Web Concepts

Posts Tagged ‘viruses’

HIV infection sends the immune system into overdrive and eventually exhausts it, which is what leads to AIDS. But removing cholesterol from HIV seems to cripple the virus' ability to over-activate part of the immune system, so it could potentially lead to a vaccine that lets the adaptive immune system attack and destroy the virus — just as it would if HIV was any other pathogen.

Dr. Adriano Boasso, an immunologist and research fellow at Imperial College London, said keeping the body’s first-responder immune cells quiet could have some benefits — the whole system may not burn out so quickly, and could potentially fight off HIV.

“Think of the immune system as a car. HIV forces the car to stay in first gear, and if you do that too long, the engine is not going to last very long,” he said in an interview. “But if we take the cholesterol away, HIV is not capable of attacking the immune system quite as well. Practically, what we’ve done is turn HIV into a normal jump-start of a car.”

Viruses replicate by invading cells and hijacking their machinery, which they use to churn out new copies of their genetic material. Among the repurposed material is cholesterol, which is important in maintaining cellular fluidity, something viruses require to interact with other cells. (This is not related to the way everyone thinks of cholesterol, which is cholesterol in the blood. That type of cholesterol, made of high-density and low-density lipoproteins, is related to heart disease, not HIV and AIDS.)

HIV quickly activates plasmacytoid dendritic cells, or pDCs, which are the first immune cells that respond to the virus. PDCs produce molecules called interferons, which both interfere with the virus’ replication and also switch on adaptive immune cells, like T cells. Boasso and other researchers believe this hyperactivation weakens the secondary immune system, undermining the body’s ability to respond.

But in a new study, Boasso and colleagues show that removing the cholesterol changes HIV, so that it cannot activate the pDCs like it normally would. By preventing these first responder cells from turning on in the first place, the secondary responders — the T cells — can organize a more effective counterassault.

“Modifying the virus affects the way the immune system sees it,” Boasso said. He said it’s like removing the weapons from HIV’s arsenal: “By removing cholesterol, we can turn those little soldiers into an armorless enemy, which can be recognized by the opponent’s army.”

Emily Deal is a postdoctoral fellow at the Gladstone Institute of Virology and Immunology, which is affiliated with the University of California-San Francisco. She studies pDC activation in viral infections, and said the cholesterol removal is allowing less of the HIV into the dendritic cells in the first place — which means there’s less of the virus for the cells to detect, which leads them to produce fewer interferons.

But keeping the pDCs from turning on could be both good and bad, she said.

“What is better for the host in the long run? Is it better to suppress replication early on, but potentially have some of your T cells die? Or what are the lon-term effects of having replication proceed in the absence of interferons, but have your T cells live?” she said. "It's a complicated system."

Ideally, further studies would look at this give-and-take relationship in monkeys, so researchers could determine if a de-cholesterolized version of HIV could be an effective form of vaccine, she said.

“I think it has a shot," she said. "However, pDCs control a lot of the immune system, and if they’re not getting turned on at all, that may have other effects. If you’re trying to use it as a vaccine, it may not induce enough of a response to be protective."

Boasso said the de-cholesterolized HIV could be studied for use in a potential vaccine, but it’s difficult to stimulate the immune system to fight off an invader when the system itself is the target.

“There’s going to be a lot of work to do,” he said.

The study, which also involved researchers at Johns Hopkins University, the University of Milan and Innsbruck University, is published in the journal Blood.

Viruses work by inserting themselves into a cell and hijacking its machinery for its own use. The invaded cell then creates more copies of the virus, which involves creating long strings of double-stranded RNA — which contains the virus’ genetic material, like DNA contains ours.

When the virus is done copying itself, its hostage cell usually dies, from the virus bursting through its walls (lysis), changes to the cell’s outer membrane, and from apoptosis, or programmed cell death.

Human cells have plenty of defenses against viral invasion, including proteins that attach to the double-stranded RNA, preventing the virus from replicating itself after successful invasion.

This new drug therapy combines those dsRNA proteins with a protein that induces apoptosis. It’s called a DRACO, Double-stranded RNA Activated Caspase Oligomerizer.

When one end of the DRACO binds to dsRNA, it signals the other end of the DRACO to induce cell suicide, an MIT News article explains. In this way, the cell is killed before the virus can take over and eventually kill it anyway. If there is no dsRNA, the healthy cells are left alone.

“In theory, it should work against all viruses,” said Todd Rider, a senior staff scientist at MIT’s Lincoln Laboratory who invented the new technology.

A handful of drugs can target specific viruses by interfering with their replication process, through addition of modified DNA building blocks or the blocking of enzymes the viruses need to stimulate the replication process. But viruses are wily bugs, and they can evolve to resist these treatments.

The DRACO therapy could be effective because it targets the host cell, not just the virus.

Rider and colleagues are testing DRACO against more viruses in mice, according to MIT. Rider hopes to license the technology for trials in larger animals and for eventual human clinical trials, too.

[MIT News]

HIV's strongest sections could be its greatest weaknesses

HIV has been so difficult to fight in part because it is such an adept mutant. It produces sloppy copies of itself as it replicates, leading to many variations that can withstand drugs and vaccines. And it can produce 100 billion new virus particles every day, as Ed Yong points out over at Discover, which leads to lots and lots of copies. Broad-spectrum drugs or vaccines can’t do very much against a target that morphs so quickly.

But not all the pieces of HIV mutate with such abandon, according to this new study. Some groups of amino acids known as HIV sectors are somewhat less fickle, staying the same while the rest of the virus morphs, according to researchers at the Ragon Institute, a research group bridging MIT, Harvard University and Massachusetts General Hospital. Researchers believe these sites must remain unchanged for the virus to survive and replicate properly.

Researchers led by HIV research pioneer Bruce Walker and MIT chemical engineering professor Arup Chakraborty say this stalwart section of the virus can be turned against it. If the immune system can be trained to attack all the amino acid portions in an HIV sector, the virus will either have to mutate to thwart the attack — thereby undermining its structural integrity, crippling itself — or not mutate, which would render it helpless against drugs or vaccines.

This new targeted approach came from Chakraborty, who thought Walker and colleagues were too limited in their search for solutions, Yong reports. The team turned to random matrix theory, developed in the 1950s to solve nuclear physics problems and which has been used to analyze stocks, as the Wall Street Journal notes. It can pinpoint correlations between groups of objects, so it can assess how one stock is linked to other groups of stocks, for instance.

Working with HIV proteins taken from a massive database, the team used random matrix theory to analyze HIV’s genetic code and find groups of amino acids whose mutations were coordinated. The segment that mutated the least was dubbed sector 3, on an HIV sector known as Gag, which makes up HIV’s honeycombed inner shell. If the shell mutates, the honeycomb won’t lock together, and the virus would collapse.

“Multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution,” the authors write in a paper on their research, which is published this week in the Proceedings of the National Academy of Sciences.

Incidentally, a rare group of patients who can fight HIV without drugs — known as “elite controllers” — use their own immune systems to attack sector 3.

All this suggests a new way of thinking about HIV treatment, the WSJ and others point out. Perhaps HIV drugs should dispense with the full-on assault and opt for targeted strikes instead.

Buoyed by this research, other teams are reportedly already planning new animal studies to test just that.

[via Wall Street Journal, Not Exactly Rocket Science]

Scientists already knew that carbon nanotubes, rolled-up sheets of graphene, could improve the efficiency of photovoltaic cells. Ideally, the nanotubes would gather more electrons that are kicked up from the surface of a PV cell, allowing a greater number of electrons to be used to produce a current.

But there are complications — carbon nanotubes come in two varieties, functioning either as semiconductors or wires, and they each behave differently. They also tend to clump together, which makes them less effective at gathering up their own electrons. MIT researchers found that a certain bacteria-attacking virus called M13 can be used to make things go more smoothly.

M13 has peptides that bind to the carbon nanotubes, keeping them in place, MIT News explains. Each virus can grip about five to 10 nanotubes each, using roughly 300 of the protein molecules. The viruses were also genetically engineered to produce a layer of titanium dioxide, which happens to be the key ingredient in Grätzel cells, a.k.a. dye-sensitized solar cells. (These cells use TiO2 instead of silicon, and their inventor, Michael Grätzel of the École Polytechnique Fédérale de Lausanne, won the Millenium Technology Prize for them last year.) This close contact between TiO2 nanoparticles helps transport the electrons more efficiently.

The viruses also make the nanotubes water-soluble, which could make them easier to incorporate into PV cells at room temperature, lowering manufacturing costs.

Graduate students Xiangnan Dang and Hyunjung Yi, MIT professor Angela Belcher and colleagues tested this method with Grätzel cells, but they say the technique could be used to build other virus-augmented solar cells, including quantum-dot and organic solar cells.

They also learned that the two flavors of nanotubes have different effects on solar cell efficiency — something that had not been demonstrated before. Semiconducting nanotubes can enhance solar cells’ performance, but the continuously conducting wires had the opposite effect. This knowledge could be useful for designing more efficient nanoscale batteries, piezoelectrics or other power-related materials.

The virus-built structures enhanced the solar cells’ power conversion efficiency to 10.6 percent from 8 percent, according to MIT News. That’s about a one-third improvement, using a viral system that makes up just 0.1 percent of the cells’ weight.

“A little biology goes a long way,” Belcher said in an MIT News article. The researchers think with further research, they can improve the efficiency even more.

[MIT News]

Destruction of the smallpox virus, which was eradicated in the 1970s, has been mulled since 1980, but World Health Organization officials renewed debate about the matter earlier this year and will decide the viruses’ fate at an upcoming meeting.

Two labs possess the last known live samples of the variola virus — the Centers for Disease Control and Prevention in Atlanta, and a Russian facility in Siberia. Officials in developing nations, where smallpox is more likely to spread should it resurface, have been pushing for their destruction since 1980. The World Health Assembly decided to kill the samples in 1996, but they have been granted stays of execution in the decade and a half since, with the United States, Russia and others arguing the virus samples could seed new vaccines and potential treatments for infected patients.

In January, WHO officials again started discussions about whether to destroy the samples. The World Health Assembly will decide in May. LiveScience reviews the controversy here.

Epidemiologists believe smallpox has killed about one-third of those it has infected throughout history, accounting for hundreds of millions of victims dating back to ancient Egypt. A decade-long global vaccination effort eliminated the virus from human populations; the last natural case was found in October 1977 in Somalia. The elimination of Rinderpest, a cattle plague, will be only the second such disease eradication story in human history.

Officials in the U.S. and Russia have said they will fight efforts to set a destruction date, arguing the viruses are needed for research and to guard against bioterrorism. Some fear nations like North Korea or Iran may possess secret samples, although those countries deny it.

[LiveScience]

Cardiac muscle cells, or cardiomyocytes, are what makes the heart beat. Scientists have been making cardiomyocytes from other cells for some time, usually by making induced pluripotent stem cells from some other cell, like skin cells or blood cells. The cells are reprogrammed into iPS cells by injecting virus particles that have been manipulated to carry genetic information.

But the viruses can cause mutations scientists don’t want, and in some cases, they cause cancer. It would be better to create new cells without involving viruses at all, but some scientists didn’t think this would be possible with heart muscle cells.


Cardiomyocytes are tricky to make in the lab, developing into clumps of regular, non-beating cells if they are not developed properly. Although plenty of labs have made them, there are no standardized recipes for the nutrient and growth factor broths that help them grow into properly beating cells.

Hopkins researchers went ahead and figured that out. Johns Hopkins postdoctoral scientist Paul Burridge pored through dozens of scientific papers and worked for nearly two years to develop a foolproof heart cell recipe. It worked for 11 different stem cell lines, including embryonic stem cells and adult stem cells.

“We took the recipe for this process from a complex minestrone to a simple miso soup,” said Elias Zambidis, M.D., Ph.D., an assistant professor of oncology and pediatrics at the Johns Hopkins Institute for Cell Engineering and the Kimmel Cancer Center.

To make the virus-free mutations, scientists used plasmids, which are ring-shaped molecules of double-stranded DNA that are separate from the DNA that’s found in chromosomes. They usually occur in bacteria, and can replicate inside cells but eventually degrade.

The team worked with stem cells from umbilical cord blood and gave them a slight shock, opening a gateway for a plasmid to insert seven genes into the cells. The plasmids caused the cells to turn into iPS cells. Then, Burridge fed them his specialized, simplified broth, designed to make them into heart cells. The researchers lowered oxygen levels to simulate the hypoxic environment these cells would experience when they grow inside an embryo. Nine days later, the nonviral iPS cells became functioning cardiac cells, according to Hopkins.

Such virus-free cells could eventually be used to test new cardiac drugs, or for stem cell-derived implants to help patients whose cardiomyocytes die in a heart attack, according to Hopkins.

Watch the cells pulse in the video below.

New technology breaks the theoretical limit on how small we can see

With the new method, there is theoretically no limit on how small an object researchers will be able to see. It could potentially see inside human cells and examine live viruses for the first time.

The standard optical microscope can only see items down to about one micrometer. To see things in the nanoscale, researchers use methods like scanning tunneling microscopes, scanning electron microscopes, transmission electron microscopy and atomic force microscopy.

But these techniques are limited in scope, especially for applications like medicine. Electron microscopes can only see the surface of a cell, rather than examining its structure, for instance. And there is no way to see a live virus in action.

The new method works by integrating a microsphere “superlens” with a traditional optical microscope. The spheres magnify images of items that are placed on the microscope plate, touching the microsphere and forming “virtual images,” according to authors Zengbo Wang, Wei Guo and Lin Li of the University of Manchester, UK. The optical microscope magnifies the virtual images, forming a greatly enhanced image.

“The microspheres are in contact with objects, and the microscope must focus below the object surface to capture the image. This is a very different practice from the normal use of microscopes,” Li said in an e-mail.

Optical diffraction limits dictate that the smallest object that can be seen is around half the optical wavelength. For visible light, this is about 200 nanometers to 700 nanometers. That means the smallest thing you can actually see is about 200 nanometers — pretty small, but not small enough to resolve interesting molecules and cells.

The new method allowed Li and colleagues to see objects at 50 nanometers, he said.

“This clearly breaks the theoretical optical imaging limit,” he said.

It also overcomes some drawbacks associated with electron microscopes. A TEM sends a beam of electrons through an object, interacting with it as they pass through it. The device forms an image of this interaction and magnifies it. An SEM scans an object with a high-energy electron beam, which also interacts with the sample. The interaction can provide information about the object’s topography and composition. An STM applies a voltage very close to an object, allowing electrons to tunnel through the space between them. This current can be monitored as the voltage tip moves across the object, and is translated into an image. And an AFM essentially feels a surface using a mechanical probe.

Optical fluorescence microscopes can see inside cells by dyeing them, but it can’t penetrate viruses, and it would be nice to see cells without having to inject them with dye. What’s more, the electron methods involve chemical reactions that must be accounted for. Last year, for instance, IBM researchers made an AFM image of a molecule to figure out its chemical composition, but some scientists wondered whether the measuring method itself interfered with the molecule’s structure. It required putting the molecule on a salt crystal, but if no one knew the shape to begin with, they can’t know whether the salt affects the shape.

So it would be nice if you could just take a look at something and see it for yourself. This new method will allow that to happen — imaging viruses, DNA and molecules in real time.

The method uses optical near-field images, which has no diffraction limit, Li said. Near-field images are within the optical wavelength of the optics involved. Far field is beyond that distance.

“Therefore, theoretically, there is no limit on how small we can see. It will depend on how much can we amplify the image using the spheres and relay it to the far field,” Li said.

The team's paper is published in the journal Nature Communications.