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HIV Virus eliminated from Cultured Human Stem cells

HIV Virus eliminated from Cultured Human Stem cells

The HIV-1 virus has proved to be tenacious, inserting its genome permanently into its victims' DNA, forcing patients to take a lifelong drug regimen to control the virus and prevent a fresh attack. Now, a team of researchers has designed a way to snip out the integrated HIV-1 genes for good.

This is one important step on the path toward a permanent cure for AIDS," says Kamel Khalili, PhD, Professor and Chair of the Department of Neuroscience at Temple. Khalili and his colleague, Wenhui Hu, MD, PhD, Associate Professor of Neuroscience at Temple, led the work which marks the first successful attempt to eliminate latent HIV-1 virus from human cells. "It's an exciting discovery, but it's not yet ready to go into the clinic. It's a proof of concept that we're moving in the right direction," added Dr. Khalili, who is also Director of the Center for Neurovirology and Director of the Comprehensive NeuroAIDS Center at Temple.

In a study published July 21 by the Proceedings of the National Academy of Sciences, Khalili and colleagues detail how they created molecular tools to delete the HIV-1 proviral DNA. When deployed, a combination of a DNA-snipping enzyme called a nuclease and a targeting strand of RNA called a guide RNA (gRNA) hunt down the viral genome and excise the HIV-1 DNA. From there, the cell's gene repair machinery takes over, soldering the loose ends of the genome back together -- resulting in virus-free cells. 

"Since HIV-1 is never cleared by the immune system, removal of the virus is required in order to cure the disease," says Khalili, whose research focuses on the neuropathogenesis of viral infections. The same technique could theoretically be used against a variety of viruses, he says.
The research shows that these molecular tools also hold promise as a therapeutic vaccine; cells armed with the nuclease-RNA combination proved impervious to HIV infection.
Worldwide, more than 33 million people have HIV, including more than 1 million in the United States. Every year, another 50,000 Americans contract the virus, according to the U.S. Centers for Disease Control and Prevention.

Although highly active antiretroviral therapy (HAART) has controlled HIV-1 for infected people in the developed world over the last 15 years, the virus can rage again with any interruption in treatment. Even when HIV-1 replication is well controlled with HAART, the lingering HIV-1 presence has health consequences. "The low level replication of HIV-1 makes patients more likely to suffer from diseases usually associated with aging," Khalili says. These include cardiomyopathy -- a weakening of the heart muscle -- bone disease, kidney disease, and neurocognitive disorders. "These problems are often exacerbated by the toxic drugs that must be taken to control the virus," Khalili adds.
Researchers based the two-part HIV-1 editor on a system that evolved as a bacterial defense mechanism to protect against infection, Khalili says. Khalili's lab engineered a 20-nucleotide strand of gRNA to target the HIV-1 DNA and paired it with Cas9. The gRNA targets the control region of the gene called the long terminal repeat (LTR). LTRs are present on both ends of the HIV-1 genome. By targeting both LTRs, the Cas9 nuclease can snip out the 9,709-nucleotides that comprise the HIV-1 genome. To avoid any risk of the gRNA accidentally binding with any part of the patient's genome, the researchers selected nucleotide sequences that do not appear in any coding sequences of human DNA, thereby avoiding off-target effects and subsequent cellular DNA damage.

The editing process was successful in several cell types that can harbor HIV-1, including microglia and macrophages, as well as in T-lymphocytes. "T-cells and monocytic cells are the main cell types infected by HIV-1, so they are the most important targets for this technology," Khalili says.
The HIV-1 eradication approach faces several significant challenges before the technique is ready for patients, Khalili says. The researchers must devise a method to deliver the therapeutic agent to every single infected cell. Finally, because HIV-1 is prone to mutations, treatment may need to be individualized for each patient's unique viral sequences.

"We are working on a number of strategies so we can take the construct into preclinical studies," Khalili says. "We want to eradicate every single copy of HIV-1 from the patient. That will cure AIDS. I think this technology is the way we can do it."

Article Source :  Press Release From Temple University Health || Quoted from ScienceDaily
Only 8% of Human DNA is Functional - Study finds

Only 8% of Human DNA is Functional - Study finds

A research conducted by oxford university researchers has revealed a shocking inference about the human genome. It has been found that only 8.2% of the human DNA has some biochemical function associated with it.

Researchers concluded the results being based on the activity that matters rather than just activity shown by the DNA. The ones with a demonstrable activity were considered functional. Back in 2012, Scientists of the ENCODE project had stated that almost 80 percent of the Human genome being Functional.

Professor Chris Pointing -Joint senior author of the MRC Functional Genomics Unit at Oxford University says that it is largely the matter of definition of the functional DNA and the figures could not be very different than that of ENCODE project if followed the same definition of the functional DNA.

The researchers used a computational approach to compare the complete DNA sequences of various mammals, from mice, guinea pigs and rabbits to dogs, horses and humans.

'But this isn't just an academic argument about the nebulous word "function". These definitions matter. When sequencing the genomes of patients, if our DNA was largely functional, we'd need to pay attention to every mutation. In contrast, with only 8% being functional, we have to work out the 8% of the mutations detected that might be important. From a medical point of view, this is essential to interpreting the role of human genetic variation in disease.'

Dr Gerton Lunter from the Wellcome Trust Centre for Human Genetics at Oxford University, the other joint senior author, explained: 'Throughout the evolution of these species from their common ancestors, mutations arise in the DNA and natural selection counteracts these changes to keep useful DNA sequences intact.'
The scientists' idea was to look at where insertions and deletions of chunks of DNA appeared in the mammals' genomes. These could be expected to fall approximately randomly in the sequence – except where natural selection was acting to preserve functional DNA, where insertions and deletions would then lie further apart.

'We found that 8.2% of our human genome is functional,' says Dr Lunter. 'We cannot tell where every bit of the 8.2% of functional DNA is in our genomes, but our approach is largely free from assumptions or hypotheses. For example, it is not dependent on what we know about the genome or what particular experiments are used to identify biological function.'
The rest of our genome is leftover evolutionary material, parts of the genome that have undergone losses or gains in the DNA code – often called 'junk' DNA.

'We tend to have the expectation that all of our DNA must be doing something. In reality, only a small part of it is,' says Dr Chris Rands, first author of the study and a former DPhil student in the MRC Functional Genomics Unit at Oxford University.
Not all of the 8.2% is equally important, the researchers explain.
A little over 1% of human DNA accounts for the proteins that carry out almost all of the critical biological processes in the body.

The other 7% is thought to be involved in the switching on and off of genes that encode proteins – at different times, in response to various factors, and in different parts of the body. These are the control and regulation elements, and there are various different types.
'The proteins produced are virtually the same in every cell in our body from when we are born to when we die,' says Dr Rands. 'Which of them are switched on, where in the body and at what point in time, needs to be controlled – and it is the 7% that is doing this job.'
In comparing the genomes of different species, the researchers found that while the protein-coding genes are very well conserved across all mammals, there is a higher turnover of DNA sequence in the regulatory regions as this sequence is lost and gained over time.
Mammals that are more closely related have a greater proportion of their functional DNA in common.

But only 2.2% of human DNA is functional and shared with mice, for example – because of the high turnover in the regulatory DNA regions over the 80 million years of evolutionary separation between the two species.

'Regulatory DNA evolves much more dynamically that we thought,' says Dr Lunter, 'but even so, most of the changes in the genome involve junk DNA and are irrelevant.'
He explains that although there is a lot of functional DNA that isn't shared between mice and humans, we can't yet tell what is novel and explains our differences as species, and which is just a different gene-switching system that achieves the same result.
Professor Ponting agrees: 'There appears to be a lot of redundancy in how our biological processes are controlled and kept in check. It's like having lots of different switches in a room to turn the lights on. Perhaps you could do without some switches on one wall or another, but it's still the same electrical circuit.'

He adds: 'The fact that we only have 2.2% of DNA in common with mice does not show that we are so different. We are not so special. Our fundamental biology is very similar. Every mammal has approximately the same amount of functional DNA, and approximately the same distribution of functional DNA that is highly important and less important. Biologically, humans are pretty ordinary in the scheme of things, I'm afraid.

'I'm definitely not of the opinion that mice are bad model organisms for animal research. This study really doesn't address that issue,' he notes.

Article Source :  Press Release From University of Oxford News || Quoted from ScienceDaily
How Pigeons Find Their Way Back To Home

How Pigeons Find Their Way Back To Home

Homing pigeons, like other birds, are extraordinary navigators, but how they manage to find their way back to their lofts is still debated. To navigate, birds require a 'map' (to tell them home is south, for example) and a 'compass' (to tell them where south is), with the sun and the earth's magnetic field being the preferred compass systems. A new paper provides evidence that the information pigeons use as a map is in fact available in the atmosphere: odors and winds allow them to find their way home.

The results are now published in Biogeosciences, an open access journal of the European Geosciences Union (EGU).

Experiments over the past 40 years have shown that homing pigeons get disoriented when their sense of smell is impaired or when they don't have access to natural winds at their home site. But many researchers were not convinced that wind-borne odors could provide the map pigeons need to navigate. Now, Hans Wallraff of the Max Planck Institute for Ornithology in Seewiesen, Germany, has shown that the atmosphere does contain the necessary information to help pigeons find their way home.

In previous research, Wallraff collected air samples at over 90 sites within a 200 km radius around a former pigeon loft near Würzburg in southern Germany. The samples revealed that the ratios among certain 'volatile organic compounds' (chemicals that can be a source of scents and odors) in the atmosphere increase or decrease along specific directions. "For instance, the percentage of compound A in the sum A+B or A+B+C+D increases the farther one moves from north to south," Wallraff explains.

These changes in compound ratios translate into changes in perceived smell. But a pigeon that has never left its loft does not know in what directions what changes occur -- unless it has been exposed to winds at its home site.

At home, a bird is thought to associate certain smells with particular wind directions. "If the percentage of compound A increases with southerly winds, a pigeon living in a loft in Würzburg learns this wind-correlated increase. If released at a site some 100 km south of home, the bird smells that the ratio of compound A is above what it is on average at its loft and flies north," Wallraff explains. To use an analogy, a person in Munich could smell an Alpine breeze when there is wind blowing from the south. When displaced closer to the mountains, they would detect a strong Alpine scent and remember that, at home, that smell is associated with southerly winds: the person would know that, roughly, they needed to travel north to find home.

But this explanation of how pigeons might use wind-borne odors to find their loft was just a hypothesis: Wallraff still needed to prove that the atmosphere does indeed contain the basis of the map system pigeons need to navigate. In the newBiogeosciences paper, he develops a model showing that 'virtual pigeons' with only knowledge of winds and odors at home, can find their way back to their lofts by using real atmospheric data.

"My virtual pigeons served as tools to select those volatile compounds whose spatial distributions, combined with variations dependent on wind direction, were most suitable for homeward navigation," explains Wallraff.

The model uses an iterative approach to imitate animal evolution by introducing random mutations in the virtual pigeons, making them most sensitive to those volatile compounds that are most effective for navigation. By selecting the best mutations in the course of thousands of generations, the model creates virtual pigeons capable of finding their bearings as well as real pigeons, showing that even inexperienced birds could use atmospheric information for navigation. The findings present a missing piece in the puzzle of homing pigeon navigation, confirming that winds and odors can indeed work as a map system.

"Work with real pigeons was the beginning of the story. In this research, I wanted to find out whether and in what way the chemical atmosphere fulfills the demands for avian navigation. Eventually, to identify the chemical compounds birds actually use for home-finding, we will need real birds again. But this is far in the future."
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