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  • richardmitnick 3:22 pm on November 18, 2014 Permalink | Reply
    Tags: AIDS, , , ,   

    From NOVA: “Why There’s No HIV Cure Yet” 

    [After the NOVA article, I tell you how you and your family, friends, and colleagues can help to find a cure for AIDS and other diseases]

    PBS NOVA

    NOVA

    27 Aug 2014
    Alison Hill

    Over the past two years, the phrase “HIV cure” has flashed repeatedly across newspaper headlines. In March 2013, doctors from Mississippi reported that the disease had vanished in a toddler who was infected at birth. Four months later, researchers in Boston reported a similar finding in two previously HIV-positive men. All three were no longer required to take any drug treatments. The media heralded the breakthrough, and there was anxious optimism among HIV researchers. Millions of dollars of grant funds were earmarked to bring this work to more patients.

    But in December 2013, the optimism evaporated. HIV had returned in both of the Boston men. Then, just this summer, researchers announced the same grim results for the child from Mississippi. The inevitable questions mounted from the baffled public. Will there ever be a cure for this disease? As a scientist researching HIV/AIDS, I can tell you there’s no straightforward answer. HIV is a notoriously tricky virus, one that’s eluded promising treatments before. But perhaps just as problematic is the word “cure” itself.

    Science has its fair share of trigger words. Biologists prickle at the words “vegetable” and “fruit”—culinary terms which are used without a botanical basis—chemists wrinkle their noses at “chemical free,” and physicists dislike calling “centrifugal” a force—it’s not; it only feels like one. If you ask an HIV researcher about a cure for the disease, you’ll almost certainly be chastised. What makes “cure” such a heated word?

    t
    HIV hijacks the body’s immune system by attacking T cells.

    It all started with a promise. In the early 1980s, doctors and public health officials noticed large clusters of previously healthy people whose immune systems were completely failing. The new condition became known as AIDS, for “acquired immunodeficiency syndrome.” A few years later, in 1984, researchers discovered the cause—the human immunodeficiency virus, now known commonly as HIV. On the day this breakthrough was announced, health officials assured the public that a vaccine to protect against the dreaded infection was only two years away. Yet here we are, 30 years later, and there’s still no vaccine. This turned out to be the first of many overzealous predictions about controlling the HIV epidemic or curing infected patients.

    The progression from HIV infection to AIDS and eventual death occurs in over 99% of untreated cases—making it more deadly than Ebola or the plague. Despite being identified only a few decades ago, AIDS has already killed 25 million people and currently infects another 35 million, and the World Health Organization lists it as the sixth leading cause of death worldwide.

    HIV disrupts the body’s natural disease-fighting mechanisms, which makes it particularly deadly and complicates efforts to develop a vaccine against it. Like all viruses, HIV gets inside individual cells in the body and highjacks their machinery to make thousands of copies of itself. HIV replication is especially hard for the body to control because the white blood cells it infects, and eventually kills, are a critical part of the immune system. Additionally, when HIV copies its genes, it does so sloppily. This causes it to quickly mutate into many different strains. As a result, the virus easily outwits the body’s immune defenses, eventually throwing the immune system into disarray. That gives other obscure or otherwise innocuous infections a chance to flourish in the body—a defining feature of AIDS.

    Early Hope

    In 1987, the FDA approved AZT as the first drug to treat HIV. With only two years between when the drug was identified in the lab and when it was available for doctors to prescribe, it was—and remains—the fastest approval process in the history of the FDA. AZT was widely heralded as a breakthrough. But as the movie The Dallas Buyer’s Club poignantly retells, AZT was not the miracle drug many hoped. Early prescriptions often elicited toxic side-effects and only offered a temporary benefit, as the virus quickly mutated to become resistant to the treatment. (Today, the toxicity problems have been significantly reduced, thanks to lower doses.) AZT remains a shining example of scientific bravura and is still an important tool to slow the infection, but it is far from the cure the world had hoped for.

    In three decades, over 25 highly-potent drugs have been developed and FDA-approved to treat HIV.

    Then, in the mid-1990s, some mathematicians began probing the data. Together with HIV scientists, they suggested that by taking three drugs together, we could avoid the problem of drug resistance. The chance that the virus would have enough mutations to allow it to avoid all drugs at once, they calculated, would simply be too low to worry about. When the first clinical trials of these “drug cocktails” began, both mathematical and laboratory researchers watched the levels of virus drop steadily in patients until they were undetectable. They extrapolated this decline downwards and calculated that, after two to three years of treatment, all traces of the virus should be gone from a patient’s body. When that happened, scientists believed, drugs could be withdrawn, and finally, a cure achieved. But when the time came for the first patients to stop their drugs, the virus again seemed to outwit modern medicine. Within a few weeks of the last pill, virus levels in patients’ blood sprang up to pre-treatment levels—and stayed there.

    In the three decades since, over 25 more highly-potent drugs have been developed and FDA-approved to treat HIV. When two to five of them are combined into a drug cocktail, the mixture can shut down the virus’s replication, prevent the onset of AIDS, and return life expectancy to a normal level. However, patients must continue taking these treatments for their entire lives. Though better than the alternative, drug regimens are still inconvenient and expensive, especially for patients living in the developing world.

    Given modern medicine’s success in curing other diseases, what makes HIV different? By definition, an infection is cured if treatment can be stopped without the risk of it resurfacing. When you take a week-long course of antibiotics for strep throat, for example, you can rest assured that the infection is on track to be cleared out of your body. But not with HIV.

    A Bad Memory

    The secret to why HIV is so hard to cure lies in a quirk of the type of cell it infects. Our immune system is designed to store information about infections we have had in the past; this property is called “immunologic memory.” That’s why you’re unlikely to be infected with chickenpox a second time or catch a disease you were vaccinated against. When an infection grows in the body, the white blood cells that are best able to fight it multiply repeatedly, perfecting their infection-fighting properties with each new generation. After the infection is cleared, most of these cells will die off, since they are no longer needed. However, to speed the counter-attack if the same infection returns, some white blood cells will transition to a hibernation state. They don’t do much in this state but can live for an extremely long time, thereby storing the “memory” of past infections. If provoked by a recurrence, these dormant cells will reactivate quickly.

    This near-immortal, sleep-like state allows HIV to persist in white blood cells in a patient’s body for decades. White blood cells infected with HIV will occasionally transition to the dormant state before the virus kills them. In the process, the virus also goes temporarily inactive. By the time drugs are started, a typical infected person contains millions of these cells with this “latent” HIV in them. Drug cocktails can prevent the virus from replicating, but they do nothing to the latent virus. Every day, some of the dormant white blood cells wake up. If drug treatment is halted, the latent virus particles can restart the infection.

    Latent HIV’s near-immortal, sleep-like state allows it to persist in white blood cells in a patient’s body for decades.

    HIV researchers call this huge pool of latent virus the “barrier to a cure.” Everyone’s looking for ways to get rid of it. It’s a daunting task, because although a million HIV-infected cells may seem like a lot, there are around a million times that many dormant white blood cells in the whole body. Finding the ones that contain HIV is a true needle-in-a-haystack problem. All that remains of a latent virus is its DNA, which is extremely tiny compared to the entire human genome inside every cell (about 0.001% of the size).
    Defining a Cure

    Around a decade ago, scientists began to talk amongst themselves about what a hypothetical cure could look like. They settled on two approaches. The first would involve purging the body of latent virus so that if drugs were stopped, there would be nothing left to restart the infection. This was often called a “sterilizing cure.” It would have to be done in a more targeted and less toxic way than previous attempts of the late 1990s, which, because they attempted to “wake up” all of the body’s dormant white blood cells, pushed the immune system into a self-destructive overdrive. The second approach would instead equip the body with the ability to control the virus on its own. In this case, even if treatment was stopped and latent virus reemerged, it would be unable to produce a self-sustaining, high-level infection. This approach was referred to as a “functional cure.”

    The functional cure approach acknowledged that latency alone was not the barrier to a cure for HIV. There are other common viruses that have a long-lived latent state, such as the Epstein-Barr virus that causes infectious mononucleosis (“mono”), but they rarely cause full-blown disease when reactivated. HIV is, of course, different because the immune system in most people is unable to control the infection.

    The first hint that a cure for HIV might be more than a pipe-dream came in 2008 in a fortuitous human experiment later known as the “Berlin patient.” The Berlin patient was an HIV-positive man who had also developed leukemia, a blood cancer to which HIV patients are susceptible. His cancer was advanced, so in a last-ditch effort, doctors completely cleared his bone marrow of all cells, cancerous and healthy. They then transplanted new bone marrow cells from a donor.

    Fortunately for the Berlin patient, doctors were able to find a compatible bone marrow donor who carried a unique HIV-resistance mutation in a gene known as CCR5. They completed the transplant with these cells and waited.

    For the last five years, the Berlin patient has remained off treatment without any sign of infection. Doctors still cannot detect any HIV in his body. While the Berlin patient may be cured, this approach cannot be used for most HIV-infected patients. Bone marrow transplants are extremely risky and expensive, and they would never be conducted in someone who wasn’t terminally ill—especially since current anti-HIV drugs are so good at keeping the infection in check.

    Still, the Berlin patient was an important proof-of-principle case. Most of the latent virus was likely cleared out during the transplant, and even if the virus remained, most strains couldn’t replicate efficiently given the new cells with the CCR5 mutation. The Berlin patient case provides evidence that at least one of the two cure methods (sterilizing or functional), or perhaps a combination of them, is effective.

    Researchers have continued to try to find more practical ways to rid patients of the latent virus in safe and targeted ways. In the past five years, they have identified multiple anti-latency drug candidates in the lab. Many have already begun clinical trials. Each time, people grow optimistic that a cure will be found. But so far, the results have been disappointing. None of the drugs have been able to significantly lower levels of latent virus.

    In the meantime, doctors in Boston have attempted to tease out which of the two cure methods was at work in the Berlin patient. They conducted bone marrow transplants on two HIV-infected men with cancer—but this time, since HIV-resistant donor cells were not available, they just used typical cells. Both patients continued their drug cocktails during and after the transplant in the hopes that the new cells would remain HIV-free. After the transplants, no HIV was detectable, but the real test came when these patients volunteered to stop their drug regimens. When they remained HIV-free a few months later, the results were presented at the International AIDS Society meeting in July 2013. News outlets around the world declared that two more individuals had been cured of HIV.

    Latent virus had likely escaped the detection methods available.

    It quickly became clear that everyone had spoken too soon. Six months later, researchers reported that the virus had suddenly and rapidly returned in both individuals. Latent virus had likely escaped the detection methods available—which are not sensitive enough—and persisted at low, but significant levels. Disappointment was widespread. The findings showed that even very small amounts of latent virus could restart an infection. It also meant meant that the anti-latency drugs in development would need to be extremely potent to give any hope of a cure.

    But there was one more hope—the “Mississippi baby.” A baby was born to an HIV-infected mother who had not received any routine prenatal testing or treatment. Tests revealed high levels of HIV in the baby’s blood, so doctors immediately started the infant on a drug cocktail, to be continued for life.

    The mother and child soon lost touch with their health care providers. When they were relocated a few years later, doctors learned that the mother had stopped giving drugs to the child several months prior. The doctors administered all possible tests to look for signs of the virus, both latent and active, but they didn’t find any evidence. They chose not to re-administer drugs, and a year later, when the virus was still nowhere to be found, they presented the findings to the public. It was once again heralded as a cure.

    Again, it was not to be. Just last month, the child’s doctors announced that the virus had sprung back unexpectedly. It seemed that even starting drugs as soon as infection was detected in the newborn could not prevent the infection from returning over two years later.
    Hope Remains

    Despite our grim track record with the disease, HIV is probably not incurable. Although we don’t have a cure yet, we’ve learned many lessons along the way. Most importantly, we should be extremely careful about using the word “cure,” because for now, we’ll never know if a person is cured until they’re not cured.

    Clearing out latent virus may still be a feasible approach to a cure, but the purge will have to be extremely thorough. We need drugs that can carefully reactivate or remove latent HIV, leaving minimal surviving virus while avoiding the problems that befell earlier tests that reactivated the entire immune system. Scientists have proposed multiple, cutting-edge techniques to engineer “smart” drugs for this purpose, but we don’t yet know how to deliver this type of treatment safely or effectively.

    As a result, most investigations focus on traditional types of drugs. Researchers have developed ways to rapidly scan huge repositories of existing medicines for their ability to target latent HIV. These methods have already identified compounds that were previously used to treat alcoholism, cancer, and epilepsy, and researchers are repurposing them to be tested in HIV-infected patients.
    The less latent virus that remains, the less chance there is that the virus will win the game of chance.

    Mathematicians are also helping HIV researchers evaluate new treatments. My colleagues and I use math to take data collected from just a few individuals and fill in the gaps. One question we’re focusing on is exactly how much latent virus must be removed to cure a patient, or at least to let them stop their drug cocktails for a few years. Each cell harboring latent virus is a potential spark that could restart the infection. But we don’t know when the virus will reactivate. Even once a single latent virus awakens, there are still many barriers it must overcome to restart a full-blown infection. The less latent virus that remains, the less chance there is that the virus will win this game of chance. Math allows us to work out these odds very precisely.

    Our calculations show that “apparent cures”—where patients with latent virus levels low enough to escape detection for months or years without treatment—are not a medical anomaly. In fact, math tells us that they are an expected result of these chance dynamics. It can also help researchers determine how good an anti-latency drug should be before it’s worth testing in a clinical trial.

    Many researchers are working to augment the body’s ability to control the infection, providing a functional cure rather than a sterilizing one. Studies are underway to render anyone’s immune cells resistant to HIV, mimicking the CCR5 mutation that gives some people natural resistance. Vaccines that could be given after infection, to boost the immune response or protect the body from the virus’s ill effects, are also in development.

    In the meantime, treating all HIV-infected individuals—which has the added benefit of preventing new transmissions—remains the best way to control the epidemic and reduce mortality. But the promise of “universal treatment” has also not materialized. Currently, even in the U.S., only 25% of HIV-positive people have their viral levels adequately suppressed by treatment. Worldwide, for every two individuals starting treatment, three are newly infected. While there’s no doubt that we’ve made tremendous progress in fighting the virus, we have a long way to go before the word “cure” is not taboo when it comes to HIV/AIDS.

    See the full article here.

    Did you know that you can help in the fight against AIDS? By donating time on your computer to the Fight Aids at Home project of World Community Grid, you can become a part of the solution. The work is called “crunching” because you are crunching computational data the results of which will then be fed back into the necessary lab work. We save researchers literally millions of hours of lab time in this process.
    Vsit World Community Grid (WCG) or Berkeley Open infrastructure for Network Computing (BOINC). Download the BOINC software and install it on your computer. Then visit WCG and attach to the FAAH project. The project will send you computational work units. Your computer will process them and send the results back to the project, the project will then send you more work units. It is that simple. You do nothing, unless you want to get into the nuts and bolts of the BOINC software. If you take up this work, and if you see it as valuable, please tell your family, friends and colleagues, anyone with a computer, even an Android tablet. We found out that my wife’s oncologist’s father in Brazil is a cruncher on two projects from WCG.

    This is the projects web site. Take a look.

    While you are visiting BOINC and WCG, look around at all of the very valuable projects being conducted at some of the worlds most distinguished universities and scientific institutions. You can attach to as many as you like, on one or a number of computers. You can only be a help here, particpating in Citizen Science.

    This is a look at the present and past projects at WCG:

    Please visit the project pages-

    Mapping Cancer Markers
    mappingcancermarkers2

    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding

    FightAIDS@Home

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
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    IBM – Smarter Planet
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    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

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  • richardmitnick 7:45 am on September 9, 2014 Permalink | Reply
    Tags: AIDS, , , ,   

    From PBS NOVA: “Why There’s No HIV Cure Yet” 

    PBS NOVA

    NOVA

    Wed, 27 Aug 2014
    Alison Hill

    Over the past two years, the phrase “HIV cure” has flashed repeatedly across newspaper headlines. In March 2013, doctors from Mississippi reported that the disease had vanished in a toddler who was infected at birth. Four months later, researchers in Boston reported a similar finding in two previously HIV-positive men. All three were no longer required to take any drug treatments. The media heralded the breakthrough, and there was anxious optimism among HIV researchers. Millions of dollars of grant funds were earmarked to bring this work to more patients.

    But in December 2013, the optimism evaporated. HIV had returned in both of the Boston men. Then, just this summer, researchers announced the same grim results for the child from Mississippi. The inevitable questions mounted from the baffled public. Will there ever be a cure for this disease? As a scientist researching HIV/AIDS, I can tell you there’s no straightforward answer. HIV is a notoriously tricky virus, one that’s eluded promising treatments before. But perhaps just as problematic is the word “cure” itself.

    Science has its fair share of trigger words. Biologists prickle at the words “vegetable” and “fruit”—culinary terms which are used without a botanical basis—chemists wrinkle their noses at “chemical free,” and physicists dislike calling “centrifugal” a force—it’s not; it only feels like one. If you ask an HIV researcher about a cure for the disease, you’ll almost certainly be chastised. What makes “cure” such a heated word?

    cells
    HIV hijacks the body’s immune system by attacking T cells.

    It all started with a promise. In the early 1980s, doctors and public health officials noticed large clusters of previously healthy people whose immune systems were completely failing. The new condition became known as AIDS, for “acquired immunodeficiency syndrome.” A few years later, in 1984, researchers discovered the cause—the human immunodeficiency virus, now known commonly as HIV. On the day this breakthrough was announced, health officials assured the public that a vaccine to protect against the dreaded infection was only two years away. Yet here we are, 30 years later, and there’s still no vaccine. This turned out to be the first of many overzealous predictions about controlling the HIV epidemic or curing infected patients.

    The progression from HIV infection to AIDS and eventual death occurs in over 99% of untreated cases—making it more deadly than Ebola or the plague. Despite being identified only a few decades ago, AIDS has already killed 25 million people and currently infects another 35 million, and the World Health Organization lists it as the sixth leading cause of death worldwide.

    HIV disrupts the body’s natural disease-fighting mechanisms, which makes it particularly deadly and complicates efforts to develop a vaccine against it. Like all viruses, HIV gets inside individual cells in the body and highjacks their machinery to make thousands of copies of itself. HIV replication is especially hard for the body to control because the white blood cells it infects, and eventually kills, are a critical part of the immune system. Additionally, when HIV copies its genes, it does so sloppily. This causes it to quickly mutate into many different strains. As a result, the virus easily outwits the body’s immune defenses, eventually throwing the immune system into disarray. That gives other obscure or otherwise innocuous infections a chance to flourish in the body—a defining feature of AIDS.
    Early Hope

    In 1987, the FDA approved AZT as the first drug to treat HIV. With only two years between when the drug was identified in the lab and when it was available for doctors to prescribe, it was—and remains—the fastest approval process in the history of the FDA. AZT was widely heralded as a breakthrough. But as the movie The Dallas Buyer’s Club poignantly retells, AZT was not the miracle drug many hoped. Early prescriptions often elicited toxic side-effects and only offered a temporary benefit, as the virus quickly mutated to become resistant to the treatment. (Today, the toxicity problems have been significantly reduced, thanks to lower doses.) AZT remains a shining example of scientific bravura and is still an important tool to slow the infection, but it is far from the cure the world had hoped for.

    In three decades, over 25 highly-potent drugs have been developed and FDA-approved to treat HIV.

    Then, in the mid-1990s, some mathematicians began probing the data. Together with HIV scientists, they suggested that by taking three drugs together, we could avoid the problem of drug resistance. The chance that the virus would have enough mutations to allow it to avoid all drugs at once, they calculated, would simply be too low to worry about. When the first clinical trials of these “drug cocktails” began, both mathematical and laboratory researchers watched the levels of virus drop steadily in patients until they were undetectable. They extrapolated this decline downwards and calculated that, after two to three years of treatment, all traces of the virus should be gone from a patient’s body. When that happened, scientists believed, drugs could be withdrawn, and finally, a cure achieved. But when the time came for the first patients to stop their drugs, the virus again seemed to outwit modern medicine. Within a few weeks of the last pill, virus levels in patients’ blood sprang up to pre-treatment levels—and stayed there.

    In the three decades since, over 25 more highly-potent drugs have been developed and FDA-approved to treat HIV. When two to five of them are combined into a drug cocktail, the mixture can shut down the virus’s replication, prevent the onset of AIDS, and return life expectancy to a normal level. However, patients must continue taking these treatments for their entire lives. Though better than the alternative, drug regimens are still inconvenient and expensive, especially for patients living in the developing world.

    Given modern medicine’s success in curing other diseases, what makes HIV different? By definition, an infection is cured if treatment can be stopped without the risk of it resurfacing. When you take a week-long course of antibiotics for strep throat, for example, you can rest assured that the infection is on track to be cleared out of your body. But not with HIV.

    A Bad Memory

    The secret to why HIV is so hard to cure lies in a quirk of the type of cell it infects. Our immune system is designed to store information about infections we have had in the past; this property is called “immunologic memory.” That’s why you’re unlikely to be infected with chickenpox a second time or catch a disease you were vaccinated against. When an infection grows in the body, the white blood cells that are best able to fight it multiply repeatedly, perfecting their infection-fighting properties with each new generation. After the infection is cleared, most of these cells will die off, since they are no longer needed. However, to speed the counter-attack if the same infection returns, some white blood cells will transition to a hibernation state. They don’t do much in this state but can live for an extremely long time, thereby storing the “memory” of past infections. If provoked by a recurrence, these dormant cells will reactivate quickly.

    This near-immortal, sleep-like state allows HIV to persist in white blood cells in a patient’s body for decades. White blood cells infected with HIV will occasionally transition to the dormant state before the virus kills them. In the process, the virus also goes temporarily inactive. By the time drugs are started, a typical infected person contains millions of these cells with this “latent” HIV in them. Drug cocktails can prevent the virus from replicating, but they do nothing to the latent virus. Every day, some of the dormant white blood cells wake up. If drug treatment is halted, the latent virus particles can restart the infection.
    Latent HIV’s near-immortal, sleep-like state allows it to persist in white blood cells in a patient’s body for decades.

    HIV researchers call this huge pool of latent virus the “barrier to a cure.” Everyone’s looking for ways to get rid of it. It’s a daunting task, because although a million HIV-infected cells may seem like a lot, there are around a million times that many dormant white blood cells in the whole body. Finding the ones that contain HIV is a true needle-in-a-haystack problem. All that remains of a latent virus is its DNA, which is extremely tiny compared to the entire human genome inside every cell (about 0.001% of the size).

    Defining a Cure

    Around a decade ago, scientists began to talk amongst themselves about what a hypothetical cure could look like. They settled on two approaches. The first would involve purging the body of latent virus so that if drugs were stopped, there would be nothing left to restart the infection. This was often called a “sterilizing cure.” It would have to be done in a more targeted and less toxic way than previous attempts of the late 1990s, which, because they attempted to “wake up” all of the body’s dormant white blood cells, pushed the immune system into a self-destructive overdrive. The second approach would instead equip the body with the ability to control the virus on its own. In this case, even if treatment was stopped and latent virus reemerged, it would be unable to produce a self-sustaining, high-level infection. This approach was referred to as a “functional cure.”

    The functional cure approach acknowledged that latency alone was not the barrier to a cure for HIV. There are other common viruses that have a long-lived latent state, such as the Epstein-Barr virus that causes infectious mononucleosis (“mono”), but they rarely cause full-blown disease when reactivated. HIV is, of course, different because the immune system in most people is unable to control the infection.

    The first hint that a cure for HIV might be more than a pipe-dream came in 2008 in a fortuitous human experiment later known as the “Berlin patient.” The Berlin patient was an HIV-positive man who had also developed leukemia, a blood cancer to which HIV patients are susceptible. His cancer was advanced, so in a last-ditch effort, doctors completely cleared his bone marrow of all cells, cancerous and healthy. They then transplanted new bone marrow cells from a donor.

    Fortunately for the Berlin patient, doctors were able to find a compatible bone marrow donor who carried a unique HIV-resistance mutation in a gene known as CCR5. They completed the transplant with these cells and waited.

    For the last five years, the Berlin patient has remained off treatment without any sign of infection. Doctors still cannot detect any HIV in his body. While the Berlin patient may be cured, this approach cannot be used for most HIV-infected patients. Bone marrow transplants are extremely risky and expensive, and they would never be conducted in someone who wasn’t terminally ill—especially since current anti-HIV drugs are so good at keeping the infection in check.

    Still, the Berlin patient was an important proof-of-principle case. Most of the latent virus was likely cleared out during the transplant, and even if the virus remained, most strains couldn’t replicate efficiently given the new cells with the CCR5 mutation. The Berlin patient case provides evidence that at least one of the two cure methods (sterilizing or functional), or perhaps a combination of them, is effective.

    Researchers have continued to try to find more practical ways to rid patients of the latent virus in safe and targeted ways. In the past five years, they have identified multiple anti-latency drug candidates in the lab. Many have already begun clinical trials. Each time, people grow optimistic that a cure will be found. But so far, the results have been disappointing. None of the drugs have been able to significantly lower levels of latent virus.

    In the meantime, doctors in Boston have attempted to tease out which of the two cure methods was at work in the Berlin patient. They conducted bone marrow transplants on two HIV-infected men with cancer—but this time, since HIV-resistant donor cells were not available, they just used typical cells. Both patients continued their drug cocktails during and after the transplant in the hopes that the new cells would remain HIV-free. After the transplants, no HIV was detectable, but the real test came when these patients volunteered to stop their drug regimens. When they remained HIV-free a few months later, the results were presented at the International AIDS Society meeting in July 2013. News outlets around the world declared that two more individuals had been cured of HIV.

    Latent virus had likely escaped the detection methods available.

    It quickly became clear that everyone had spoken too soon. Six months later, researchers reported that the virus had suddenly and rapidly returned in both individuals. Latent virus had likely escaped the detection methods available—which are not sensitive enough—and persisted at low, but significant levels. Disappointment was widespread. The findings showed that even very small amounts of latent virus could restart an infection. It also meant meant that the anti-latency drugs in development would need to be extremely potent to give any hope of a cure.

    But there was one more hope—the “Mississippi baby.” A baby was born to an HIV-infected mother who had not received any routine prenatal testing or treatment. Tests revealed high levels of HIV in the baby’s blood, so doctors immediately started the infant on a drug cocktail, to be continued for life.

    The mother and child soon lost touch with their health care providers. When they were relocated a few years later, doctors learned that the mother had stopped giving drugs to the child several months prior. The doctors administered all possible tests to look for signs of the virus, both latent and active, but they didn’t find any evidence. They chose not to re-administer drugs, and a year later, when the virus was still nowhere to be found, they presented the findings to the public. It was once again heralded as a cure.

    Again, it was not to be. Just last month, the child’s doctors announced that the virus had sprung back unexpectedly. It seemed that even starting drugs as soon as infection was detected in the newborn could not prevent the infection from returning over two years later.
    Hope Remains

    Despite our grim track record with the disease, HIV is probably not incurable. Although we don’t have a cure yet, we’ve learned many lessons along the way. Most importantly, we should be extremely careful about using the word “cure,” because for now, we’ll never know if a person is cured until they’re not cured.

    Clearing out latent virus may still be a feasible approach to a cure, but the purge will have to be extremely thorough. We need drugs that can carefully reactivate or remove latent HIV, leaving minimal surviving virus while avoiding the problems that befell earlier tests that reactivated the entire immune system. Scientists have proposed multiple, cutting-edge techniques to engineer “smart” drugs for this purpose, but we don’t yet know how to deliver this type of treatment safely or effectively.

    As a result, most investigations focus on traditional types of drugs. Researchers have developed ways to rapidly scan huge repositories of existing medicines for their ability to target latent HIV. These methods have already identified compounds that were previously used to treat alcoholism, cancer, and epilepsy, and researchers are repurposing them to be tested in HIV-infected patients.
    The less latent virus that remains, the less chance there is that the virus will win the game of chance.

    Mathematicians are also helping HIV researchers evaluate new treatments. My colleagues and I use math to take data collected from just a few individuals and fill in the gaps. One question we’re focusing on is exactly how much latent virus must be removed to cure a patient, or at least to let them stop their drug cocktails for a few years. Each cell harboring latent virus is a potential spark that could restart the infection. But we don’t know when the virus will reactivate. Even once a single latent virus awakens, there are still many barriers it must overcome to restart a full-blown infection. The less latent virus that remains, the less chance there is that the virus will win this game of chance. Math allows us to work out these odds very precisely.

    Our calculations show that “apparent cures”—where patients with latent virus levels low enough to escape detection for months or years without treatment—are not a medical anomaly. In fact, math tells us that they are an expected result of these chance dynamics. It can also help researchers determine how good an anti-latency drug should be before it’s worth testing in a clinical trial.

    Many researchers are working to augment the body’s ability to control the infection, providing a functional cure rather than a sterilizing one. Studies are underway to render anyone’s immune cells resistant to HIV, mimicking the CCR5 mutation that gives some people natural resistance. Vaccines that could be given after infection, to boost the immune response or protect the body from the virus’s ill effects, are also in development.

    In the meantime, treating all HIV-infected individuals—which has the added benefit of preventing new transmissions—remains the best way to control the epidemic and reduce mortality. But the promise of “universal treatment” has also not materialized. Currently, even in the U.S., only 25% of HIV-positive people have their viral levels adequately suppressed by treatment. Worldwide, for every two individuals starting treatment, three are newly infected. While there’s no doubt that we’ve made tremendous progress in fighting the virus, we have a long way to go before the word “cure” is not taboo when it comes to HIV/AIDS.

    See the full article here.

    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

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  • richardmitnick 11:05 am on August 19, 2014 Permalink | Reply
    Tags: AIDS, , ,   

    From Brown: “Intimacy a strong motivator for PrEP HIV prevention” 

    Brown University
    Brown University

    August 19, 2014
    David Orenstein

    Men in steady same-sex relationships where both partners are HIV negative will often forgo condoms out of a desire to preserve intimacy, even if they also have sex outside the relationship. But the risk of HIV still lurks. In a new study of gay and bisexual men who reported at least one instance of condomless anal sex in the last 30 days, researchers found that the same desire for intimacy is also a strong predictor of whether men would be willing to take antiretroviral medications to prevent HIV, an emerging practice known as pre-exposure prophylaxis or PrEP.

    Earlier this year the U.S. Public Health Service recommended that people at high risk of getting HIV use PrEP, including gay or bisexual men who have condomless anal sex. But as the recommendation becomes clinical practice, many people are wondering whether men will make PrEP part of their daily lives and what will keep them motivated to adhere to it strictly, which is required if the medication is to have its protective effect.

    The new study, published in the Annals of Behavioral Medicine, suggests that PrEP’s appeal to many men who have sex with men (MSM) in romantic relationships with HIV-negative partners is the perception that it can allow them to remain intimate with their partners while still having some protection from HIV.

    kg
    Kristi Gamarel
    “Sex doesn’t happen in a vacuum — interpersonal and relationship context really matter.”

    “In this sample of men who are in a relationship with a perceived HIV-negative man, we found that intimacy motivation was the strongest predictor [of adopting PrEP],” said Kristi Gamarel, a psychiatry and human behavior postdoctoral researcher in the Warren Alpert Medical School of Brown University. She was at the City University of New York with senior author and principal investigator for the NIH-funded project, Sarit Golub, when she performed the research. “Sex doesn’t happen in a vacuum — interpersonal and relationship context really matter. Many HIV infections are occurring between people who are in a primary relationship.”

    The study is based on extensive interviews with 164 HIV-negative MSMs who were in steady same-sex relationships and who had condomless anal sex at least once in the prior 30 days. The researchers found in a multivariate statistical analysis that those who rated intimacy highly as a reason why they sometimes engage in condomless sex also were 55 percent more likely to say they would adopt PrEP if it were available for free (likely a hypothetical condition for many, but not necessarily all, recipients).

    In basic analyses reported in the paper, there were several other factors in the study that also predicted a greater likelihood of adopting PrEP: older age, higher perception of HIV risk, sex (either protected or not) with partners outside the main relationship, and having less than a bachelor’s degree level of education. But upon controlling for possible overlap among factors, desire for intimacy, low education levels and to a lesser extent older age survived as the strongest predictors of using PrEP.

    Relationships matter

    An important implication of the study’s findings are that as physicians and counselors discuss PrEP with MSM in steady relationships, Gamarel said, they should consider that a desire for intimacy in the relationship appears to be a prime motivation.

    “For people who are disseminating PrEP or talking to patients about PrEP, I think it’s important to think about their relationships,” Gamarel said. “Something that’s being supported and endorsed right now by the World Health Organization is couples voluntary testing and counseling. That may be a way to disseminate PrEP and to allow couples to have a discussion about whether PrEP is good for their relationship and how they can support each other using PrEP.”

    Gamarel cautioned that the study results cannot be taken as evidence that PrEP will reduce condom use. The men in this study were already forgoing condoms at times without being on PrEP, Gamarel notes. The study simply sought to ascertain whether these men would adopt PrEP and to determine why. Condoms remain uniquely important to gay men’s sexual health, she noted, both because they reduce the risk of HIV transmission and because they can block other sexually transmitted infections that PrEP does not.

    The National Institute of Mental Health funded the study (grant: R01MH095565 to Golub).

    See the full article here.

    Welcome to Brown

    Rhode Island Hall: Rhode Island Hall’s classical exterior was recently renovated with a modern interiorRhode Island Hall: Rhode Island Hall’s classical exterior was recently renovated with a modern interior

    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

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  • richardmitnick 6:08 pm on July 28, 2014 Permalink | Reply
    Tags: AIDS, , , ,   

    From M.I.T.: “Forced mutations doom HIV” 


    MIT News

    July 28, 2014
    Anne Trafton

    Fifteen years ago, MIT professor John Essigmann and colleagues from the University of Washington had a novel idea for an HIV drug. They thought if they could induce the virus to mutate uncontrollably, they could force it to weaken and eventually die out — a strategy that our immune system uses against many viruses.

    The researchers developed such a drug, which caused HIV to mutate at an enhanced rate, as expected. But it did not eliminate the virus from patients in a small clinical trial reported in 2011. In a new study, however, Essigmann and colleagues have determined the mechanism behind the drug’s action, which they believe could help them develop better versions that would destroy the virus more quickly.

    This type of drug could, they say, help combat the residual virus that remains in the T cells of patients whose disease has been brought into long-term remission by the triple-drug combination typically used to treat HIV. These viruses re-emerge periodically, which is why patients must stay on the drug cocktail indefinitely and are not considered “cured.”

    “This has really been the biggest problem in HIV,” says Essigmann, the William R. and Betsy P. Leitch Professor of Chemistry, Toxicology, and Biological Engineering at MIT. “What we would hope is that over a long period of time on this type of therapy, a person would potentially have their latent pool mutated to the extent that it no longer causes active disease.”

    In the new study, which appears in the Proceedings of the National Academy of Sciences (PNAS) the week of July 28, the researchers discovered exactly how the drug, known as KP1212, induces the HIV genome to mutate. The paper’s lead authors are MIT postdocs Deyu Li, Bogdan Fedeles, and Vipender Singh, along with recent MIT PhD graduate Chunte Sam Peng. Essigmann and Andrei Tokmakoff, a former MIT professor who is now at the University of Chicago, are the paper’s senior authors.

    Too much mutation

    After HIV infects a cell, it rapidly begins making copies of its genetic material. This copying is very error-prone, so the virus mutates swiftly. This usually helps the virus survive by allowing it to evade both the immune system and human-made drugs. However, at a conference in the late 1990s, Essigmann learned from an evolutionary biologist that if the virus could be forced to double its mutation rate, it would no longer be able to produce functional proteins.

    Essigmann and Lawrence Loeb, a professor of biochemistry at the University of Washington, started working together to exploit this idea. Essigmann had been developing compounds that mimic natural nucleotides — the A, C, T, and G “letters” that form DNA base pairs — but that induce genetic mutations by binding with the wrong partner. Loeb is an expert on polymerases, the enzymes that string nucleotides together to form DNA or RNA.

    Together with James Mullins, an immunology professor and HIV expert at the University of Washington, Essigmann and Loeb designed a molecule called 5-hydroxycytosine, described in a 1999 PNAS paper. When given to HIV-infected cells grown in the lab, this molecule was incorporated into the viral genome in place of the natural form of cytosine. Within 25 viral replication cycles, HIV populations in those infected cells collapsed.

    The researchers then formed a company, Koronis Pharmaceuticals, which developed KP1212, a compound that is 100 times more mutagenic than 5-hydroxycytosine. In a four-month clinical trial of 32 patients, mutations accumulated in the patients’ viral DNA, but not enough to induce a population crash. The drug was also found to be safe: It did not mutate the patients’ own DNA, in part because the drug was designed so that human forms of DNA polymerase could not accept it.

    Shape-shifting molecules

    In the new PNAS paper, the researchers used advanced spectroscopy techniques to analyze KP1212’s ability to promote tautomerism, a chemical phenomenon that involves the migration of protons among the nitrogen and oxygen atoms on nucleic-acid bases. This allowed the researchers to see that once KP1212 inserts itself into the genome, it can switch among five different shapes, or tautomers. Some of these behave like cytosine, by pairing with guanine. However, some of the tautomers resemble thymine, so they will pair with adenine, introducing mutations.

    “The five molecules are changing shape on a nanosecond timescale, and each shape has a different base-pairing property, so you will see a promiscuity in terms of the bases with which KP1212 pairs,” Singh says.

    To see this shape-shifting, the researchers used NMR and a form of 2-D infrared spectroscopy developed by Tokmakoff. This technology allows scientists to determine the atomic composition and structure of nucleic-acid bases.

    Then, using a genetic tool developed in the Essigmann lab, the researchers determined that KP1212 induces a mutation rate of exactly 10 percent in the HIV genome. Based on these findings, Essigmann estimates that if KP1212 doubles the mutation rate of HIV, it could clear the virus from patients in one to two years.

    He says that Koronis hopes to run a longer trial of KP1212 and is also interested in developing drugs that would work faster, which could be accomplished by altering some of the chemical features of the molecule and testing whether they speed up the mutation rate.

    “This technology allows you to detect the quantitative contribution of different tautomers to the types and frequencies of mispairing by nucleoside analogs,” says Loeb, who was not involved in the new paper. “It would allow you to test ahead of time what is making the mispairing occur with the compound that you’re using.”

    The paper also identified other factors that scientists could manipulate to improve the drug’s performance.

    “There are other variables that are important to calculate the time it would take to eradicate a virus,” Fedeles says. “That includes the concentration that the drug needs to achieve inside the cell, and the ability of a cell to convert the nucleoside, the molecule without the phosphate, to the triphosphate version, which is the one incorporated by the polymerase.”

    “We’re building up a new strategy that can give us a lot of insights into how to design a new molecule,” Li says. “It’s a new toolset for developing future drugs. Those drugs are not limited to HIV. They could be candidates for dengue fever, or some other viruses such as yellow fever.”

    Ribavirin, a drug used to treat hepatitis C, and the influenza drug T-705 are also believed to provoke hypermutation in their target viruses. The MIT team also plans to work with Loeb to test the possibility of using similar compounds to force tumor cells to mutate themselves into extinction.

    The research was funded by the National Institutes of Health, the National Science Foundation, and the MIT Laser Biomedical Research Center.

    See the full article here.


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  • richardmitnick 3:22 pm on July 16, 2014 Permalink | Reply
    Tags: AIDS, , , , ,   

    From FAAH@home: “Improved efficiency and processing capabilities for FightAIDS@Home” 

    FAAH
    FightAIDS@home

    16 Jul 2014
    The FightAIDS@Home research team

    Summary
    New methods and processes help the research team process World Community Grid data more efficiently and provide more accurate docking techniques.

    As the volume of data generated by World Community Grid volunteers for our FightAIDS@Home (FAAH) project has increased, so has our need to optimize how we handle and store that data. In this project update, we discuss new improvements in how we process the extremely high result data rate you generate, which is allowing us to focus more resources toward the analysis of FAAH data. Further, improved docking techniques are being created and applied from the results of deeper analysis coupled with ongoing experimental data from our collaborators.

    model
    Example of repositioned side-chain, histidine, by Vina cycling through the original space-filling representation, original stick representation (orange), and new position compared to old position (dotted black lines).

    Processing your results faster

    Managing the very large data throughput generated by World Community Grid volunteers for FAAH is a great challenge. Beside the scientific results we have achieved over the years, we also have developed novel software and protocols to process, analyze and store the results you generate quickly and efficiently.

    Recently, we exploited the parallel computational resources available at Scripps. In the last few months, we have shifted our processing of the incoming World Community Grid data to our local High Performance Computing cluster, Garibaldi. Since the implementation of the AutoDock Vina software for FAAH last year, you have generated several terabytes of compressed docking results each month, which was putting a strain on our storage system. Until recently, most of our work and resources have been focused on processing this data to make it suitable for deeper analysis. We had to devote most of our local computational power to this processing. With our new methods, we have increased the processing rate by several orders of magnitude with the use of multiple processors and the optimization of processing scripts. Processing a batch that used to take between 30 minutes to few hours now takes just a few minutes. Streamlined scripts and parallel processing has yielded 180,000 processed batches in two weeks.

    We have created new analysis programs using structural and statistical methods to mine more information from the results you generate. Statistical analysis tools will first be used to reduce over 5 million docked compounds to a few thousand top-ranking candidates. Structural information will then be used to cull the list further by filtering for key intermolecular interactions and against unfavorable interactions. A new database structure that will incorporate these programs is being developed to handle this large and fast-growing flood of results. Once optimized, the whole processing and analysis workflow will be fully automated.

    Importantly, what we have learned and are learning from these refined methods to handle big data will be made available in the AutoDockTools suite, which is utilized by many research labs worldwide.

    Improved protein-ligand binding modeling capabilities

    Proteins are typically large molecules and often can bend or flex in various ways at various points and at normal temperatures they rapidly bend to many or all of the possible configurations (bent shapes). When searching for ligands that might attach to a protein target, the ligand might not match the shape of the protein in one of its configurations, but might match in another configuration of the protein. By considering more configurations of the protein, it is more likely that a ligand can be found which matches one of the protein’s configurations. Since February 2014, we have been running flexible receptor side-chain Vina jobs on FAAH, which we expect to enhance our docking results. While our typical docking methods hold the protein structure rigid, the flexibility feature in AutoDock Vina allows selected residue side chain conformations to be sampled along with the flexible ligand molecule. This enables the protein pocket to adopt alternate shapes to better model protein-ligand binding and the so-called “induced fit”, minimizing the bias of using a rigid target structure. Currently, we are testing this approach on several sites (LEFGF, FBP, and Y3) in HIV integrase.

    The downside of performing flexible receptor calculations is that the search complexity increases, and computing run-times are therefore 5 to 10 times longer. The World Community Grid staff has been adjusting their methods to account for the different Flexible Vina work unit. Once these dockings have finished and the analyses performed, we will be able to optimize our application of Flexible Vina on World Community Grid and extend it to other targets.

    Another way to minimize rigid-protein bias in traditional docking is to dock to an ensemble of protein structures. Two ways to generate these ensembles, both used in FAAH dockings, are molecular dynamics (MD) simulations and simply using multiple available structures for a given protein receptor. The last hundred experiments have included ensembles ranging from tens to sometimes hundreds of receptor structures. Ensembles add another layer of analysis with the goal of achieving a more accurate ranking of compounds from several sources of data.

    Further experimentation

    Despite the encouraging results on the first hits previously reported, we are encountering experimental issues that are making the process of identifying hits very challenging. As often happens in science (and particularly in HIV-related experiments!), it is hard to achieve robust and consistent statistics from biological assays.

    See the full article here.

    FightAIDS@Home is a project run by the Olson Laboratory that uses distributed computing to contribute your computer’s idle resources to accelerate research into new drug therapies for HIV, the virus that causes AIDS. FightAIDS@Home made history in September 2000 when it became the first biomedical Internet-based grid computing project. FightAIDS@Home was started with Scott Kurowski, founder of Entropia. People all around the World continue to donate their home computer’s idle cycles to running our AutoDock software on HIV-1 protease inhibitor docking problems. With the generous assistance of IBM, we joined World Community Grid in late 2005, and launched FightAIDS@Home on World Community Grid on 21 November, 2005.

    How do I join the FightAIDS@Home Project?

    All you need to do is download and install the free client software. Once you have done this, your computer is then automatically put to work and you can continue using your computer as usual.

    Faah Screensaver


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  • richardmitnick 9:26 am on February 11, 2014 Permalink | Reply
    Tags: AIDS, , , ,   

    From Caltech: “Caltech-Developed Method for Delivering HIV-Fighting Antibodies Proven Even More Promising” 

    Caltech Logo
    Caltech

    02/09/2014
    Kimm Fesenmaier

    In 2011, biologists at the California Institute of Technology (Caltech) demonstrated a highly effective method for delivering HIV-fighting antibodies to mice—a treatment that protected the mice from infection by a laboratory strain of HIV delivered intravenously. Now the researchers, led by Nobel Laureate David Baltimore, have shown that the same procedure is just as effective against a strain of HIV found in the real world, even when transmitted across mucosal surfaces.

    dlon't know

    The findings, which appear in the February 9 advance online publication of the journal Nature Medicine, suggest that the delivery method might be effective in preventing vaginal transmission of HIV between humans.”The method that we developed has now been validated in the most natural possible setting in a mouse,” says Baltimore, president emeritus and the Robert Andrews Millikan Professor of Biology at Caltech. “This procedure is extremely effective against a naturally transmitted strain and by an intravaginal infection route, which is a model of how HIV is transmitted in most of the infections that occur in the world.”The new delivery method—called Vectored ImmunoProphylaxis, or VIP for short—is not exactly a vaccine. Vaccines introduce substances such as antigens into the body to try to get the immune system to mount an appropriate attack—to generate antibodies that can block an infection or T cells that can attack infected cells. In the case of VIP, a small, harmless virus is injected and delivers genes to the muscle tissue, instructing it to generate specific antibodies. The researchers emphasize that the work was done in mice and that the leap from mice to humans is large. The team is now working with the Vaccine Research Center at the National Institutes of Health to begin clinical evaluation.The study, “Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission,” was supported by the UCLA Center for AIDS Research, the National Institutes of Health, and the Caltech-UCLA Joint Center for Translational Medicine. Caltech biology researchers Alejandro B. Balazs, Yong Ouyang, Christin H. Hong, Joyce Chen, and Steven M. Nguyen also contributed to the study, as well as Dinesh S. Rao of the David Geffen School of Medicine at UCLA and Dong Sung An of the UCLA AIDS Institute.

    See the full article here.

    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
    Caltech buildings


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  • richardmitnick 2:27 pm on January 28, 2014 Permalink | Reply
    Tags: AIDS, , , ,   

    From U.C Berkeley: “Researchers open door to new HIV therapy” 

    UC Berkeley

    January 28, 2014
    Robert Sanders

    People infected with the Human Immunodeficiency Virus (HIV) can stave off the symptoms of AIDS thanks to drug cocktails that mainly target three enzymes produced by the virus, but resistant strains pop up periodically that threaten to thwart these drug combos.

    aids
    The AIDS virus enters immune cells by binding to CD4 receptors embedded in the membrane (parallel lines) of the cell. But once a virus enters the cell, it makes a protein, Nef, that binds to the protein complex underlying CD4, tagging it for the waste bin. Potential anti-HIV drugs would disable one of the proteins (colored blobs) to which Nef binds, interfering with HIV’s strategy for spreading through the body. Image by James Hurley, UC Berkeley.

    Researchers at the University of California, Berkeley, and the National Institutes of Health have instead focused on a fourth protein, Nef, that hijacks host proteins and is essential to HIV’s lethality. The researchers have captured a high-resolution snapshot of Nef bound with a main host protein, and discovered a portion of the host protein that will make a promising target for the next-generation of anti-HIV drugs. By blocking the part of a key host protein to which Nef binds, it may be possible to slow or stop HIV.

    “We have imaged the molecular details for the first time,” said structural biologist James H. Hurley, UC Berkeley professor of molecular and cell biology. “Having these details in hand puts us in striking distance of designing drugs to block the binding site and, in doing so, block HIV infectivity.”

    Hurley, cell biologist Juan Bonifacino of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health and their colleagues report their findings in a paper published today (Jan. 28) by the open-access, online journal eLife.

    See the full article here.

    Founded in the wake of the gold rush by leaders of the newly established 31st state, the University of California’s flagship campus at Berkeley has become one of the preeminent universities in the world. Its early guiding lights, charged with providing education (both “practical” and “classical”) for the state’s people, gradually established a distinguished faculty (with 22 Nobel laureates to date), a stellar research library, and more than 350 academic programs.

    UC Berkeley Seal


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  • richardmitnick 7:34 pm on December 4, 2012 Permalink | Reply
    Tags: AIDS, , , , , ,   

    From GPUGrid.net via BOINC: “GPUgrid.net announces AIDS breakthrough” 

    From GPUgrid.net

    GPUgrid.net

    Crucial step in AIDS virus maturation simulated for first time

    Bioinformaticians at IMIM (Hospital del Mar Medical Research Institute) and UPF (Pompeu Fabra University) have used molecular simulation techniques to explain a specific step in the maturation of the HIV virions, i.e., how newly formed inert virus particles become infectious, which is essential in understanding how the virus replicates. These results, which have been published in the latest edition of [Proceedings of the National Academy of Sciences, could be crucial to the design of future antiretrovirals.

    image
    HIV proteasa cutting the poly-protein chain. Source: IMIM

    Using ACEMD a software for molecular simulations and a technology known as GPUGRID.net, Gianni De Fabritiis
    ’ group has demonstrated that the first ‘scissors proteins’ can cut themselves out from within the middle of these poly-protein chains. They do this by binding one of their connected ends (the N-terminus) to their own active site and then cutting the chemical bond that connects them to the rest of the chain. This is the initial step of the whole HIV maturation process. If the HIV protease can be stopped during the maturation process, it will prevent viral particles, or virions, from reaching maturity and, therefore, from becoming infectious.

    This work was performed using GPUGRID.net, a voluntary distributed computing platform [running on BOINC software] that harnesses the processing power of thousands of NVIDIA GPU accelerators from household computers made available by the public for research purposes*. It’s akin to accessing a virtual supercomputer. One of the benefits of GPU acceleration is that it provides computing power that is around 10 times higher than that generated by computers based on CPUs alone. It reduces research costs accordingly by providing a level computational power that previously was only available on dedicated, multi-million dollar supercomputers.”

    [*Rest assured, while a small number of projects run on GPU processors, most projects running on BOINC software are CPU based and do not use GPU processing.]

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience. BOINC is more properly the Berkeley Open Infrastructure for Network Computing, developed at UC Berkeley.

    Visit the BOINC web page, click on Choose projects and check out some of the very worthwhile studies you will find. Then click on Download and run BOINC software/ All Versons. Download and install the current software for your 32bit or 64bit system, for Windows, Mac or Linux. When you install BOINC, it will install its screen savers on your system as a default. You can choose to run the various project screen savers or you can turn them off. Once BOINC is installed, in BOINC Manager/Tools, click on “Add project or account manager” to attach to projects. Many BOINC projects are listed there, but not all, and, maybe not the one(s) in which you are interested. You can get the proper URL for attaching to the project at the projects’ web page(s) BOINC will never interfere with any other work on your computer.

    MAJOR PROJECTS RUNNING ON BOINC SOFTWARE

    SETI@home The search for extraterrestrial intelligence. “SETI (Search for Extraterrestrial Intelligence) is a scientific area whose goal is to detect intelligent life outside Earth. One approach, known as radio SETI, uses radio telescopes to listen for narrow-bandwidth radio signals from space. Such signals are not known to occur naturally, so a detection would provide evidence of extraterrestrial technology.

    Radio telescope signals consist primarily of noise (from celestial sources and the receiver’s electronics) and man-made signals such as TV stations, radar, and satellites. Modern radio SETI projects analyze the data digitally. More computing power enables searches to cover greater frequency ranges with more sensitivity. Radio SETI, therefore, has an insatiable appetite for computing power.

    Previous radio SETI projects have used special-purpose supercomputers, located at the telescope, to do the bulk of the data analysis. In 1995, David Gedye proposed doing radio SETI using a virtual supercomputer composed of large numbers of Internet-connected computers, and he organized the SETI@home project to explore this idea. SETI@home was originally launched in May 1999.”


    SETI@home is the birthplace of BOINC software. Originally, it only ran in a screensaver when the computer on which it was installed was doing no other work. With the powerand memory available today, BOINC can run 24/7 without in any way interfering with other ongoing work.

    seti
    The famous SET@home screen saver, a beauteous thing to behold.

    einstein@home The search for pulsars. “Einstein@Home uses your computer’s idle time to search for weak astrophysical signals from spinning neutron stars (also called pulsars) using data from the LIGO gravitational-wave detectors, the Arecibo radio telescope, and the Fermi gamma-ray satellite. Einstein@Home volunteers have already discovered more than a dozen new neutron stars, and we hope to find many more in the future. Our long-term goal is to make the first direct detections of gravitational-wave emission from spinning neutron stars. Gravitational waves were predicted by Albert Einstein almost a century ago, but have never been directly detected. Such observations would open up a new window on the universe, and usher in a new era in astronomy.”

    MilkyWay@Home Milkyway@Home uses the BOINC platform to harness volunteered computing resources, creating a highly accurate three dimensional model of the Milky Way galaxy using data gathered by the Sloan Digital Sky Survey. This project enables research in both astroinformatics and computer science.”

    Leiden Classical “Join in and help to build a Desktop Computer Grid dedicated to general Classical Dynamics for any scientist or science student!”

    World Community Grid (WCG) World Community Grid is a special case at BOINC. WCG is part of the social initiative of IBM Corporation and the Smarter Planet. WCG has under its umbrella currently eleven disparate projects at globally wide ranging institutions and universities. Most projects relate to biological and medical subject matter. There are also projects for Clean Water and Clean Renewable Energy. WCG projects are treated respectively and respectably on their own at this blog. Watch for news.

    Rosetta@home “Rosetta@home needs your help to determine the 3-dimensional shapes of proteins in research that may ultimately lead to finding cures for some major human diseases. By running the Rosetta program on your computer while you don’t need it you will help us speed up and extend our research in ways we couldn’t possibly attempt without your help. You will also be helping our efforts at designing new proteins to fight diseases such as HIV, Malaria, Cancer, and Alzheimer’s….”

    GPUGrid.net “GPUGRID.net is a distributed computing infrastructure devoted to biomedical research. Thanks to the contribution of volunteers, GPUGRID scientists can perform molecular simulations to understand the function of proteins in health and disease.” GPUGrid is a special case in that all processor work done by the volunteers is GPU processing. There is no CPU processing, which is the more common processing. Other projects (Einstein, SETI, Milky Way) also feature GPU processing, but they offer CPU processing for those not able to do work on GPU’s.

    gif

    These projects are just the oldest and most prominent projects. There are many others from which you can choose.

    There are currently some 300,000 users with about 480,000 computers working on BOINC projects That is in a world of over one billion computers. We sure could use your help.

    My BOINC

    graph


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  • richardmitnick 4:34 pm on November 5, 2011 Permalink | Reply
    Tags: AIDS, , , , ,   

    FightAIDS@Home, A Public Distributed Project at WCG 

    “HIV, the virus that causes AIDS, infects over 30 million people throughout the world, and approximately 2 million new people are infected each year. HIV kills more people than any other virus on Earth. Even if/when we can eventually prevent new HIV infections, we will still need to discover new drugs that can treat the millions of people who are currently living with an HIVinfection. The need to discover new types of drugs against HIV is especially urgent, since new multi-drug-resistant mutant “superbugs” of HIV are constantly evolving and spreading throughout humanity. In addition, other scientists have recently shown that treating HIV with effective drugs also helps decrease the probability of spreading the infection to new people. When effective drugs are given to a particular patient, the number of infectious viral particles in that patient (or the “viral load”) decreases, which lowers the probability of them infecting other people. It doesn!t eliminate the possibility of spreading the infection, but it does reduce the probability.

    The FightAIDS@Home Project uses the volunteered computer power of IBM!s World CommunityGrid to test candidate compounds against the variations (or “mutants”) of HIV that can arise and cause drug resistance. We test these candidates by docking flexible models of them against 3-D, atomic-scale models of different drug targets from HIV, to predict (a) how tightly these compounds might be able to bind, (b) where these compounds prefer to bind on the protein target, and (c) what
    specific interactions are formed between the candidate and the target. That is, we use these calculations to predict the affinity/potency of the compound, the location where it binds on the molecular target, and the mode it uses to potentially disable the target. Compounds that can bind
    tightly to the right regions of particular proteins from HIV have the potential to “gum up” the viralmachinery and, thus, help advance the discovery of new types of drugs to treat HIV infections.”

    You could help in the vital work of this Public Distributed Computing project and other projects in Cancer, Dengue Fever, Clean Water, Clean Energy, and Leishmaniasis. Visit the WCG web site, download and install the BOINC software on which the projects run. Then, read about the projects and attach to those of interest.

    See the full article here.

     
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