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Bone Marrow Transplant Cures Two Men of HIV
Two patients have been taken off their HIV drugs after bone-marrow transplants seemed to clear the virus from their bodies, doctors report.
One of the patients has spent nearly four months without taking medication with no sign of the virus returning.
The team at Brigham and Women's Hospital, in the US, caution that it is far too soon to talk about a cure as the virus could return at any point. The findings were presented at the International Aids Society Conference.
It is difficult to get rid of an HIV infection because it hides inside human DNA, forming untouchable "reservoirs" in body. Anti-retroviral drugs keep the virus in check within the bloodstream - but when the drugs stop, the virus comes back.
The two men, who have not been identified, had lived with HIV for about 30 years. They both developed a cancer, lymphoma, which required a bone-marrow transplant.
Bone marrow is where new blood cells are made and it is thought to be a major reservoir for HIV. After the transplant, there was no detectable HIV in the blood for two years in one patient and four in the other.
It is far too early to call this a cure for HIV. And even if it was a cure, it wouldn't be a very good one.
It is very expensive and often leads to "graft-v-host" disease. There is a 15-20% mortality rate within the first few years after the transplant.
This occurs when new immune cells produced by the graft treat the rest of the body as foreign and attack it.
The two patients in this study have replaced their regimen of anti-retroviral drugs, with those to suppress the immune system.
The procedure was carried out in these patients only because they had cancer that needed to be treated. The real value of this research for the majority of people with HIV will come from a deeper understanding of the virus and HIV reservoirs. The pair came off their anti-retroviral drugs earlier this year.
One has gone 15 weeks, and the other seven, since stopping treatment, and no signs of the virus have been detected so far.
Dr Timothy Henrich told the BBC the results were exciting. But he added: "We have not demonstrated cure, we're going to need longer follow-up.
"What we can say is if the virus does stay away for a year or even two years after we stopped the treatment, that the chances of the virus rebounding are going to be extremely low. "It's much too early at this point to use the C-word [cure]."
It is thought that the transplanted bone marrow was initially protected from infection by the course of anti-retrovirals. Meanwhile the transplant also attacked the remaining bone marrow, which was harbouring the virus.
However Dr Henrich cautioned that the virus could be still be hiding inside brain tissue or the gastrointestinal track.
"If the virus does return, it would suggest that these other sites are an important reservoir of infectious virus and new approaches to measuring the reservoir at relevant sites will be needed to guide the development of HIV curative strategies," he said.
The two US cases both received bone marrow from normal donors. There was also a report of an HIV cure in a baby born in Mississippi, US. She was treated with anti-retroviral drugs at birth so it is thought the virus was cleared from the body before reservoirs were established.
Dr Michael Brady, the medical director of the Terrence Higgins Trust, said: "It is too early to know whether HIV has been eradicated from these men's bodies or whether it might return.
Doctors say it is far too soon to talk about a cure for HIV, as James Gallagher reports "However, the case suggests that what happened to Timothy Brown, the Berlin Patient was perhaps not a one-off.
"A bone marrow transplant is a complex and expensive procedure, which comes with significant risks. "For most people with HIV, it would be more dangerous to undergo a transplant than to continue managing the virus with daily medication.
"So while this is by no means a workable cure, it does give researchers another signpost in the direction of one."
The head of the Foundation for AIDS Research, Kevin Frost, said: "These findings clearly provide important new information that might well alter the current thinking about HIV and gene therapy.
"While stem-cell transplantation is not a viable option for people with HIV on a broad scale because of its costs and complexity, these new cases could lead us to new approaches to treating, and ultimately even eradicating, HIV."
HIV Exploits a Human Cytokine in Semen to Promote Its Own Transmission
A new report suggests that the concentration of one human cytokine, interleukin 7 (IL-7), in the semen of HIV-1-infected men may be a key determinant of the efficiency of HIV-1 transmission to an uninfected female partner. In their study published February 7 in the Open Access journal PLOS Pathogens, a research group from the Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD) led by Leonid Margolis report that the increased IL-7 concentration in semen facilitates HIV transmission to cervical tissue ex vivo.
Semen is a complex biological fluid containing not only spermatozoa but also cytokines, a group of extracellular proteins that modulate immune responses. As a result of HIV infection, the concentrations of various cytokines in semen is profoundly modified, in particular the concentration of interleukin 7 (IL-7) is greatly increased. Despite this evidence of strikingly elevated IL-7 levels in seminal plasma, there was limited knowledge about any effects this cytokine might have on HIV-1 sexual transmission.
To investigate the question about the effects of this increased IL-17 on HIV-1 sexual transmission, Andrea Introini and colleagues from the Margolis lab developed a system of explants of cervico-vaginal tissue that can be maintained outside of the body in culture for up to two weeks while preserving the cytoarchitecture of the tissue. In this system, HIV transmission can be simulated and studied under controlled laboratory conditions. When researchers added IL-7 in concentrations comparable to that found in the semen of HIV-1 infected men, HIV was transmitted more efficiently and replicated to a higher level than without IL-7. Normally, HIV-1-infected cells quickly die as the result of apoptosis, a programmed death triggered by HIV infection. IL-7 inhibits apoptosis of infected cells, allowing them to produce more virus and thus increasing the chances of the incoming virus to disseminate through the tissue. Also, IL-7 stimulates T cell proliferation, thereby also providing to HIV even more potential targets to infect.
The authors speculate that IL-7, together with other cytokines, may determine sexual transmission rates of HIV-1 and that changes in the seminal cytokine load may explain differences in HIV transmission from different individuals. However, whether the effect of IL-7 that has been demonstrated ex vivo occurs also for sexual partners in vivo, is a subject for future research. If this increase does occur in vivo, then it should be investigated whether HIV-1 infected individuals that have been treated systemically with IL-7 in order to increase their T cell counts may have also resulted in the unintended increase of their seminal IL-7 levels. Finally, this study suggests that seminal cytokines may become new targets for HIV-preventive strategies.
Stem-cell transplants may purge HIV
Two men with HIV may have been cured after they received stem-cell transplants to treat the blood cancer lymphoma, their doctors announced today at the International AIDS Society Conference in Kuala Lumpur.
One of the men received stem-cell transplants to replace his blood-cell-producing bone marrow about three years ago, and the other five years ago. Their regimens were similar to one used on Timothy Ray Brown, the 'Berlin patient' who has been living HIV-free for six years and is the only adult to have been declared cured of HIV. Last July, doctors announced that the two men — the ‘Boston patients’ — appeared to be living without detectable levels of HIV in their blood, but they were still taking antiretroviral medications at that time.
Timothy Henrich, an HIV specialist at Brigham and Women’s Hospital in Boston, Massachusetts, who helped to treat the men, says that they have now stopped their antiretroviral treatments with no ill effects. One has been off medication for 15 weeks and the other for seven. Neither has any trace of HIV DNA or RNA in his blood, Henrich says.
If the men stay healthy, they would be the third and fourth patients ever to be cured of HIV, after Brown and a baby in Mississippi who received antiretroviral therapy soon after birth.
But Henrich and Daniel Kuritzkes, a colleague at Brigham who also worked with the men, caution that it is still too early know whether or not the Boston patients have been cured. For that, doctors will need to follow the men closely for at least a year, because the virus may be hiding out in 'reservoirs' — parts of the men’s bodies, such as their brain or gut, that can harbour the virus for decades.
“We’re being very careful not to say that these patients are cured,” Kuritzkes says. “But the findings to date are very encouraging.”
HIV researcher Steven Deeks of the University of California, San Francisco, says that doctors might need to wait at least two years before declaring that a cure has been achieved. “Any evidence that we might be able to cure HIV infection remains a major advance,” Deeks says. But, he adds, “there have been cases of patients who took many weeks off therapy before the virus took off”.
Exciting news
Still, researchers and doctors are excited about the news, especially because the Boston patients’ treatment differed from the Berlin patient’s regimen in one key way. Brown was given stem cells that were predisposed to resist HIV infection, because the donor happened to have a mutated version of a key protein — CCR5 — that is needed for HIV to infect cells. So Brown’s transplant was akin to gene therapy with HIV-resistant cells.
But the Boston patients received stem cells without the protective mutation. The transplanted cells must therefore have been protected from infection by the antiretroviral drugs taken during cancer treatment. Their doctors think that an immune response called graft-versus-host disease — a post-transplant reaction in which donated cells kill off a patient’s own cells — may have then wiped out the patients’ HIV reservoirs, potentially curing the men.
Transplant specialist Christine Durand of Johns Hopkins University School of Medicine in Baltimore, Maryland, says that the case of the Boston patients may show that current antiretroviral drugs are powerful enough, on their own, to protect the transplanted cells. “If cure has been achieved in the Boston patients, then it was the antiretroviral therapy, not gene therapy, that protected the donor cells,” she says.
The finding is very important for people with HIV who also need blood-cell transplants, but the treatment is unlikely to be used more generally because the risks from transplants are high. Durand says that Johns Hopkins is now revising its transplant procedures to keep people with both cancer and HIV on antiretroviral drugs during the transplant regimen.
Separately, the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group, based in Silver Spring, Maryland, is trying to replicate the Berlin patient’s cure by giving CCR5-mutated HIV-resistant blood from umbilical cords to children and adults with HIV and cancer.
Everyone with HIV could benefit from this work, researchers say, because it could yield valuable information about how to eliminate the HIV reservoir.
“We are still a long way off from a viable cure option for most patients,” Durand says. “But every step counts, and these cases can teach us important lessons.”
New Way to Induce Programmed Cell Death, or Apoptosis
Researchers from the Hebrew University of Jerusalem and the Weizmann Institute of Science have developed a technique to cause apoptosis, or programmed cell death, that could lead to new approaches to treating cancer.
Apoptosis is an essential defense mechanism against the spread of abnormal cells such as cancer. It is a complex process that occurs through networks of proteins that interact with each other. Cancer cells usually avoid this process due to mutations in the genes that encode the relevant proteins. The result is that the cancer cells survive and take over while healthy cells die.
The research, by graduate student Chen Hener-Katz at the Hebrew University, involved collaboration between Prof. Assaf Friedler of the Hebrew University's Institute of Chemistry and Prof. Atan Gross of the Weizmann Institute's Department of Biological Regulation. It was published in the Journal of Biological Chemistry under the title ''Molecular Basis of the Interaction between Proapoptotic Truncated BID (tBID) Protein and Mitochondrial Carrier Homologue 2 (MTCH2) Protein.''
The study examined the interaction between two important proteins involved in cell death: mitochondrial carrier homologue 2 (MTCH2), which was discovered in the lab of Prof. Gross, and truncated BID (tBID), which are both involved in the apoptotic process. The researchers found the regions in the two proteins that are responsible for binding to each other, a critical step in initiating apoptosis. Following their discovery, the researchers developed short synthetic protein fragments, or peptides, that mimicked the areas on the proteins that bind to each other, and by doing so inhibited this binding. In lab experiments conducted on cell cultures, this resulted in the death of cancer cells of human origin.
''These protein segments could be the basis of future anti-cancer therapies in cases where the mechanism of natural cell death is not working properly,'' said Prof. Friedler. ''We have just begun to uncover the hidden potential in the interaction between these proteins. This is an important potential target for the development of anticancer drugs that will stimulate apoptosis by interfering with its regulation. ''
Prof. Friedler is the head of the school of chemistry at the Hebrew University. His major research interests are using peptides to study protein-protein interactions in health and disease, and developing peptides as drug leads that modulate these interactions, specifically in relation to HIV and cancer. Prof. Friedler won the prestigious starting grant from the ERC (European Research Council) as well as the outstanding young scientist prize by the Israeli Chemical Society. His research was supported by a grant from the Israel Ministry of Health and by a starting grant from the European Research Council.
Genetically Modified Tobacco Plants Produce Antibodies to Treat Rabies
Smoking tobacco might be bad for your health, but a genetically altered version of the plant might provide a relatively inexpensive cure for the deadly rabies virus. In a new research report appearing in The FASEB Journal, scientists produced a monoclonal antibody in transgenic tobacco plants that was shown to neutralize the rabies virus. This new antibody works by preventing the virus from attaching to nerve endings around the bite site and keeps the virus from traveling to the brain.
"Rabies continues to kill many thousands of people throughout the developing world every year and can also affect international travelers," said Leonard Both, M.Sc., a researcher involved in the work from the Hotung Molecular Immunology Unit at St. George's, University of London, in the United Kingdom. "An untreated rabies infection is nearly 100 percent fatal and is usually seen as a death sentence. Producing an inexpensive antibody in transgenic plants opens the prospect of adequate rabies prevention for low-income families in developing countries."
To make this advance, Both and colleagues "humanized" the sequences for the antibody so people could tolerate it. Then, the antibody was produced using transgenic tobacco plants as an inexpensive production platform. The antibody was purified from the plant leaves and characterized with regards to its protein and sugar composition. The antibody was also shown to be active in neutralizing a broad panel of rabies viruses, and the exact antibody docking site on the viral envelope was identified using certain chimeric rabies viruses.
"Although treatable by antibodies if caught in time, rabies is bad news," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "This is especially true for people in the developing world where manufacturing costs lead to treatment shortages. Being able to grow safe, humanized antibodies in genetically modified tobacco should reduce costs to make treatments more accessible, and save more lives."
AccuTarget™ Custom Designed siRNA Synthesis
Gene silencing by RNA interference (RNAi) technology using small interfering RNA (siRNA) is a powerful tool for studying functional genomics, drug target identification and validation, pathway elucidation, and therapeutic development. The advantage is in the algorithm we use for siRNA design. Our Turbo si-Designer software identifies highly effective siRNA target sites with remarkably high siRNA knockdown rates. Critical parameters including base composition, thermodynamic instability and base preference are all considered in the design algorithm. siRNAs spanning SNP sites are removed and finally, non-specific siRNAs are eliminated following homology searching by BLAST and Smith-Waterman algorithms. The result is an siRNA with extraordinary siRNA knockdown efficiency and minimal off-target effects. The performance of Turbo si-Designer has been extensively evaluated by testing the siRNA knockdown efficiency of thousands of siRNAs targeting STE Kinases, TK Kinases, genes involved in the NF-kappaB and Caspase Pathways using Real-time PCR analysis. The results of the evaluation indicated the design algorithm was highly effective in selecting effective siRNAs; 80% of the tested siRNAs showed > 70% knockdown and 38% elicited knockdown of > 90%.
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AccuTarget Control siRNAs
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See the first ultra-high resolution, 3D scan of the entire human brain
An international research team has produced the first-ever ultra-high resolution 3D digital reconstruction of a complete human brain. At the astonishingly low resolution of 20-microns, the new scans are providing an unprecedented glimpse into the inner workings of the mind.
And remarkably, it could also be seen as a precursor to brain preservation and mind uploading. But more on that in just a bit. First, the breakthrough.
It’s called BigBrain, and it’s a part of the $1.6 billion European Human Brain Project that's seeking to simulate the human brain on a supercomputer. Over the course of the next ten years, HBP researchers will work to understand and map the network of over a hundred billion neuronal connections that elicit emotions, volitional thought, and even consciousness itself. And to do so, the researchers will be using a progressively scaled-up multilayered simulation running on a supercomputer.
But to get there, the researchers are going to have to peer deep inside the human brain. Hence the BigBrain project.
The Map is Not the Territory
There is a risk, however, of overstating the importance of this breakthrough.
As it has often been said, anatomy is not explanation. Just because we have a remarkably fine map of the human brain doesn’t mean that we’ll be able to understand it. No doubt, it will certainly help. But neuroscientists will still need to confer with cognitive scientists and other specialists if we ever hope to gain a full understanding of the human mind.
The researchers are also unduly optimistic when it comes to their timelines. They plan to simulate the entire human brain — from the molecular level to the interaction of entire brain regions — on a supercomputer in ten years. I think that’s highly unlikely. But they are on the right track by developing these sorts of techniques.
Genes Get in Your Eye
Using mouse eyes as a setting for directed evolution, scientists have created a new version of the gene therapy vector adeno-associated virus (AAV) that can deliver genes deep into the retina, according to a paper published online today (June 12) in Science Translational Medicine. Such a vector could improve therapeutic gene delivery to target cells and lead to safer and less invasive gene therapy treatments.
“This is a beautifully planned, executed, and powerfully presented paper,” said Jean Bennett, a professor of ophthalmology at the University of Pennsylvania in Philadelphia, who was not involved in the study. “It shows the results of a very clever system to evolve AAV to target cells in the retina efficiently from an intravitreal injection.”
Intravitreal injection, whereby a needle is pushed into the eye’s vitreous, or gel-like core, is a common drug delivery procedure performed under local anesthetic in a doctor’s office, explained Bennett. But using this routine injection technique in trials of gene therapy for retinal degeneration has thus far proven impossible.
The problem, explained David Schaffer, a professor of chemical and biomolecular engineering, bioengineering, and neuroscience at the University of California, Berkeley, who led the research, is that current AAV vectors are incapable of penetrating deep into the retina where the target cells for retinal diseases are located. “AAV is a respiratory virus and so it evolved to infect lung epithelial cells,” explained Schaffer. “It never evolved to penetrate deep into tissue.”
Patients receiving gene therapy have therefore undergone a direct intraretinal injection, which requires hospitalization and general anesthetic, and can sometimes even damage the retina. If it were possible to inject AAV into the vitreous instead of the retina and still get gene delivery to the target cells, said Bennett, “one could envision the [doctor saying], ‘Ok, well just come into the office and get your gene therapy, tomorrow afternoon at two.’”
With that aim, Schaffer and colleagues evolved AAV to be better at tissue penetration. They injected regular AAV into the vitreous of mouse eyes and one week later collected photoreceptor cells from deep within the retina. The tiny percentage of AAV vectors that made it into those cells were then amplified, repackaged into virus particles and injected into the vitreous again. They repeated the injection, recovery, and amplification a total of six times, finally isolating 48 AAV variants for sequencing. Two thirds of those isolates turned out to the same variant, and Schaffer and colleagues named it 7m8.
The team then performed intravitreal injection of the 7m8 AAV vector to deliver missing genes into two mouse models of retinal degeneration—retinoschisis and Leber’s congenital amaurosis. In both models, the treated mice showed improved retinal function. Mice receiving their missing genes via intravitreal injection of the standard AAV vector, on the other hand, did not.
Lastly, to determine whether the 7m8 vector would be likely to show similar deep penetration in the human retina, Schaffer injected the vector fused to a fluorescent protein into the vitreous of macaque eyes. Primate retinas are considerably thicker than those of mice, and the vector did not consistently reach the deep cell layers—showing a spotty penetration pattern rather than the wide and even pan-retinal penetration that had been seen in the mice. However, 7m8 did effectively target photoreceptor cells of the fovea—a thinner part of the primate retina that is essential for the sharp detailed vision humans use when reading and driving. “That’s a really important region to protect,” said Schaffer. “For the quality of life of patients who are going blind, if you can at least protect the fovea that would be a huge improvement.”
Schaffer and colleagues don’t yet know what makes the 7m8 vector so much better at tissue penetration than its AAV ancestor, but they plan to find out and use that knowledge to further improve its penetration in the primate retina.
They also plan to use similar directed evolution strategies to improve vector penetration into other body tissues “What this paper illustrates is the ability of purpose-directed vector evolution to achieve a specific anatomic transduction goal,” said Kathy High, a University of Pennsylvania professor of pediatrics who was not involved in the study. “And that’s an important development not just for ocular applications but for others like the liver or central nervous system.”
Vaccine against smoking?!
Nicotine degradation before reaching the heart and brain, innovative vaccine greatly reduces dependence on nicotine products, taking away the pleasant effects of their use.
Smoking is a difficult habit to quit. It has been shown that the pharmacological and behavioral aspects of this, there is still a form of legal drugs, are similar to those of addiction to cocaine and heroin. But if you did not initially develop an addiction?
Researchers from the Medical College of Cornell University, New York, have developed a drug that inhibits the effects of nicotine intoxication. Although it is only 0.6 to 3% by dry weight of most tobacco, nicotine is a very potent drug. Once entered in the blood, it needs 10 to 20 seconds to pass the blood-brain barrier. Despite this his speed, nicotine is powerless before the new detergent. The vaccine stimulates the liver to produce significant quantities of antibodies that destroy the nicotine molecule almost as soon as it enters the bloodstream. So totally disappears relaxing and calming effect of a cigarette.
Similar mechanism therapies have long existed, but have a huge disadvantage - including regular, weekly administration of a cocktail of drugs that have very adverse effects and should be combined with immunosuppressants. The new product is applied only once and ensure sustainable long-term effects. The tool can be used both for prevention in young people at risk who would succumb to the habit, and in heavy smokers, have exhausted all other alternatives to combat addiction.