Chemical From Medicinal Plants May Be Used To Fight HIV

Like other kinds of cells, immune cells lose the ability to divide as they age because a part of their chromosomes known as a telomere becomes progressively shorter with cell division. As a result, the cell changes in many ways, and its disease fighting ability is compromised.

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But a new UCLA AIDS Institute study has found that a chemical from the Astragalus root, frequently used in Chinese herbal therapy, can prevent or slow this progressive telomere shortening, which could make it a key weapon in the fight against HIV.

"This has the potential to be either added to or possibly even replace the HAART (highly active antiretroviral therapy), which is not tolerated well by some patients and is also costly," said study co-author Rita Effros, a professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA and member of the UCLA AIDS Institute.

A telomere is a region at the end of every cell chromosome that contains repeated DNA sequences but no genes; telomeres act to protect the ends of the chromosomes and prevent them from fusing together — rather like the plastic tips that keep shoelaces from unraveling. Each time a cell divides, the telomeres get shorter, eventually causing the cell to reach a stage called replicative senescence, when it can no longer divide. This seems to indicate that the cell has reached an end stage, but, in fact, the cell has changed into one with new genetic and functional characteristics.

A great deal of cell division must take place within the immune system for the system to function properly. For example, the so-called "killer" CD8 T-cells that help fight infection have unique receptors for particular antigens. When a virus enters the body, the killer T-cells whose receptors recognize that virus create, through division, versions of themselves that fight the invader.

Generally, the telomeres in cells are sufficiently long that they can divide many times without a problem. Moreover, when fighting infections, T-cells can turn on an enzyme called telomerase, which can prevent the telomeres from shortening.

"The problem is that when we're dealing with a virus that can't be totally eliminated from the body, such as HIV, the T-cells fighting that virus can't keep their telomerase turned on forever," Effros said. "They turn off, and telomeres get shorter and they enter this stage of replicative senescence."

Previous studies have shown that injecting the telomerase gene into T-cells can keep the telomeres from shortening, enabling them to maintain their HIV-fighting function for much longer. This gene-therapy approach, however, is not a practical way to treat the millions of people living with HIV.

For the present study, rather than utilizing gene therapy, the researchers used a chemical called TAT2, which was originally identified from plants used in traditional Chinese therapy and which enhances telomerase activity in other cell types.

They tested TAT2 in several ways. First, they exposed the CD8 T-cells from HIV-infected persons to TAT2 to see if the chemical not only slowed the shortening of the telomeres but improved the cells' production of soluble factors called chemokines and cytokines, which had been previously shown to inhibit HIV replication. It did.

They then took blood samples from HIV-infected individuals and separated out the CD8 T-cells and the CD4 T-cells — those infected with HIV. They treated the CD8 T-cells with TAT2 and combined them with the CD4 T-cells in the dish-and found that the treated CD8 cells inhibited production of HIV by the CD4 cells.

"The ability to enhance telomerase activity and antiviral functions of CD8 T-lymphocytes suggests that this strategy could be useful in treating HIV disease, as well as immunodeficiency and increased susceptibility to other viral infections associated with chronic diseases or aging," the researchers write.

In addition to Effros, researchers were Steven Russell Fauce, Beth D. Jamieson, Ronald T. Mitsuyasu, Stan T. Parish, Christina M. Ramirez Kitchen, and Otto O. Yang, all of UCLA, and Allison C. Chin and Calvin B. Harley of the Geron Corp.

The Geron Corp., TA Therapeutics Ltd., the National Institutes of Health and the Frank Jernigan Foundation funded this study.

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Journal reference:

1. . Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes. Journal of Immunology, Nov. 15, 2008
   

Alzheimer's Disease

• Overview
  • Alternative Names
  • Causes
  • Symptoms
  • Exams and Tests
  • Treatment
  • Support Groups
  • Outlook (Prognosis)
  • Possible Complications
  • When to Contact a Medical Professional
  • Prevention
  • References

Coping With Alzheimer’s

A Descent Into Alzheimer's

Alzheimer's: Quest for Understanding

Alzheimer's: The Rarest Gene

Illustrations

• Aged Nervous Tissue

Alzheimer's disease (AD), one form of dementia, is a progressive, degenerative brain disease. It affects memory, thinking, and behavior.

Memory impairment is a necessary feature for the diagnosis of this or any type of dementia. Change in one of the following areas must also be present: language, decision-making ability, judgment, attention, and other areas of mental function and personality.

The rate of progression is different for each person. If AD develops rapidly, it is likely to continue to progress rapidly. If it has been slow to progress, it will likely continue on a slow course.

Alternative Names

Senile dementia/Alzheimer's type (SDAT)

The older you get, the greater your risk of developing AD, although it is not a part of normal aging. Family history is another common risk factor.

In addition to age and family history, risk factors for AD may include:

• Longstanding high blood pressure
• History of head trauma
• High levels of homocysteine (a body chemical that contributes to chronic illnesses such as heart disease, depression, and possibly AD)
• Female gender -- because women usually live longer than men, they are more likely to develop AD

There are two types of AD -- early onset and late onset. In early onset AD, symptoms first appear before age 60. Early onset AD is much less common, accounting for only 5-10% of cases. However, it tends to progress rapidly.

The cause of AD is not entirely known but is thought to include both genetic and environmental factors. A diagnosis of AD is made based on characteristic symptoms and by excluding other causes of dementia.

Prior theories regarding the accumulation of aluminum, lead, mercury, and other substances in the brain leading to AD have been disproved. The only way to know for certain that someone had AD is by microscopic examination of a sample of brain tissue after death.

The brain tissue shows "neurofibrillary tangles" (twisted fragments of protein within nerve cells that clog up the cell), "neuritic plaques" (abnormal clusters of dead and dying nerve cells, other brain cells, and protein), and "senile plaques" (areas where products of dying nerve cells have accumulated around protein). Although these changes occur to some extent in all brains with age, there are many more of them in the brains of people with AD.

The destruction of nerve cells (neurons) leads to a decrease in neurotransmitters (substances secreted by a neuron to send a message to another neuron). The correct balance of neurotransmitters is critical to the brain.

By causing both structural and chemical problems in the brain, AD appears to disconnect areas of the brain that normally work together.

About 10 percent of all people over 70 have significant memory problems and about half of those are due to AD. The number of people with AD doubles each decade past age 70. Having a close blood relative who developed AD increases your risk.

Early onset disease can run in families and involves autosomal dominant, inherited mutations that may be the cause of the disease. So far, three early onset genes have been identified.

Late onset AD, the most common form of the disease, develops in people 60 and older and is thought to be less likely to occur in families. Late onset AD may run in some families, but the role of genes is less direct and definitive. These genes may not cause the problem itself, but simply increase the likelihood of formation of plaques and tangles or other AD-related pathologies in the brain.

Symptoms »

In the early stages, the symptoms of AD may be subtle and resemble signs that people mistakenly attribute to "natural aging." Symptoms often include:

• Repeating statements
• Misplacing items
• Having trouble finding names for familiar objects
• Getting lost on familiar routes
• Personality changes
• Losing interest in things previously enjoyed
• Difficulty performing tasks that take some thought, but used to come easily, like balancing a checkbook, playing complex games (such as bridge), and learning new information or routines

In a more advanced stage, symptoms are more obvious:

• Forgetting details about current events
• Forgetting events in your own life history, losing awareness of who you are
• Problems choosing proper clothing
• Hallucinations, arguments, striking out, and violent behavior
• Delusions, depression, agitation
• Difficulty performing basic tasks like preparing meals and driving

At end stages of AD, a person can no longer survive without assistance. Most people in this stage no longer:

• Understand language
• Recognize family members
• Perform basic activities of daily living such as eating, dressing, and bathing

Exams and Tests »

The first step in diagnosing Alzheimer's disease is to establish that dementia is present. Then, the type of dementia should be clarified. A health care provider will take a history, do a physical exam (including a neurological exam), and perform a mental status examination.

Tests may be ordered to help determine if there is a treatable condition that could be causing dementia or contributing to the confusion of AD. These conditions include thyroid disease, vitamin deficiency, brain tumor, drug and medication intoxication, chronic infection, anemia, and severe depression.

AD usually has a characteristic pattern of symptoms and can be diagnosed by history and physical exam by an experienced clinician. Tests that are often done to evaluate or exclude other causes of dementia include computed tomography (CT), magnetic resonance imaging (MRI), and blood tests.

In the early stages of dementia, brain image scans may be normal. In later stages, an MRI may show a decrease in the size of the cortex of the brain or of the area of the brain responsible for memory (the hippocampus). While the scans do not confirm the diagnosis of AD, they do exclude other causes of dementia (such as stroke and tumor).

Treatment

Unfortunately, there is no cure for AD. The goals in treating AD are to:

• Slow the progression of the disease.
• Manage behavior problems, confusion, and agitation.
• Modify the home environment.
• Support family members and other caregivers.

The most promising treatments include lifestyle changes, medications, and antioxidant supplements like vitamin E and ginkgo biloba.

LIFESTYLE CHANGES

The following steps can help people with AD:

• Walk regularly with a caregiver or other reliable companion. This can improve communication skills and prevent wandering.
• Use bright light therapy to reduce insomnia and wandering.
• Listen to calming music. This may reduce wandering and restlessness, boost brain chemicals, ease anxiety, enhance sleep, and improve behavior.
• Get a pet dog.
• Practice relaxation techniques.
• Receive regular massages. This is relaxing and provides social interactions.

DRUG TREATMENT

Several drugs are available to try to slow the progression of AD and possibly improve the person's mental capabilities. Memantine (Namenda) is currently the only drug approved for the treatment of moderate-to-severe Alzheimer’s disease.

Other medicines include donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne, formerly called Reminyl), and tacrine (Cognex). These drugs affect the level of a neurotransmitter in the brain called acetylcholine. They may cause nausea and vomiting. Tacrine also causes an elevation in liver enzymes and must be taken four times a day. It is now rarely used.

Aricept is taken once a day and may stabilize or even improve the person's mental capabilities. It is generally well tolerated. Exelon seems to work in a similar way. It is taken twice a day.

Other medicines may be needed to control aggressive, agitated, or dangerous behaviors. These are usually given in very low doses.

It may be necessary to stop any medications that make confusion worse. Such medicines may include pain killers, cimetidine, central nervous system depressants, antihistamines, sleeping pills, and others. Never change or stop taking any medicines without first talking to your doctor.

SUPPLEMENTS

Folate (vitamin B9) is critical to the health of the nervous system. Together with some other B vitamins, folate is also responsible for clearing homocysteine (a body chemical that contributes to chronic illnesses) from the blood. High levels of homocysteine and low levels of both folate and vitamin B12 have been found in people with AD. Although the benefits of taking these B vitamins for AD is not entirely clear, it may be worth considering them, particularly if your homocysteine levels are high.

Antioxidant supplements, like ginkgo biloba and vitamin E, scavenge free radicals. These products of metabolism are highly reactive and can damage cells throughout the body.

Vitamin E dissolves in fat, readily enters the brain, and may slow down cell damage. In at least one well-designed study of people with AD who were followed for 2 years, those who took vitamin E supplements had improved symptoms compared to those who took a placebo pill. Patients who take blood-thinning medications like warfarin (Coumadin) should talk to their doctor before taking vitamin E.

Ginkgo biloba is an herb widely used in Europe for treating dementia. It improves blood flow in the brain and contains flavonoids (plant substances) that act as antioxidants. Although many of the studies to date have been somewhat flawed, the idea that ginkgo may improve thinking, learning, and memory in those with AD has been promising. DO NOT use ginkgo if you take blood-thinning medications like warfarin (Coumadin) or a class of antidepressants called monoamine oxidase inhibitors (MAOIs).

If you are considering any drugs or supplements, you MUST talk to your doctor first. Remember that herbs and supplements available over the counter are NOT regulated by the FDA.

SUPPORT AT HOME

Someone with AD will need support in the home as the disease worsens. Family members or other caregivers can help by trying to understand how the person with AD perceives his or her world. Simplify the patient's surroundings. Give frequent reminders, notes, lists of routine tasks, or directions for daily activities. Give the person with AD a chance to talk about their challenges and participate in their own care.

OTHER PRACTICAL STEPS

The person with AD should have their eyes and ears checked. If problems are found, hearing aids, glasses, or cataract surgery may be needed.

Those with AD may have particular dietary requirements such as:

• Extra calories due to increased physical activity from restlessness and wandering.
• Supervised meals and help with feeding. People with AD often forget to eat and drink, and can become dehydrated as a result.

The Safe Return Program, implemented by the Alzheimer's Association, requires that a person with AD wear in identification bracelet. If he or she wanders, the caregiver can contact the police and the national Safe Return office, where information about the person is stored and shared nationwide.

Eventually, 24-hour monitoring and assistance may be necessary to provide a safe environment, control aggressive or agitated behavior, and meet physiologic needs. This may include in-home care, nursing homes, or adult day care.

For additional information and resources for people with Alzheimer's disease and their caregivers, see Alzheimer's disease support groups.

Outlook (Prognosis)

The probable outcome is poor. The disorder usually progresses steadily. Total disability is common. Death normally occurs within 15 years, usually from an infection or a failure of other body systems.

Possible Complications

• Loss of ability to function or care for self
• Bedsores, muscle contractures (loss of ability to move joints because of loss of muscle function), infection (particularly urinary tract infections and pneumonia), and other complications related to immobility during end-stages of AD
• Falls and broken bones
• Loss of ability to interact
• Malnutrition and dehydration
• Failure of body systems
• Reduced life span
• Harmful or violent behavior toward self or others
• Abuse by an over-stressed caregiver
• Side effects of medications

When to Contact a Medical Professional

Call your health care provider if someone close to you experiences symptoms of senile dementia/Alzheimer's type.

Call your health care provider if a person with this disorder experiences a sudden change in mental status. (A rapid change may indicate other illness.)

Discuss the situation with your health care provider if you are caring for a person with this disorder and the condition deteriorates to the point where you can no longer care for the person in your home.

Prevention »

Although there is no proven way to prevent AD, there are some practices that may be worth incorporating into your daily routine, particularly if you have a family history of dementia. Talk to your doctor about any of these approaches, especially those that involve taking a medication or supplement.

• Consume a low-fat diet.
• Eat cold-water fish (like tuna, salmon, and mackerel) rich in omega-3 fatty acids, at least 2 to 3 times per week.
• Reduce your intake of linoleic acid found in margarine, butter, and dairy products.
• Increase antioxidants like carotenoids, vitamin E, and vitamin C by eating plenty of darkly colored fruits and vegetables.
• Maintain a normal blood pressure.
• Stay mentally and socially active throughout your life.
• Consider taking nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Advil, Motrin), sulindac (Clinoril), or indomethacin (Indocin). Statin drugs, a class of medications normally used for high cholesterol, may help lower your risk of AD. Talk to your doctor about the pros and cons of using these medications for prevention.

In addition, early testing of a vaccine against AD is underway.

References »

Rakel P. Conn ’s Current Therapy 2005. 57th ed. Philadelphia, Pa: Saunders; 2005.

Moore DP, Jefferson JW. Handbook of Medical Psychiatry. 2nd ed. St. Louis, Mo: Mosby; 2004.

Goetz CG, Pappert EJ. Textbook of Clinical Neurology. 2nd ed. Philadelphia, Pa: Saunders; 2003.

Brain slows at 40, starts body decline

WASHINGTON - Think achy joints are the main reason we slow down as we get older? Blame the brain, too: The part in charge of motion may start a gradual downhill slide at age 40.
How fast you can throw a ball or run or swerve a steering wheel depends on how speedily brain cells fire off commands to muscles. Fast firing depends on good insulation for your brain's wiring.
Now new research suggests that in middle age, even healthy people begin to lose some of that insulation in a motor-control part of the brain - at the same rate that their speed subtly slows.
That helps explain why "it's hard to be a world-class athlete after 40," concludes Dr. George Bartzokis, a neurologist at the University of California, Los Angeles, who led the work.
And while that may sound depressing, keep reading. The research points to yet another reason to stay physically and mentally active: An exercised brain may spot fraying insulation quicker and signal for repair cells to get to work.
To Bartzokis, the brain is like the Internet. Speedy movement depends on bandwidth, which in the brain is myelin, a special sheet of fat that coats nerve fibres.
Healthy myelin - good thick insulation wound tightly around those nerve fibres - allows prompt conduction of the electrical signals the brain uses to send commands. Higher-frequency electrical discharges, known as "actional potentials," speed movement - any movement, from a basketball rebound to a finger tap.
Consider someone like Michael Jordan. "The circuitry that made him a great basketball player was probably myelinated better than most other mortals," Bartzokis notes.
But while myelin builds up during adolescence, when does production slow enough that we fall behind in the race to repair fraying, older insulation?
Enter the new research. First, Bartzokis recruited 72 healthy men, ages 23 to 80, to perform a simple test: How fast they tapped an index finger. Anyone can do this; it doesn't depend on strength or fitness.
Researchers counted how many taps the men made in 10 seconds, recording the two fastest of 10 attempts. Then, brain scans checked for myelin in need of repair in the region that orders a finger to tap.
Strikingly, tapping speed and myelin health both peaked at age 39. Then both gradually declined with increasing age, the researchers reported last month in the journal Neurobiology of Aging.
That doesn't mean the rest of the brain is equally affected. Bartzokis has some evidence that myelin starts to fray a decade or so later in brain regions responsible for cognitive functions - higher-level thinking - than in motor-control areas.
So back to his example of Jordan, who last played professionally at age 40: "Even he started getting older. That circuitry started breaking down a little," contends Bartzokis. "He can become Michael Jordan the big-shot businessman ... but not be Michael Jordan the super-duper basketball player anymore."
Bartzokis isn't looking to build a better athlete. His ultimate goal is to fight Alzheimer's disease. The connection: Building memories requires high-frequency electrical bursts, too, and Bartzokis' earlier research suggests an Alzheimer's-linked gene may thwart myelin repair.
But the new research has broader implications because it sheds light on normal aging, says Dr. Zoe Arvanitakis, a neurologist at Chicago's Rush University Medical Center.
"We knew at some age you peak and there's a sense it would disintegrate as you grow older. But we didn't have a sense of where that age would be," says Arvanitakis, who next wants to see if myelin and cognitive functions show a similar trajectory.
Bartzokis' research supports a recent report from German scientists, that with age comes a weakening of the system that's supposed to repair broken myelin, adds Dr. Bradley Wise of the National Institute on Aging.
"Any disruption in these neural circuits and networks will have problems for functioning," says Wise, who says the two reports are spurring increased interest into myelin's role in aging. Until recently, most myelin research has focused on multiple sclerosis, where myelin doesn't gradually degrade but disappears.
While much more research is needed, Bartzokis has some practical advice:
-Keeping active and treating high blood pressure, high cholesterol and diabetes already are deemed important for good brain health. But physical and mental activity also may stimulate myelin repair, while unused neural pathways wouldn't send out a "help" signal, he says.
"Remember, these are average people I tested," Bartzokis says. "Someone that's really practising could make it (myelin) last longer because you're sending the signals to repair, repair, repair."
-Stress hormones, however, may hurt myelin.
-He's also testing whether consumption of omega-3 fatty acids - the oils, found in fatty fish, already recommended for cardiovascular health - might help maintain myelin

Biologists Spy On The Secret Inner Life Of A Cell

The transportation of antibodies from a mother to her newborn child is vital for the development of that child's nascent immune system. Those antibodies, donated by transfer across the placenta before birth or via breast milk after birth, help shape a baby's response to foreign pathogens and may influence the later occurrence of autoimmune diseases.
Images from biologists at the California Institute of Technology (Caltech) have revealed for the first time the complicated process by which these antibodies are shuttled from mother's milk, through her baby's gut, and into the bloodstream, and offer new insight into the mammalian immune system.
Newborns pick up the antibodies with the aid of a protein called the neonatal Fc receptor (FcRn), located in the plasma membrane of intestinal cells. FcRn snatches a maternal antibody molecule as it passes through a newborn's gut; the receptor and antibody are enclosed within a sac, called a vesicle, which pinches off from the membrane. The vesicle is then transported to the other side of the cell, and its contents--the helpful antibody--are deposited into the baby's bloodstream.
Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech and an investigator with the Howard Hughes Medical Institute, and her colleagues were able to watch this process in action using gold-labeled antibodies (which made FcRn visible when it picked up an antibody) and a technique called electron tomography. Electron tomography is an offshoot of electron microscopy, a now-common laboratory technique in which a beam of electrons is used to create images of microscopic objects. In electron tomography, multiple images are snapped while a sample is tilted at various angles relative to the electron beam. Those images can then be combined to produce a three-dimensional picture, just as cross-sectional X-ray images are collated in a computerized tomography (CT) scan.
"You can get an idea of movement in a series of static images by taking them at different time points," says Bjorkman, whose laboratory studies how the immune system recognizes its targets, work that is offering insight into the processes by which viruses like HIV and human cytomegalovirus invade cells and cause disease.
The electron tomography images revealed that the FcRn/antibody complexes were collected within cells inside large vesicles, called "multivesicular bodies," that contain other small vesicles. The vesicles previously were believed to be responsible only for the disposal of cellular refuse and were not thought to be involved in the transport of vital proteins.
The images offered more surprises. Many vesicles, including multivesicular bodies and other more tubular vesicles, looped around each other into an unexpected "tangled mess," often forming long tubes that then broke off into the small vesicles that carry antibodies through the cell. When those vesicles arrived at the blood-vessel side of the cell, they fused with the cell membrane and delivered the antibody cargo. The vesicles also appeared to include a coat made from a molecule called clathrin, which helps form the outer shell of the vesicles. Researchers previously believed that a vesicle's clathrin cage was completely shed before the vesicle fused with the cell membrane. The new results suggest that only a small section of that coating is sloughed off, which may allow the vesicle to more quickly drop its load and move on for another.
"We are now studying the same receptor in different types of cells in order to see if our findings can be generalized, and are complementing these studies with fluorescent imaging in live cells," Bjorkman says. "The process of receptor-mediated transport is fundamental to many biological processes, including detection of developmental decisions made in response to the binding of hormones and other proteins, uptake of drugs, signaling in the immune and nervous systems, and more. So understanding how molecules are taken up by and transported within cells is critical for many areas of basic and applied biomedical research," she adds.
The work was supported by the National Institutes of Health, a Max Planck Research Award, the Gordon and Betty Moore Foundation, the Agouron Institute, and National University of Singapore AcRF start-up funds

How Hepatitis C Replicates

The hepatitis C virus is a prolific replicator, able to produce up to a trillion particles per day in an infected person by hijacking liver cells in which to build up its viral replication machinery. Now new research — in which scientists have for the first time used fluorescent proteins to image hepatitis C virus replication in live cells — shows that the microscopic viral factories are a diverse mix of big, immobile structures and tiny replication complexes that zip zanily around inside the cell.
The scientists say their results offer new insights into how this difficult-to-treat virus, and perhaps others in its class, ensures efficient reproduction of itself — knowledge that could help design next-generation treatments.
“There is so much that we don’t know about this virus, so a better understanding of how the pathogen cleverly forms lots of large and small factories to reproduce itself so that it can infect new hosts may be of great benefit,” says study coauthor Benno Wölk, a former postdoctoral researcher in the Rockefeller University Laboratory of Virology and Infectious Disease. He is now a researcher and physician at Hannover Medical School in Germany.
An estimated 170 million people worldwide are chronically infected with hepatitis C, which is a major cause of liver cirrhosis and liver cancer. So progress in understanding and treating the infection is crucial, says the study’s senior investigator, Charles M. Rice, Maurice R. and Corinne P. Greenberg Professor in Virology and director of the Center for the Study of Hepatitis C. “There is no vaccine available for hepatitis C, and current therapies are not always effective because the virus fights back against drugs developed to block replication,” Rice says.
Scientists had until now believed that the virus’s replication process occurred in one or several large complexes inside a cell. It was hard to learn more because in order to see the virus it had to be killed. “Up to this study, researchers have only been able to look at infected cells when they were fixed and immobile,” Wölk says. “They found areas where the cell membrane was altered and found viral proteins in these structures that suggested that was where replication took place.”
To visualize the replication process, the researchers selected one of the proteins that the hepatitis C virus uses to make its replication factories and fused it to a green fluorescent protein, which emits a green glow when exposed to a specific wavelength of light. They were surprised to see that the small hepatitis C virus replication complexes were transported around the cell. “It’s remarkable that the virus hijacks the cell’s transport machinery to move the viral replication complex around,” Wölk says. “We also learned that for the first several hours after infection only small structures, like dots, formed, which were quickly spread all over the cell. Then the big structures took shape, and they didn’t move.”
The researchers theorize that the small structures are the actual sites of viral replication and that the big structures are clusters of the smaller factories — perhaps formed after the virus has already successfully settled in with the cell. “It is questionable whether the virus even needs the big structures to replicate. They could be performing other functions or they could just represent garbage cans of the cell,” Wölk says. “This is very different from the traditional view.”
Although they can’t say for sure, the group, which also includes Benjamin Büchele of the University of Freiburg in Germany, and Darius Moradpour of the University of Lausanne in Switzerland, suspects that these small, mobile, replication complexes are more efficient and elegant than large structures because they do two things: distribute the factories so that the integrity of the cell is maintained, and keep the complexity of the replication factories to independent, small, manageable units that are easier to control for the virus.
What the researchers discovered in the hepatitis C virus may also prove to be true for related single-strand RNA viruses in the Flaviviridae family, Wölk says. “If that is the case, then we may be able to find a new treatment target for not just one, but many viral infections.”

Evolution Of Genes That Trigger The Body's Immune Response To Viral Infection

Virginia Commonwealth University Institute of Molecular Medicine researchers have traced the evolutionary origin of two genes that serve as primary cellular sensors of infection with RNA viruses, such as influenza, poliovirus, West Nile virus, and HIV, which may ultimately provide researchers with insight into a possible new pathway for the development of innate immunity.
Recent studies by other investigators have provided information on exactly how humans respond to virus infection and the role of innate immunity in protection from viral pathogenesis. Induction of innate immunity is closely associated with the production of type I interferons. Interferons are a class of proteins that are secreted by the body in response to a viral infection such as rhinovirus, the cause of the common cold.
In the study, published online in the Early Edition of the Proceedings of the National Academy of Sciences the week of October 20-24, the VCU team reported that melanoma differentiation associated gene-5 (MDA-5) and retinoic acid inducible gene-I (RIG-I) originated specifically in mammals. These genes induce the production of type I interferons.
“Understanding how these unique genes developed and evolved provides a unique opportunity to understand the origins of innate immunity and to develop ways of exploiting this process to develop new types of therapies for pathogenic viruses,” said lead investigator Paul B. Fisher, M.Ph., Ph.D., professor and chair of the Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine in the VCU School of Medicine.
According to Fisher, MDA-5, but not RIG-I, orthologs are found in fish, indicating that MDA-5 might have evolved before RIG-I. The unique domain arrangement of MDA-5 and RIG-I evolved independently by domain grafting and not by a simple gene-duplication event of the entire four-domain arrangement. This process may have been initiated by differential sensitivity of these proteins to viral infection.
“Our studies provide insights into the shuffling of gene regions, which culminated in a unique mechanism for protection against viral infection. Additionally, our phylogenetic analyses of these domains provides one of the first direct insights into the temporal pathways of development of innate immunity,” said Fisher.
According to Fisher, expression of both MDA-5 and RIG-I can limit viral replication post-entry in cells. In this context, identifying drugs that can effectively turn on either or both of these genes offers promise for decreasing virus-induced pathogenesis.
In related work, the team has identified the promoter region, which controls expression of MDA-5 and RIG-I. Studies are now under way at the VCU Institute of Molecular Medicine and the Burnham Institute for Medical Research in La Jolla, Calif., to use these promoters as part of a screening paradigm to identify small molecules that can be developed into drugs to treat infectious diseases.
This work was supported by grants from the National Institutes of Health.

Weight Gain In Pregnancy Linked To Overweight In Kids

Pregnant women who gain excessive or even appropriate weight, according to current guidelines, are four times more likely than women who gain inadequate weight to have a baby who becomes overweight in early childhood. These findings are from a new study at the Department of Ambulatory Care and Prevention of Harvard Medical School and Harvard Pilgrim Health Care and are published in the April issue of the American Journal of Obstetrics and Gynecology.
"Maternal weight gain during pregnancy is an important determinant of birth outcomes," says lead author Emily Oken, MD, MPH, instructor in the Department of Ambulatory Care and Prevention. "These findings suggest that pregnancy weight gain can influence child health even after birth and may cause the obstetric community to rethink current guidelines."
Oken and colleagues examined data from 1,044 mother-child pairs in Project Viva, a prospective study of pregnant women and their children based at the Department of Ambulatory Care and Prevention's Obesity Prevention Program. The authors studied whether pregnancy weight gain within or above the recommended range increased the risk of a child being overweight at age 3 years.
In 1990, the Institute of Medicine (IOM) published guidelines for gestational weight gain ("Nutrition During Pregnancy") that were motivated by evidence that low weight gain in pregnant women may cause low birth weight. These guidelines call for smaller gains in mothers with a higher body mass index (BMI) and generally permit greater gains than previous recommendations.
The IOM report remains the standard for clinical recommendations regarding gestational weight gain. However, some have questioned whether evidence is sufficient that greater gains promote better birth outcomes in modern developed nations. More weight gain may cause undesirable birth outcomes, such as increased rates of babies born at high birth weight and cesarean section, and is associated with higher postpartum weight retention and later risk of maternal obesity.
In this study, 51 percent of women gained excessive weight, 35 percent gained adequate weight, and 14 percent gained inadequate weight, according to the IOM guidelines. Women with adequate or excessive gain were approximately four times more likely than those with inadequate gain to have an overweight child, as measured at age 3. The authors defined overweight as a BMI greater than the 95th percentile for the child's age and sex.
"Our study shows that excessive weight gain during pregnancy was directly associated with having an overweight child," says Oken. "Just like adults, children who are overweight are at higher risk for a number of health conditions such as high blood pressure, diabetes, and high cholesterol."
The likelihood of having a baby that was heavy for gestational age was greater in women with excessive gain. Children of mothers who gained more weight also had somewhat higher systolic blood pressure, a cardiovascular risk factor related to weight even in young children.
The authors calculated total gestational weight gain as the difference between the last weight recorded before delivery and self-reported prepregnancy weight. The authors categorized women as having gained inadequate, adequate, or excessive weight according to the IOM guidelines. These guidelines recommend that women with a prepregnancy BMI between 19.8 and 26 kg/m2, (considered normal by the IOM guidelines) should gain 11.5 to 16kg (25 to 35 pounds); that women with a BMI of less than 19.8 kg/m2 (considered underweight by the IOM guidelines) should gain 7 to 11.5 kg (15 to 25 pounds); and that women with a BMI of more than 29 kg/m2 (considered obese by the IOM guidelines) should gain at least 6 kg (13 pounds).
Gestational weight gain may be linked to child overweight through several potential pathways. Mothers who gain weight readily because of genetic, dietary, or other behavioral factors may have children who are more likely to gain weight. Also, the amount of weight gained during pregnancy may alter the intrauterine environment, not only influencing fetal growth but also possibly resulting in persistent programming of child weight.
"Because childhood obesity is increasing in prevalence and effective treatment remains elusive, preventing childhood obesity remains critical," says Oken. "The IOM may need to reevaluate its recommendations for gestational weight gain, considering not only birth outcomes but also risk of obesity for both mother and child. While our study signals the potential need to adjust guidelines, further studies will need to occur to determine just what the appropriate weights should be."
Like the United States population as whole, many mothers and their children in this study were overweight. Even mothers with adequate gain according to the IOM guidelines had a substantially higher risk than mothers with inadequate weight gain of having overweight children, with no difference in risk of undesirable birth outcomes, such as small or large size for gestational age or birth by cesarean section.
"It has been 17 years since the IOM came out with its last set of recommendations, before the obesity epidemic hit with full force," says Matthew Gillman, MD, associate professor in the Department of Ambulatory Care and Prevention and senior author of the study. "Now, women are coming into pregnancy at higher weights and likely gaining excessively more than they used to. We need to find out how to counter this trend--but not go too far back in the other direction when women were gaining too little weight."
The Project Viva team is currently evaluating the children in this study who are now age seven.
This work was supported by the National Institutes of Health, Harvard Medical School, and the Harvard Pilgrim Health Care Foundation.