Tag Archives: DNA

Have you ever wondered what HIV sounds like?

sounds-of-hiv

The majority of us enjoy music to some degree or another, pop, classical, rock R&B but have you ever wondered what HIV would sound like?

There is a range of sound and music, which lies beyond the range of human hearing. “Sounds of HIV” is a musical translation of the genetic code of HIV, the human immunodeficiency virus. In this album, segments of the virus are assigned musical pitches that correspond to the segment’s scientific properties. In this way, the sounds reflect an accurate, musical nature of the virus. When listening from beginning to end, the listener hears the entire genome of HIV.”

You may think that expressing nucleotides of the genome of a virus as pitches of the melodic scale as a promotional stunt, why would you draw a connection between adenosine and A, between cytosine and C and so on?

University of Georgia graduate student Alexandra Pajak’s instrumental sequence ensemble which draws inspiration from the physical properties of HIV itself!

“Sounds of HIV,” is a 17-track, 52-minute long musical adaptation of HIV’s genetic code. Pajak assigned pitches to the four basic nucleotides in DNA — A for Adenine, C for Cytosine, G for Guanine and D for Thymine — but the score contains much more than these for notes

Applying scientific rigour to music is nothing new and has been done in the past with math so why not with biochemistry? Alexandra Pajak, native of Athens, Georgia studied both composition and sciences and her work reveals a fascination with both subjects. Then there is a general sense of unease, creeping in. This undeniably beautiful music expresses HIV, a virus responsible for the destruction of much beauty and art. On one hand, it’s tempting to assume that nature’s creations achieve a high level of symmetry and beauty and a virus should not be exempt from that principle.

On the other hand, what terrible beauty is there to be found should we glimpse inside the genome of the plague, syphilis, smallpox or even flu? These ruminations tend to accompany listening to this oddly-concordant composition, performed with aplomb by the Sequence Ensemble.

In a way, the strange and disturbing recording reveals itself beautiful yet disturbing as the sounds reflect the true nature of the virus. When listening from beginning to end, the listener hears the entire genome of HIV.”

Unfortunately, we’re unable to stream the full album however here’s the links to it on Google Music or Spotify, if you’re more old school, here’s the CD on Amazon.

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HIV defies attempt to edit virus out of human cells with CRISPR

Crispr

Vanquishing HIV just got that little bit harder. A promising technique to weaken the virus has in some cases made it stronger.

HIV’s ability to evolve resistance to antiretroviral drugs has become legendary. It had been thought that a new precision gene-editing tool called CRISPR would have more success, enabling the viral genome to be “cut” from all infected cells. Now it seems that hope may be in vain – at least for now.

Curing people with HIV has proved impossible so far. Several prominent reports of cures three years ago turned out to provide false hope, after the virus bounced back.

The problem begins with the fact that HIV integrates its genome into the host cell’s DNA. While antiretroviral drugs keep people free of active infection, this viral DNA hides out in parts of the body they can’t reach, ready to revive active infection if the drug treatment is stopped.

Story via New Scientist
newscientist

CRISPR cuts

Using CRISPR to cut up the HIV genome in all cells – including those where it’s hiding out – is one of several promising strategies to clear the infection.

But it has been hit with a serious setback. Research shows that the use of CRISPR to destroy the virus in white blood cells by messing up its DNA is a double-edged sword.

Chen Liang of McGill University AIDS Center in Montreal, Canada, and his team used CRISPR to cut up the viral DNA that had been incorporated into the host cell. The idea was that when the cell’s natural repair mechanisms patched up the broken genetic sequence it would introduce genetic “scar tissue” that would prevent the viral DNA from functioning.

Sometimes this did, indeed, happen – the gene alterations “killed” the virus. But to the surprise of the researchers, in other cases the scar tissue made the virus stronger – sometimes it was able to replicate faster, for example.

What’s more, because the patched up DNA looks different, the CRISPR cutting system couldn’t recognise and attack it again. HIV had become resistant to the gene-editing technique.

Double-edged sword

“On the one hand, CRISPR inhibits HIV, but on the other, it helps the virus to escape and survive,” says Liang. “The surprise is that the resistance mutations are not the products of error-prone viral DNA copying, but rather are created by the cell’s own repair machinery.”

But all is not yet lost.

“The bright side is that when you know what the problem is, you can come up with the means to overcome it,” says Liang. “Just as HIV is able to escape all antiretroviral drugs, understanding how HIV escapes only helps you discover better drugs or treatments.”

One possibility is to “carpet-bomb” HIV with CRISPR at many sites within its DNA instead of just the one targeted in the experiment. This, says, Liang, would make it much more difficult for the virus to evolve resistance.

HIV neutralised

Another potential ploy is to attack the virus with CRISPR-like techniques that rely on different DNA repair machinery, making it less likely that the repair process itself would help the virus become resistant to editing.

Another team reporting early success against HIV using CRISPR isn’t discouraged by the setback, echoing the possibility that the “carpet-bombing” solution could be the answer.

“The key could be using multiple viral sites for editing,” says Kamel Khalili of Temple University in Philadelphia, Pennsylvania. “This would reduce any chance for virus escape or the emergence of virus resistant to the initial treatment,” he says.

Earlier this year Khalili’s team showed that CRISPR neutralises HIV in cells that are latently as well as actively infected, suggesting that a cure could one day be possible.

Journal reference: Cell Reports, DOI: 10.1016/j.celrep.2016.03.042
 

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HIV vaccine that transforms cell DNA brings fresh hope

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A radical new approach to vaccination seems to completely protect monkeys from HIV, US scientists report.

Vaccines normally train the immune system to fight an infection.

Instead, researchers at the Scripps Research Institute in California have altered the DNA of monkeys to give their cells HIV-fighting properties.

The team describe it as “a big deal” and want to start human trials soon. Independent experts say the idea is worth “strong consideration”.

This technique uses gene therapy to introduce a new section of DNA inside healthy muscle cells.

That strip of DNA contains the instructions for manufacturing the tools to neutralise HIV, which are then constantly pumped out into the bloodstream.

Experiments, reported in the journal Nature, showed the monkeys were protected from all types of HIV for at least 34 weeks.

As there was also protection against very high doses, equivalent to the amount of new virus that would be produced in a chronically infected patient, the researchers believe the approach may be useful in people who already have HIV.

Lead researcher Prof Michael Farzan told the BBC: “We are closer than any other approach to universal protection, but we still have hurdles, primarily with safety for giving it to many, many people.

Shifting target

“We’re very proud of it and we think it’s a big deal, but we are biased.”

HIV vaccines have struggled because the virus mutates so rapidly it is a constantly shifting target.

This one targets areas that HIV struggles to change.

“The real strength of this thing is that it is more potent than any antibody,” Prof Farzan said.

However, there are safety questions.

After conventional vaccination, the immune system responds only after it is presented with a threat.

The gene therapy approach turns cells into factories that constantly spew out the artificial HIV-killers, and the long-term implications of that are unknown.

‘Important step’

The team want to begin trials in patients who have HIV but are unable to take conventional drug therapies within the next year.

Prof Nancy Haigwood, of Oregon Health & Science University, commented: “In the absence of a vaccine that can elicit broadly protective immunity and prevent infection, and given the lack of major breakthroughs on the horizon to provide one, the idea of conferring potent, sustained vaccine-like protection against HIV infection through gene therapy is certainly worth strong consideration.”

Dr Anthony Fauci, of the US National Institutes of Health, said: “It would be advantageous to curb HIV infection without daily antiretroviral drugs because of their cost, the potential for negative side-effects from lifelong therapy, and the difficulties some patients have adhering to daily drug regimens and tolerating certain drugs.

“This innovative research marks an important step toward our goal of putting HIV into sustained remission in chronically infected people.”

via BBC

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‘Good virus’ believed to help increase survival chances in Ebola and HIV infections

All viruses may not be harmful, says a study hinting at beneficial effect of some.

All viruses may not be harmful, says a study hinting at beneficial effect of some.

A common virus that infects billions at some point of their lives is believed to deliver some protection against other deadlier viruses like HIV and Ebola.

David O’Connor, a pathology professor at the University of Wisconsin in Madison, found the genetic fingerprints of the virus GBV-C in the records of 13 samples of blood plasma from Ebola patients.

While six of the 13 people who were co-infected with Ebola and GBV-C died, seven survived.

Combined with earlier studies that have hinted persistent infection with the virus slowed disease progression in some HIV patients, researchers think the virus could be beneficial.

The results could also simply mean that people aged 20 to 40 are more likely to be infected with GBV-C and more likely to survive Ebola.

“We’re very cautious about over-interpreting these results,” O’Connor told NPR. He is now waiting to get a bigger sample, to see if there really is a strong connection between GBV-C infection and survival.

The GB Virus-C came from a small monkey — a marmoset — that had been used in an experiment to diagnose a surgeon with hepatitis.

The virus infects a type of white blood cell and dampens part of the immune system. With HIV, the virus helps reduce inflammation, and that in turn helps slow the onset of Aids.

Cancer link

Similarly, it might also reduce inflammation in some people fighting off an Ebola infection.
However, the virus is not entirely harmless.

A National Institutes of Health study last year suggests a cancer link to the virus. People with a cancer of the lymphatic system, non-Hodgkin lymphoma, were seen to be more likely to be infected with GBV-C.

HIV mostly targets CD4 T lymphocytes, a cell involved in initiating an immune response. The virus hijacks the cell’s reproductive process to produce more copies of itself which infect and kill other cells.

Filoviruses like Ebola get all their genetic material from RNA, instead of DNA and most of the genetic information stored in the RNA codes for a handful of proteins as compared to about 20,000 in humans.

One of these proteins, glycoprotein, is suspected to play a big role in Ebola. A version of this protein is believed to bind to host cells, enter and replicate inside while another version is suspected to work by suppressing the immune system.

There is still much not known about the working of these two deadly viruses, which have also seen to mutate rapidly and deter drug treatments.

via IBM Times

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Human Genome Tinkering Could Be Our Best Bet to Beat HIV

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The human immunodeficiency virus (HIV) is a crafty little beast, constantly mutating to mask itself from our body’s defenses, but always entering cells through the same molecular door. The design of that cellular door is governed by our DNA, so why not change the lock by modding our genetic code?

In 2006, a minor medical miracle occurred. HIV-positive leukemia patient Timothy Ray Brown—the second Berlin Patient—received a bone marrow transplant that saved his life in more ways than one. The marrow that he received was from a donor with a unique double mutation to a gene on the 3rd chromosome known as CCR5. This gene codes for the surface protein that the HIV virus uses to gain entry into our white blood cells (specifically, CD4+ T-cells); however the double mutation shuts down these sites and provides a natural immunity to HIV. This mutation is exceptionally rare, only occurring in about one percent of Caucasians and nowhere else. It’s been hypothesized that it’s this same natural immunity that allowed a small portion of Europeans to make it through the Black Plague unscathed.

While that was fantastic news for Brown, who nearly a decade later remains off of his retroviral drug regimen and maintains an undetectable level of the virus in his system, it’s not of much use to the rest of us. With both the mutation prevalence and bone marrow compatibility matches in general being so rare, there was no effective means of using transplants as delivery vectors for this beneficial genetic condition. And it’s worth noting that the very process of becoming HIV-free nearly killed Brown. But that’s where Professor Yuet Kan’s team at UCSF comes in.

Kan figured that if integrating this double mutation wouldn’t work on the macro level—that is, replacing a patient’s bone marrow with that of a naturally HIV-immune person’s—maybe it would at the molecular level, thereby allowing researchers to confer the benefits while cutting out the marrow donation. To that end, he and a team of researchers from the University of San Francisco are employing cutting-edge genetic editing techniques to snip out the beneficial length of DNA coding and integrate it with a patient’s own genome.

The technique they’re using is known as CRISPR (Cas9) genome-editing. CRISPRs, (clustered regularly interspaced short palindromic repeats) are DNA delivery vectors that replace the existing base codes at a specific part of a specific chromosome with new base pair sets. Cas9, on the other hand are the “molecular scissors” that Kan’s team employs to first cut out the offending DNA. It sounds easy, sure—just find the string of DNA you want to replace, then snip it out with Cas9 DNA scissors, and install some new DNA using a CRISPR—however the nuts and bolts of the process are far more technically challenging.

The patient’s own blood cells would be employed as a precursor. Researchers would then have to convert those cells into induced pluripotent stem (iPS) cells by modulating a number of genetic switches, thereby instigating their regression to more basic stem cells. After that, the offending CCR5 gene would need to be knocked out and replaced with the better, double-mutated version before the now fortified blood cells were transfused back into the patient. Not only is there no chance of the body rejecting the new cells (they are the patient’s own after all), the technique also neatly sidesteps the whole embryonic stem cell issue.

While the technique is still in its early stages of development and no human trial dates have yet been set, it holds huge promise. Not just for the 35 million people annually infected by HIV, but also sufferers of sickle cell anemia and cystic fibrosis—two deadly diseases caused by a single protein deformation—could benefit from similar techniques. By figuring out which genes do what on our iPS cells, we could even theoretically grant everyone on Earth immediate immunity to any number of diseases.

Of course, being able to update and augment our genetic code opens up a whole slew of potential concerns, objections, and abuses. Just look at the ire raised over the use of embryonic stem cells in the early 2000s. People were lost their minds because they thought scientific progress was being built on the backs of fetuses. Researchers had to go and invent an entirely new way of making stem cells (the iPS lines) just to get around that one moralized sticking point, so you can bet there will be plenty of chimera, master race, and Island of Dr. Moreaureferences bandied about should we ever begin seriously discussing the prospect of upgrading our genes. And could certainly slow progress in this specific research.

That’s not to say that the hysteria that accompanies seemingly every news cycle these days is completely off base. Like cars, styrofoam, pressure cookers, and thermonuclear bombs, this technology can be used for evil just as easily as it can be for good. And while we’re not nearly as genetically complex as, say, an ear of corn, wrangling the myriad of interactions between our various genes is still an incredibly complex task and one with severe consequences should something go awry—even if we can avoid creating unwanted mutations through stringent testing and development methodology as we do with today’s pharmaceutical development. So why not turn ourselves into the ultimate GMOs? It certainly beats everyone becoming cyborgs.

Article via Gizmodo

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Another Major HIV Breakthrough

ProfLewin

Yesterday, the world was taken by storm when it was announced that a baby, born with HIV had been cured.  On the same day, it was announced a team from The Alfred hospital have uncovered HIV’s genetic hiding place and found a drug able to wake it up so that it can be destroyed.

The Alfred’s director of infectious diseases, Prof Sharon Lewin, said waking up HIV with doses of a highly toxic cancer drug was a huge step in curing a disease that has already claimed an estimated 30 million lives.

“What we thought would happen happened: the virus woke up, and we could measure it,” Prof Lewin said. “That is a big step.

“There are more possibilities of getting rid of it by making it visible to drugs and visible to the immune system (and) that we now know we can do.  Now the big challenge is working out, once it is visible, what are the ways to get rid of that infected cell.”

Traditional antiviral medications have been able to stop the virus infecting cells, giving patients a greater life expectancy.

But the virus remained “sleeping” in their DNA, unable to be found or treated, so patients had to take expensive medication daily to suppress its effects.

“It jumps in, buries itself into the DNA and sits there lurking. At any time, if the cell becomes active, the virus then becomes active,” Prof Lewin said.

“It is like having the embers of a fire sitting there . . . the minute you take away the anti-HIV drugs, the embers relight the fire and the whole thing gets going again.”

But by using cancer drug, Vorinostat, for two weeks, Prof Lewin had been able to turn on sleeping HIV-infected cells so they could be detected.

Researchers at The Alfred were able to bring the virus to notice in 18 of 20 HIV patients in a trial that concluded in January.

Prof Lewin hopes a new generation of drugs able to kick-start the immune system may now be able to kill the virus.

Prof Lewin and her team — which included collaboration with Monash University, the Burnet Institute, the Peter MacCallum Cancer Centre and the National Association of People Living with HIV/AIDS — will soon publish their full results.

For David Menadue, who has lived with HIV for almost 30 years, the results bring a new hope.

“Just having the existence of HIV in your body does do damage to your body every day. It puts pressure on your organs, your heart, your kidney, your liver.

“People with HIV would just love to get rid of this and go back to a normalised life. We are never really going to be able to get on top of the virus in developing countries without some sort of magical cure.”

Original Article via Herald Sun

Channel 4 news interviewed Professor Lewin yesterday, click here to see. (Sorry, we can’t embed this video)

Professor Lewin’s news isn’t new, she spoke about this at the 2012 CROI (Conference on Retroviruses and Opportunistic Infections)  – He she speaks with Matt Sharp about HIV Latency and Eradication using Vorinostat.

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Researchers Work on Developing New HIV Vaccines

lymphocyte with HIV cluster

Scanning electron microscope image of a lymphocyte with HIV cluster. (Image: National Cancer Institute)

With the recent launch of MIT’s Institute for Medical Engineering and Science, MIT News examines research with the potential to reshape medicine and health care through new scientific knowledge, novel treatments and products, better management of medical data, and improvements in health-care delivery.

Studying infectious diseases has long been primarily the domain of biologists. However, as part of the Ragon Institute, MIT engineers and physical scientists are joining immunologists and physicians in the battle against HIV, which currently infects 34 million people worldwide.

The mission of the Ragon Institute — launched jointly in 2009 by Massachusetts General Hospital (MGH), MIT and Harvard University — is to develop new HIV vaccines through better understanding of how the immune system responds to infection. Bruce Walker, the MGH physician who directs the institute, says it was important to enlist engineers and physical scientists, who have usually been excluded from traditional HIV research, to help in this effort.

“It seemed to me that if we could break down some of those silos, there were probably tools in the toolbox that could be applied to the problem right now that weren’t being applied,” Walker says. “MIT has brought a lot to the table — not only expertise, but also a different way of thinking about approaching problems.”

The Ragon Institute also encourages its researchers to develop new technology and pursue ideas that might not be funded through traditional channels. These include new materials for vaccine delivery and new technology for studying the virus’s interactions with the immune system.

“It has encouraged people, like the engineers here, to start working in areas that they wouldn’t have worked in otherwise,” says Christopher Love, an MIT associate professor of chemical engineering and an associate member of the Ragon Institute. “That kind of momentum can sometimes be hard to establish. The Ragon has been a catalyst for new research innovations and a very effective one at that.”

Single-cell analysis

Love is now helping in the search for a new vaccine using technology he developed to study immune responses of individual cells. His system allows thousands of immune cells to be studied at once: The cells are placed into tiny wells on a plate, and secretions from each cell are imprinted on a glass slide placed over the wells. The slide is then tested for the presence of specific proteins such as cytokines, which provoke inflammation.

Because each cell has its own “address” on the slide, the secretions can be traced back to individual cells. This technology generates a huge amount of data for each cell under study. “You can now make measurements on 10,000 cells and generate 20 to 30 parameters of data on each cell that’s present in that sample. That kind of data density hasn’t really been feasible previously,” says Love, who is a member of MIT’s David H. Koch Institute for Integrative Cancer Research.

Love first used the system to study immune-cell responses to food allergens and infectious agents, and began using it to study HIV responses after becoming part of the Ragon Institute in 2009.

In a study published in 2011, Love and his colleagues analyzed the cytokines secreted by T cells from HIV-infected patients, as well as the cells’ ability to kill HIV-infected cells. Previous studies had suggested that high levels of a cytokine called interferon gamma might correlate with cell-killing ability, but the MIT team found that while the percentage of T cells that secrete interferon gamma is similar to the percentage of those that kill infected cells, the populations do not entirely overlap.

Love is now searching for biomarkers that do reveal which T cells are most effective at killing HIV-infected cells. He also hopes to scale up the device so it could be used to rapidly monitor the immune responses of participants in vaccine trials.

New vaccine targets

Arup Chakraborty, director of the Institute for Medical Engineering and Science (IMES) and a professor of chemical engineering, chemistry, physics, and biological engineering at MIT, who uses computational models to study the immune system, had never studied HIV until meeting Walker in 2008. He is now using his computational approaches to seek better HIV vaccine targets.

So far, the virus has proven very difficult to target because it mutates so rapidly. In recent years, scientists have tried targeting amino acids in HIV proteins where mutations appear to weaken the virus. However, this approach has had limited success because compensatory mutations elsewhere in the viral protein can overcome the harmful effects of the vaccine-induced mutation.

To overcome this, Chakraborty’s lab identified groups of amino acids in HIV proteins that evolve independently of those in other groups. In a subset of these groups, computer models predicted the virus to be vulnerable to multiple simultaneous mutations. By targeting amino acids in such groups, vaccine designers may be able to cut off the virus’s escape route.

In 2011, Chakraborty and Walker showed that a particularly vulnerable group exists in a subunit of the Gag protein, which forms the envelope that surrounds the virus’s genetic material. They also found that T cells in patients who can fight off HIV on their own disproportionately target the amino acids identified in the study. HIV strains with multiple mutations in these amino acids are rare, offering further evidence that these could make good vaccine targets.

Special delivery

Darrell Irvine, an MIT professor of materials science and engineering and member of the Koch Institute, is working on alternative ways to deliver vaccines. Most vaccines used to protect against diseases such as chicken pox and influenza are made from deactivated forms of the virus. That approach is thought too risky for HIV, so many researchers are instead pursuing vaccines made from protein or sugar molecules that the virus produces, known as antigens. Another possible approach is injecting DNA that codes for viral proteins.

However, injecting those molecules on their own doesn’t always produce a strong-enough immune response in the vaccine recipient, so Irvine and his lab are seeking ways to elicit stronger responses, using two strategies: delivering antigen along with another type of molecule, known as an adjuvant, that helps to provoke the immune system, and delivering the antigen directly to the target cells, using nanoparticles or polymer films.

Recently, Irvine and his colleagues developed a new polymer film that can deliver DNA vaccines under the skin. DNA vaccines were first tested about 20 years ago, and found to elicit strong immune responses in rodents. However, DNA vaccines have thus far failed to provoke any protective response in human clinical trials.

With the new polymer film developed by Irvine and his colleagues, DNA vaccines are embedded in layers of polymer films that gradually degrade, releasing the vaccine over days or weeks. The film also includes an adjuvant consisting of a strand of RNA similar to viral RNA. This molecule provokes inflammation in the target tissue, which helps to recruit immune cells to the area, so they can encounter the antigen encoded by the DNA.

The vaccine-delivering film showed success in tests of mice, and the researchers now hope to test it in nonhuman primates.

Much of this work would probably never have happened without both funding from the Ragon Institute and the interdisciplinary collaborations that have arisen because of the institute.

“It’s been absolutely fantastic for me and many of the MIT faculty that have been involved,” Irvine says. “There are really two paths being followed at all times: a very focused mission to try and get an HIV vaccine developed, but also an interest in making sure that we don’t miss new opportunities in the basic science that might bring totally new vaccine concepts forward.”

via mit.edu

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