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Innate immune system can kill HIV when a viral gene is deactivated


Human cells have an intrinsic capacity to destroy HIV. However, the virus has evolved to contain a gene that blocks this ability. When this gene is removed from the virus, the innate human immune system destroys HIV by mutating it to the point where it can no longer survive.

This phenomenon has been shown in test tube laboratory experiments, but now researchers at the University of North Carolina School of Medicine have demonstrated that the same phenomenon occurs in a humanized mouse model, suggesting a promising new target for tackling the virus, which has killed nearly 30 million people worldwide since it first appeared three decades ago.

A family of human proteins called APOBEC3 effectively restrict the growth of HIV and other viruses, but this action is fully counteracted by the viral infectivity factor gene (vif) in HIV. In the study, researchers intravenously infected humanized mice with HIV. They found that the most commonly transmitted strains of HIV are completely neutralized by APOBEC3 proteins when vif is removed from the virus.

“Without the vif gene, HIV can be completely destroyed by the body’s own immune system,” said J. Victor Garcia, PhD, professor of medicine at the UNC School of Medicine and senior author on the study. “These results suggest a new target for developing drugs fully capable of killing the virus.”

Garcia and his colleagues pioneered the humanized mouse model used for these studies. The aptly named “BLT” mouse is created by introducing human bone marrow, liver and thymus tissues into animals without an immune system of their own. The mice have a fully functioning human immune system and can be infected with HIV in the same manner as humans. In previous research, Garcia and his team have effectively prevented intravenous, rectal, vaginal and oral transmission of HIV in the mice with pre-exposure prophylaxis (PrEP).

For the current study, Garcia and his colleagues also infected BLT mice with another, highly harmful strain of the virus. The results show that this strain of HIV does continue to replicate, even without vif, but at a much slower rate and without harming the human immune system. Further, the researchers found that virus replication in this case was limited to one tissue—the thymus—in the entire body.

“These findings demonstrate a fundamental weakness in HIV,” said John F. Krisko, PhD, lead author on the study. “If this weakness can be exploited, it might eventually lead to a cure for HIV/AIDS,” Krisko said.

 

Journal reference:

John F. Krisko, Francisco Martinez-Torres, John L. Foster, J. Victor Garcia. HIV Restriction by APOBEC3 in Humanized MicePLoS Pathogens, 2013; 9 (3): e1003242 DOI: 10.1371/journal.ppat.1003242

Provided by University of North Carolina Health Care

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Dengue virus increases mosquito’s lust for blood

May 6, 2012 1 comment

Between 50 million and 100 million dengue infections occur each year, according to the World Health Organization.

VIRUS CARRIER: This picture shows the presence of the dengue virus in the mosquitoes’ chemosensory (antennae and palp) and feeding organs (proboscis). (Photo: Johns Hopkins Bloomberg School of Public Health)

Mosquitoes are already blood-sucking machines, but new research indicates that the dengue virus, which the mosquitoes transmit to humans, makes them even thirstier for blood.

The virus specifically turns on mosquito genes that make them hungrier for a blood meal; the activated genes also enhance mosquitoes’ sense of smell, something that likely improves their feeding skills. The result is a mosquito better able to serve the virus by carrying it more efficiently to human hosts.

“The virus may, therefore, facilitate the mosquito’s host-seeking ability, and could — at least theoretically — increase transmission efficiency, although we don’t fully understand the relationships between feeding efficiency and virus transmission,” study researcher George Dimopoulus, of the Johns Hopkins Bloomberg School of Public Health, said in a statement. “In other words, a hungrier mosquito with a better ability to sense food is more likely to spread dengue virus.”

Dengue dangers

The virus doesn’t hurt the mosquitoes that carry it, a specific species called Aedes aegypti, but it lives in them. When the mosquito bites a human, it spreads the deadly disease through its saliva. More than 2.5 billion people live in areas where dengue fever-infected mosquitoes live. The World Health Organization estimates that between 50 million and 100 million dengue infections occur each year.

The researchers analyzed the mosquito genes before and after being infected with the virus, finding changes in 147 genes. These post-infection genes make proteins that are involved in processes that include virus transmission, immunity, blood feeding and host seeking, they found.

“Our study shows that the dengue virus infects mosquito organs, the salivary glands and antennae that are essential for finding and feeding on a human host,” Dimopoulus said. “This infection induces odorant-binding protein genes, which enable the mosquito to sense odors.”

Zombified behavior

“We have, for the first time, shown that a human pathogen can modulate feeding-related genes and behavior of its vector mosquito, and the impact of this on transmission of disease could be significant,” Dimopoulos said.

This is just one of many recent examples of a parasite taking control of an animal for its own benefit. Other examples include a fungus that turns ants into zombiesand a virus that causes caterpillars to dissolve and then rain virus particles down on other potential hosts.

The study was published on March 29 in the journal PLoS Pathogens.

Source:

http://www.mnn.com/earth-matters/animals/stories/dengue-virus-increases-mosquitos-lust-for-blood by Jennifer Welsh, LiveScience

Reference:

Sim S, Ramirez JL, Dimopoulos G (2012) Dengue Virus Infection of the Aedes aegypti Salivary Gland and Chemosensory Apparatus Induces Genes that Modulate Infection and Blood-Feeding Behavior. PLoS Pathog 8(3): e1002631. doi:10.1371/journal.ppat.1002631

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002631

Cracks in the Plaques: Mysteries of Alzheimer’s Slowly Yielding to New Research

February 6, 2012 Leave a comment

Science is bringing some understanding of the heritability, prevalence, and inner workings of one of the most devastating diseases.

 
 
 
 
(left) A PET scan’s bright areas reveal the concentration of amyloid beta, a protein that forms a plaque in Alzheimer’s patients. The scan compares the brains of a healthy patient (left) and a patient suffering from Alzheimer’s (right). Image: Alzheimer’s Disease Education and Referral Center, NIH
 
 
 
 
 
 

This has been a big week in Alzheimer’s news as scientists put together a clearer picture than ever before of how the disease affects the brain. Three recently published studies have detected the disease with new technologies, hinted at its prevalence, and described at last how it makes its lethal progress through the brain.

The existence of two forms of Alzheimer’s—early- and late-onset—has long baffled scientists. Of the estimated five million Americans who suffer from Alzheimer’s, only a few thousand are diagnosed with an early-onset form of the affliction, which affects people before the age of 65. This rare early-onset form is thought to be hereditary and scientists have associated multiple genetic mutations contributing to its occurrence. Late-onset Alzheimer’s, although more common, has been the bigger mystery. One variant of the APOE gene-—sometimes known as the Alzheimer’s gene—is linked to the late-onset disease. But the APOE gene, unlike dominant early-onset genes, does not determine whether a person will ultimately have dementia.

Now there’s evidence that late-onset Alzheimer’s has a genetic basis similar to that of early-onset Alzheimer’s. By sequencing select genes associated with the latter, along with frontotemporal dementia, researchers at Washington University in Saint Louis and other institutions found that patients with late-onset Alzheimer’s carry some of the same genetic mutations as those with the early-onset form. The evidence, published on Wednesday in PLoS ONE, bolsters the argument that the forms of Alzheimer’s that appear at different life stages should be classified as the same disease. As to why the disease appears earlier in some cases, the scientists speculated that those patients diagnosed relatively early in life carry more genetic risk factors for the disease.

This study’s use of rapid genetic sequencing, the authors noted, may provide a model for more precise identification of dementias. Within the study, the researchers identified patients who may have been misdiagnosed as having Alzheimer’s; the genes of these patients suggested that they had another type of dementia. Given the heritable component, patients with a family history could be screened to detect and diagnose Alzheimer’s early.

Other genetic research unveiled in the past week or so has shed light on the biological processes that underlie how Alzheimer’s affects the brain. Certain mutations may lead to an increased production of a protein called amyloid beta in the region of the brain that creates memory. This excess amyloid beta, naturally secreted by brain cells, then becomes a complex called an oligomer. These oligomers may interrupt the signals transmitted between neurons. As in other neurodegenerative diseases like Parkinson’s or Huntington’s, the spread of oligomers appears to be driving the disease process.

Oligomer-linked diseases are relatively common, in part because oligomers can also play an essential biological role in the brain. A recent investigation using fruit flies reveals that the presence of a specific oligomer is actually required for the flies to form long-term memories.

In an early stage of Alzheimer’s, the naturally secreted amyloid beta protein builds up as oligomers in the brain, which then go on to form larger aggregates called plaques. Later in the disease, another aberrant form of a protein called tau starts to build up, in the entorhinal cortex. Normally, tau helps provide structure crucial to neuron functioning. The buildup of tau, however, causes the protein to tangle and eventually kill brain cells. What was unknown until recently, however, was how the tau protein spreads through different brain regions.

Two studies—one to be published in Neuron and the other published in PLoS ONE on Wednesday—have answered this question using brain samples from mice genetically engineered to express tau as it occurs in the human brain. Using a staining technique to highlight tau’s distribution in the brain, they compared samples from mice of different ages to analyze how tau moved through brain cells over time. They found the protein spread from neuron to neighboring neuron, traveling along synapses.

Understanding how this protein moves may allow scientists to stop tau in its tracks. “This opens up a whole new world of biology,” says Columbia University’s Karen Duff, an author on the study published in PLoS ONE. Tau is implicated in 30 different forms of dementia. In addition, the movement of tau may be similar to the spread of oligomers associated with Parkinson’s and Huntington’s. Nonetheless, we are still a long way from a therapeutic solution and stopping tau, which comes at a relatively late stage of Alzheimer’s, might be a very limited therapy.

As the world’s population continues to age, Alzheimer’s becomes a threat to more of us with every passing day. Although we may not yet have new treatments from this work, the take-away on these findings is clear: If we really are going to win the war, or even a battle, against Alzheimer’s, we need basic research that can delve into the complex biology that contorts proteins and kills brain cells to find treatments for this disease.

Story Source:

The above story is reprinted from Scientific American, written by Daisy Yuhas.