Subtype C,D,F,G,H,J,K, or HIV-2, you might be eligible to donate plasma and earn $1200 or more. Visit www.plasmamedpatients.com for more info or call/text 561-962-5065.

Human antibody for Zika virus promising for treatment, prevention

Researchers have determined the structure of a human antibody bound to the Zika virus, revealing details about how the antibody interferes with the infection mechanism — findings that could aid in development of antiviral medications.

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From Purdue University:

The new findings also suggest the antibody might be especially effective because a lower concentration than expected is needed to inhibit a key mechanism of infection, making it more potent than previous antibodies studied. The research was performed by a team from Purdue University, Vanderbilt University Medical Center and the Washington University School of Medicine.

The human antibody was isolated by the Vanderbilt and Washington University researchers, who reported their findings earlier this year. Those findings showed that the antibody, which was isolated from a person previously infected with Zika virus, neutralizes Zika strains that belong to African, Asian and American lineages and is able to reduce fetal infection and death in mice.

“However, until now what remained unknown was the mechanism of neutralization of Zika infection by the antibody and the structural basis for neutralization,” said Michael Rossmann, Purdue’s Hanley Distinguished Professor of Biological Sciences.

The findings are being reported today (March 16) in the journal Nature Communications.

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This color-coded image depicts the surface view of the Zika virus bound to fragments of a human antibody, shown as red knobs. Researchers have determined the structure of the antibody bound to the virus, findings that could aid in development of antiviral medications.
Credit: Purdue University image/S. Saif Hasan

The research team was led by Rossmann and Richard Kuhn, both professors in Purdue’s Department of Biological Sciences, and senior postdoctoral scientist S. Saif Hasan. Research to isolate the antibody was led by James E. Crowe Jr., a professor of pediatrics, pathology, microbiology and immunology at Vanderbilt, and Michael S. Diamond, the Herbert S. Gasser Professor at Washington University.

Zika belongs to a family of viruses called flaviviruses, which includes dengue, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitic viruses.

In the new findings, researchers determined the combined three-dimensional structure of the Zika virus while attached to a key binding site on the antibody known as the antigen binding fragment, or a Fab molecule.

“It has potential to be a therapeutic neutralizing human antibody” said Kuhn, director of the Purdue Institute of Inflammation, Immunology and Infectious Disease (PI4D).

The genome of the Zika virus is housed inside a protective shell that includes 60 repeating units, each containing three envelope proteins, or E proteins. As the virus attaches to a host cell’s outer membrane a difference in pH, or acidity, in the membrane causes these “trimers” to expose “fusion peptides,” leading to the transfer of the viral RNA genome, a step critical to infection. The new findings show the antibody’s binding to Zika inhibits this pH-triggering mechanism, neutralizing the virus by “cross-linking” the E proteins, tying them up and preventing their reorganization into “fusogenic” trimers.

“This hypothesis is supported by pre- and post-neutralization assays of Zika infection, showing the antibody is able to significantly inhibit infection,” Rossmann said. “This approach should provide broad-range protection against virtually all strains of Zika.”

Moreover, considering that the surface of Zika is made of 60 copies of three E proteins, it would be expected that 180 copies of the antibody’s Fab molecules would be needed for neutralization.

“However, one antibody binds for six E proteins, so only 30 are needed,” Hasan said. “Therefore, you don’t need a high concentration of antibodies to achieve neutralization.”

The findings primarily will aid in the development of antiviral drugs but also will help researchers identify important sites on the virus for human antibodies to hook onto, which could be useful in developing vaccines down the road, Kuhn said.

The researchers determined the structure at a resolution of 6.2 Ångstroms using a technique called cryo-electron microscopy.

The Zika virus has been associated with a birth defect called microcephaly that causes brain damage and an abnormally small head in babies born to mothers infected during pregnancy. The virus also has been associated with the autoimmune disease Guillain-Barré syndrome, which can lead to temporary paralysis.

“Given the severity of the symptoms caused by Zika infection in humans, it is crucial to understand the immune response elicited by the infection to develop neutralizing anti-Zika therapies,” Rossmann said. “In contrast to other flaviviruses that are spread mainly by insects, recent evidence suggests that Zika can be transmitted sexually and from mother to child in addition to transmission by mosquitoes.”

The first major outbreak of the Zika virus was recorded in 2007 in Micronesia and then in 2013-14 in Oceania. The latest outbreak, which started in Brazil in 2014-15, has spread to other countries in South America, North America and the Caribbean. Four cases of fetal deformities were reported in December 2016 in New York City.

Read article here.

 

If you have been diagnosed with Zika, you might be eligible to donate a blood specimen and earn money. Visit www.plasmamedpatients.com for more info.

Toxoplasma’s balancing act explained

Toxoplasma keeps the immune response low enough so that it can thrive, but high enough so that its human hosts generally live healthy lives and can incubate parasites.

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From Phys.org:

The parasite Toxoplasma gondii is a silent success. It infects up to 95% of people in many regions of the world, and most of them never know it, due to the parasite’s artful manipulation of its host’s immune response. Toxoplasma keeps the immune response low enough so that it can thrive, but high enough so that its human hosts generally live healthy lives and can incubate parasites. Scientists at EMBL and the Institute for Advanced Biosciences (IAB, an INSERM – CNRS – Université Grenoble-Alpes research centre) have uncovered one of the ways it maintains this balance, in a paper published today in Structure.

“The parasite rewires the host’s inflammatory response,” says Matthew Bowler, who led the research at EMBL. “It completely subverts the that would normally trigger our body’s defenses.”

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The Toxoplasma protein GRA24 (long, light blue) binds very tightly to two copies of p38α, the human protein that triggers our inflammatory response. Credit: Matthew Bowler/EMBL

When a cell in your body detects a parasite, it sets off a chain reaction. Inside that cell, a series of molecules activate each other until a protein called p38α is activated and moves into the cell’s nucleus. There, it turns on the genes that trigger the inflammatory response. Among other things, the purpose of that response is to eliminate the pathogen. One would expect parasites like Toxoplasma to want to subdue that response, but Mohamed-Ali Hakimi and colleagues at IAB discovered a few years ago that Toxoplasma secretes a protein, GRA24, which does just the opposite: it activates and controls our inflammatory response.

Bowler and Hakimi discovered that GRA24 bypasses the cell’s chain reaction, activating p38α directly, and pulling it into the nucleus to turn on inflammatory response genes. Using a combination of techniques, they found that the Toxoplasma protein attaches itself much more strongly to p38α than the cell’s own proteins do. So by producing a protein that binds directly, and very tightly, to p38α, Toxoplasma controls the level of the and sustains it by making it inaccessible to the proteins that would usually turn it off. This is why Toxoplasma isn’t considered a serious health threat except for pregnant women and people with compromised immune systems.

This research has generated a new way to assess the efficacy of anti-inflammatory drugs, many of which are designed to block p38α. So far it has been difficult to assess how effective they are, because scientists haven’t had a good way to produce an active form of p38α in the lab. In producing GRA24 bound to p38α, Bowler, Hakimi and colleagues – with the help of EMBL’s Protein Expression and Purification Core Facility – created just that. The tight interaction with the parasite protein keeps p38α in its active state, so researchers can now subject it to the drugs they’d like to test, and evaluate how well they block p38α’s active site, which the Toxoplasma doesn’t interfere with.

Read more at: https://phys.org/news/2016-11-toxoplasma.html#jCp

If you have been diagnosed with Toxoplasmosis, you might be eligible to donate plasma and earn $1200 or more. Visit www.plasmamedpatients.com for more info or call/text 561-962-5065.

Mayo Clinic researchers find new experimental drug that shrinks tumors in multiple myeloma patients

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Mayo Clinic researchers have found that an experimental drug, LCL161, stimulates the immune system, leading to tumor shrinkage in patients affected by multiple myeloma. The findings are published in Nature Medicine.

Multiple myeloma is a blood cancer that affects plasma cells – white blood cells that normally produce antibodies to fight infection. Rather than produce helpful antibodies, the cancer cells, as they grow, secrete large amounts of a single antibody that accumulate in the body, causing kidney problems and infections.

“The drug, LCL161, was initially developed to promote tumor death,” says Marta Chesi, Ph.D., a Mayo Clinic biochemist and lead author of the study of 25 Multiple Myeloma patients. “However, we found that the drug does not kill tumor cells directly. Rather, it makes them more visible to the immune system that recognizes them as foreigner invaders and eliminates them.”

Mayo Clinic researchers will conduct a follow-up clinical trial of LCL161 in combination with an inhibitor of immune checkpoints that has been widely used in many cancer treatments to evaluate if LCL161 could represent a potential new treatment option.

“The model for preclinical studies to predict with great accuracy which drugs would work in the clinic was developed a decade ago,” says Dr. Chesi. “And it has been instrumental in the prioritization of which experimental therapeutics should be tested in patients with multiple myeloma.”

The research highlights the importance of studying the effects of drugs not only on the tumor cells in a culture plate, but also on the interaction of the tumor cells with their own microenvironment. The finding that LCL161 is active against multiple myeloma suggests that similar drugs may have broader clinical activity than previously thought.

The work of Dr. Chesi and her team reflects Mayo Clinic’s focus to bridge basic science discoveries into clinical trials through collaboration, beginning with unmet patient needs.

Read article here.

If you have been diagnosed with Multiple Myeloma, you might be eligible to donate plasma or a blood specimen and earn $50-300 or more. Visit www.plasmamedpatients.com for more info or call/text 561-962-5065.

CMV virus is way more common than Zika. But expectant mothers don’t know their babies are at risk.

CMV can cause birth defects, but prevention steps are considered “burdensome,” say doctors

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By

WHEAT RIDGE — When Megan Wiedel was pregnant with her second child, she did just as her doctor told her to.

No raw fish. No soft cheeses. No lunch meat.

All along, a much bigger risk — one that her doctor never told her about — loomed.

So, unaware, when Wiedel’s first daughter sniffled, she held her. When Wiedel herself caught a cold in the second trimester, she shrugged it off. And when her second daughter, Anna, was born — at only 5 pounds, full term — and then failed the newborn hearing test, Wiedel and her husband tried not to worry as the pediatrician ordered more tests.

Two weeks later, the results came back. Anna would be deaf for the rest of her life. She might never be able to walk or even hold her head up. It was because she had a virus called CMV.

Wiedel hung up the phone and thought to herself: Why had she never heard about CMV?

Megan Wiedel and her daughter Anna take American Sign Language tutoring sessions at their home in Wheat Ridge, Colorado.

“When you talk about it, it seems like it’s really rare,” Wiedel said. “But it’s not. A lot of kids have CMV.”

“That’s the hardest piece for me is that this is a preventable, prevalent, quiet disease.”

But, now, a small community of mothers and medical workers are trying to make CMV awareness a little less quiet.

Cytomegalovirus, or CMV, is the most common nongenetic cause of childhood deafness in the country. Every year, approximately 30,000 babies are born in the United States infected with CMV, and as many as 8,000 of those children suffer lifetime consequences from the disease — which can also include blindness, cognitive delays and microcephaly. As many as 400 infants die every year from CMV, according to the National CMV Foundation.

It is vastly more common than the Zika virus, which prompted alarm last summer for its potential to cause birth defects. But, while Congress invested $1.1 billion in fighting Zika, funding for CMV lags behind, and numerous studies show that as many as 85 percent of expectant mothers have no idea what CMV is. The American College of Obstetricians and Gynecologists does not advise doctors to talk to expectant mothers about CMV — despite the fact that it is an easily spread virus that is present in nearly every elementary school and day care center in the country.

At Children’s Hospital Colorado, physician assistant Shannon Hughes has developed an outpatient clinic for kids dealing with the aftereffects of CMV. The clinic has served about 40 kids in the past two years. Nearly all of the parents she meets had never heard of CMV before finding out that it would forever alter their children’s lives.

“Obviously, that has a big impact on them emotionally that they think they did something wrong and should have prevented it,” she said.

Neonatal nurse practitioner Erin Mestas, who also works at Children’s as well as at Poudre Valley Hospital, is also trying to raise awareness among both mothers and health care workers about CMV.

“There needs to be more education about CMV risk reduction,” Mestas said. “I think childbearing women need to be more educated.”

In some ways, CMV’s ubiquity accounts for its invisibility.

Most adults have been exposed to CMV at some point in their lifetimes, meaning they have antibodies to fight off a new CMV infection. For women with CMV antibodies, then, being exposed to the virus while pregnant is usually no big deal.

But there is no vaccine for CMV, and a small subset of women don’t have the antibodies. If they catch CMV while pregnant, they will likely pass the infection onto their unborn child, who is then at risk of developmental impairments. The earlier in her pregnancy a vulnerable mother catches CMV, the worse the outcome likely is for the child.

Because CMV is most common among kids, pregnant women who already have children or who work in schools or day cares are particularly at risk.

The ways to prevent a CMV infection are familiar to anyone who has ever tried to dodge a cold during flu season. CMV spreads through saliva or urine, so pregnant women should wash their hands frequently — especially after changing diapers — and avoid kissing their toddlers on the mouth or sharing food or drinks with them.

In a bulletin published in 2015, the American College of Obstetricians and Gynecologists — the country’s largest association for women’s health doctors — wrote that these prevention steps “often are considered impractical or burdensome,” which is why the organization does not recommend doctors talk to expectant mothers about CMV.

“At present, such patient instruction remains unproven as a method to reduce the risk of congenital CMV infection,” the bulletin states..

But recent studies have challenged that analysis.

A study in Utah published last year found that women were generally receptive to practicing CMV prevention once they understood the consequences. And a study from 2015 found that women who had never been exposed to CMV before were significantly less likely to contract the virus while practicing the prevention methods than if they didn’t.

Plus, as Wiedel points out, women can be tested before getting pregnant to determine if they are at risk for a first-time CMV infection, and, if they contract the virus while pregnant, there is a drug they can take that may help limit the damage it causes. Children born with CMV can also have better outcomes if started on treatment right away. But all of this means that means doctors would need to be more proactive in talking about and testing for CMV.

“I think part of the ignorance is willful ignorance,” Wiedel said.

Anna is now almost 2 years old and, though she began walking later than most children, she now happily races across the living room floor. Cochlear implants have brought her hearing — she still hears nothing when they are off — and Anna is both learning to talk and how to use sign language.

Those are blessings considering what could have been, Wiedel said. But, while she wouldn’t want to change her daughter, Wiedel said it is frustrating to think that, had she known more while pregnant, she could have saved Anna from some of the struggle.

Wiedel now acts as an informal resource to friends, relatives and neighbors with questions about CMV. It’s a role she enjoys but wishes she didn’t have to inhabit.

“I have to be the educator,” she said. “And it’s exhausting

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Read original article here.

If you have been diagnosed with CMV, you might be eligible to donate plasma or a blood specimen and earn $50-300 or more. Visit www.plasmamedpatients.com for more info or call/text 561-962-5065.

Research will see if antibodies can more selectively target & kill HIV-infected cells

Hope in antibodies.

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by Emily Newman

Early in January, Gilead Sciences announced an astounding $22 million HIV cure grants program benefitting 12 research teams around the world. The projects supported range in scope from basic science research to ethical and community-based social science research.

Galit Alter, PhD, a researcher at the Ragon Institute of MGH, MIT and Harvard and her team were one recipient of Gilead’s funding. Over the next three years, they will be developing a portfolio of broadly functional antibodies and testing them to see if they’re able to help eradicate cells that are latently infected with HIV from the body. Alter spoke with BETA to answer some questions about her research—and explain why she’s hopeful that an antibody-based cure therapy may prove to be both effective and realistic.

Plasma cell B lymphocyte producing antibodies isolated on white

Read article here.

If you have been diagnosed with HIV Group O, HIV Subtype C,D,F,G,H,J,K, or HIV-2, you might be eligible to donate plasma and earn $1200 or more. Visit www.plasmamedpatients.com for more info or call/text 561-962-5065.

What exactly is Multiple Sclerosis?

Nerve cells, or neurons, have basically two sections. The long, stringy section is called the axon and the more circular, bulbous section is the cell body. The cell body is joined by a series of projections called dendrites. These dendrites receive nerve impulses from adjacent axons and, in turn, the neuron sends the wave down its own axon to the next cell. This rapid-fire electrochemical wave brings information into the brain through sensory neurons and sends commands out to the body through motor neurons to muscles and glands.

Many neurons are covered in a whitish-colored myelin sheath and are thereby said to be myelinated. This is what differentiates white matter from gray matter in the central nervous system. This myelin sheath is critical to the conductivity of the axon as it passes impulses through. In Multiple Sclerosis, the myelin sheath is attacked. This sheath is maintained and protected by special cells called oligodendrocytes. In Multiple Sclerosis these oligodendrocytes are damaged and cannot adequately maintain the sheath. When the myelin sheaths become damaged and degraded, the conductivity of the axons is severely impaired and loss of function occurs.

The cause of MS is believed to be an immune system-mediated response that involves genetics, environmental factors, and possibly infectious agents as well. The participation of the immune system places it under the broad heading of an autoimmune disorder.

Diagnosis depends on the patient’s symptoms, which most frequently include visual, motor, and sensory problems. This is then corroborated by the use of tools such as MRI to visually identify areas of demyelination. The use of evoked potentials, a test that quantifies the loss of conductivity along a nerve pathway, is often necessary.

There is no known cure for MS. Treatment often involves the use of corticosteroids, the interferons, and a number of disease-modifying therapies.

We at Plasma MedResearch, LLC are proud to provide biospecimens to the research community to aid in their efforts to find a cure for this disease.

If you have been diagnosed with MS, you might be eligible to donate plasma or a blood specimen and earn $50-300 or more. Visit www.plasmamedpatients.com for more info or call/text 561-962-5065.