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  • richardmitnick 12:43 pm on January 14, 2016 Permalink | Reply
    Tags: AIDS, ,   

    From Scripps: “Getting closer to an HIV Vaccine” 

    Scripps
    Scripps Research Institute

    January 2016
    No writer credit found

    1
    Authors of the new paper [no paper reference in article] included (left to right) James Voss, Raiees Andrabi, Dennis Burton, Bryan Briney and Chi-Hui Liang.

    For more than 30 years, an effective vaccine against HIV has eluded scientists, and more than two million people are still newly infected with the virus each year. In a recent study, scientists at The Scripps Research Institute gained a new weapon in that long fight. They identified four antibodies targeting a specific weak spot on HIV that provided key information for the design of a potential HIV vaccine candidate.

    “This study [no paper reference in article]is an example of how we can learn from natural infection and translate that information into vaccine development,” said TSRI Research Associate Raiees Andrabi. “This is an important advance in the field of antibody-based HIV vaccine development.”

    Dr. Andrabi served as first author of the study, working in the lab of senior author TSRI Professor Dennis R. Burton, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI.

    The findings build on the success of several recent TSRI studies showing that, with prompting, the immune system can develop antibodies to neutralize many strains of HIV. In the new study, the researchers carried out a series of experiments involving virus modifications and protein and antibody engineering. They found that four antibodies targeted a single spot on HIV’s surface called the V2 apex. This was significant because the V2 apex could be recognized by these antibodies on about 90 percent of known HIV strains – and even related strains that infect other species, meaning a vaccine that targets this region could protect against many forms of the virus.

    “This region helps stabilize the virus, so it’s an important area to target if you want to neutralize HIV,” said Dr. Andrabi.

    Investigating further, the researchers noticed that two of the four antibodies had an unusual feature that could prove important in vaccine design. The immune system usually begins its fight against infection by activating immune B cells that express “germline” forms of antibodies on their surface to bind invading pathogens. Germline antibodies rarely bind viruses very effectively themselves; instead, they are precursors for more developed antibodies, which mutate and hone their response to the invader.

    Yet in the new study, two of the antibodies did not need to mutate to bind with the V2 apex; instead, these antibodies used part of their basic germline structure, encoded by non-mutated genes. This means any patient with HIV should, in theory, have the ability to kick-start the right immune response.

    To generate that response, it was critical for the scientists to find the right proteins in HIV that the antibodies could recognize and bind to. In the new study, the researchers succeeded in mimicking a structure on HIV called the native HIV coat protein. This enabled them to design proteins that do indeed bind well to the germline antibodies and hopefully start a useful immune response. The next step will be to test the vaccine candidates in animal models.

    See the full article here .

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 9:43 pm on December 28, 2015 Permalink | Reply
    Tags: AIDS, ,   

    From UC Davis: “Turning the Tables on Hidden HIV” 

    Temp 1

    Thirty years ago, contracting HIV was a death sentence.

    The virus attacks the immune system, specifically T-cells, until immunity breaks down completely. Patients would eventually develop AIDS, and ultimately succumb to opportunistic infections.

    The development of highly active antiretroviral therapies or HAART changed all that, converting a deadly disease into a chronic one. As long as patients stayed on the drug regimen, they could live normal lifespans. Their immune systems would recover and viral levels would decline to nearly zero.

    But there’s a catch. Nearly zero is not the same as zero. HIV has a latency mode, during which the virus is dormant – evading both HAART and the body’s immune system. Remove HAART treatment, and the virus comes roaring back.

    That means a lifetime consuming powerful and expensive treatments – if one’s body and health status can tolerate them in the first place. And no one knows how the drugs will affect patients after 20, 30 or 40 years.

    “We’ve made great progress, but at the end of the day you still have more than 30 million people living with HIV,” says Satya Dandekar, professor and chair of the UC Davis Department of Medical Microbiology and Immunology. “Without drugs, the virus can come back at the same threat level for patients.

    “Actually eradicating HIV is extremely critical.”

    For decades, UC Davis researchers have worked with that ultimate goal in mind. Scientists have learned important details about how HIV operates along the way; for example, that it first attacks immune cells in the gut.

    But now we’ve reached a new stage in the battle against HIV. The goal is no longer to control the disease, but to cure it. Two UC Davis groups are beginning clinical trials in hopes of doing just that.

    Shock and kill

    It would be hard to overstate the significance of HIV latency. The virus’s ability to evade treatment has made it difficult, if not impossible, to cure. The challenge for clinicians is to identify a two-pronged strategy: shock the latent virus out of hibernation, and hit it with immune treatments to kill it.

    2
    No image credit found

    Dandekar, along with dermatologist Emanual Maverakis, are about to test the first part of that strategy. Just a few months ago, the Dandekar lab identified several agents that “wake up” HIV. One in particular, PEP005, has shown striking results. Even better, the drug is already approved by the U.S. Food and Drug Administration.

    “We found this was really effective at reactivating HIV and works beautifully with other latency reactivating agents,” says Dandekar. “The thing that’s really exciting is that the molecule is in the drug PICATO, which treats skin cancer. It’s already approved and being used by patients.”

    Now the UC Davis group hopes to extend PICATO’s uses to attacking HIV latency as well, and is launching a small clinical trial to test the drug’s safety in HIV patients. If the trial is successful, the team hopes to combine PICATO, and other drugs that reactivate HIV, with immunotherapies that would destroy the virus as it comes out of hiding.

    “It will have to be a combination,” says Dandekar. “Just reactivating HIV from latency won’t be enough. We need to position the patient so those reactivated cells can be cleared.”

    Reboot the system

    UC Davis researchers are moving another promising approach into clinical trials as well. It involves taking blood stem cells from patients, genetically engineering them with anti-HIV genes, and returning them to the patients – essentially “rebooting” their immune systems and empowering them to eradicate or adequately suppress remaining HIV on their own over the long term.

    “We are using our understanding of basic HIV biology to engineer each patient’s own stem cells to fight the virus,” says Joseph Anderson, an assistant adjunct professor who researches infectious diseases at the UC Davis Institute for Regenerative Cures, the university’s main stem cell research center. “We’re hoping that by reintroducing these cells in a bone marrow transplant, we can rebuild the immune system to resist HIV.”

    Temp 3

    Anderson and Mehrdad Abedi, a hematology professor and stem cell transplant specialist, are trying to replicate the treatment that cured Timothy Brown, also known as the “Berlin Patient.” Brown received a stem cell transplant from a donor whose genome contained an HIV-resistant mutation. That was seven years ago – and Brown remains HIV-free.

    Anderson, who has been investigating anti-HIV genes since he was a Ph.D. student, is using three different genes to attack the virus, each one hitting a different mechanism associated with HIV infection. Like the drug cocktails used for HAART, multiple attack vectors may reduce the virus’s ability to evade treatment.

    But a new key to the UC Davis team’s gene therapy strategy is also an improved viral vector that Anderson developed to help boost the treatment’s potency. The vector contains a gene that “tags” the surface of the stem cells that are HIV-resistant, allowing researchers to maximize their volume and potential power by culling out non-resistant cells before transplantation.

    Anderson and Abedi have received an $8.5 million grant from the state’s stem cell agency, the California Institute for Regenerative Medicine or CIRM, to conduct the trial. The study will test the engineered stem cells in patients with HIV-related lymphoma, since they already require bone marrow transplants to treat their cancer. This trial will also test the therapy’s safety.

    The team hopes the treatment will be a complete cure, but even a partial response would be great news for HIV patients.

    “Maybe we won’t be able to eradicate it in some patients,” said Anderson, “but hopefully we are giving them enough of an HIV-resistant immune system that they can live the rest of their lives without having to take the antiretroviral drugs.”

    See the full article here .

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    UC Davis Campus

    The University of California, Davis, is a major public research university located in Davis, California, just west of Sacramento. It encompasses 5,300 acres of land, making it the second largest UC campus in terms of land ownership, after UC Merced.

     
  • richardmitnick 2:27 pm on October 15, 2015 Permalink | Reply
    Tags: AIDS, ,   

    From Brown: “Team describes rapid, sensitive test for HIV mutations” 

    Brown University
    Brown University

    October 15, 2015
    David Orenstein
    david_orenstein@brown.edu
    401-863-1862

    1
    RNA reconnaissance
    A Brown team has developed a new method for analyzing the the RNA (green strands) of HIV for mutations (red dot) that convey drug resistance. The system does not require transcription of RNA to DNA, as current technologies do, and works. Image: Lei Zhang/Brown University

    Tests that can distinguish whether HIV-positive people are infected with a drug-resistant strain or a non-resistant strain allow patients to get the most effective treatment as quickly as possible. In the November edition of the Journal of Molecular Diagnostics, a team of Brown University researchers describes a new method that works faster and more sensitively in lab testing than the current standard technologies.

    The main advance enabling that improved performance is that the system operates directly on the virus’ more readily available RNA rather than requiring extra, potentially error-prone steps to examine DNA derived from RNA. In a single tube, the system can first combine two engineered probes (ligation) if a mutation is present and then make many copies of those combined probes (amplification) for detection.

    “LRA (ligation on RNA amplification) uniquely optimizes two enzymatic reactions — RNA-based ligation, and quantitative PCR (polymerase chain reaction) amplification — into a single system,” said Anubhav Tripathi, professor of engineering at Brown and corresponding author on the paper. “Each HIV contains about 10,000 nucleotides, or building blocks, in its genetic material, and a drop of blood from a patient with resistant HIV can contain thousands to millions of copies of HIV. To find that one virus, out of thousands to millions, which is mutated at just a single nucleotide is like finding a needle in a haystack.”

    The experiments reported in the paper show that the LRA test was sensitive enough to find a commonly sought K103N mutation in concentrations as low as one mutant per 10,000 strands of “normal” viral RNA. The LRA detection worked within two hours, while alternative technologies such as ASPCR or pyrosequencing, can take as long as eight.

    LRA works by sending in many copies of a pair of short engineered probes of genetic material to complement the RNA in the HIV sample. Under optimized conditions, those pairs that perfectly match the target HIV RNA containing a mutation that causes drug resistance can rapidly become fused together, or ligated, by an enzyme. If there is a single nucleotide difference, the pair won’t fuse.

    The fusing of the engineered genetic probes is designed to happen at room temperature. After a short period, the LRA system then heats the slightly alkaline solution, which shuts off the fusing reaction but turns on the amplification (copying) of fused pairs. That allows the LRA system to produce a strong signal of fused pairs, if there are any. All this happens in a single step, without any need to change solution.

    Aiming for the clinic

    The development of LRA is the product of a collaboration led by Tripathi and Dr. Rami Kantor, associate professor of medicine in the Warren Alpert Medical School. Kantor, who is also an HIV specialist at The Miriam Hospital and co-senior author of the paper, works in developing nations such as Kenya and India, monitoring HIV resistance. One day when Tripathi was at the Lifespan/Tufts/Brown Center for AIDS Research Retrovirology Core Laboratory to discuss his work, Kantor suggested a collaboration with the end goal of developing a cheap, quick and accurate HIV drug resistance mutation detection system for use in developing nations.

    “We met soon thereafter and started working together on various developments and implementations of the ideas and on the integration of our worlds,” Kantor said.

    The authors acknowledge in the paper that what they demonstrate, while successful in the lab, is clearly not ready for deployment in the field. The lab tests, for example, are shown to work on HIV RNA derived from plasmids, laboratory viral strains, not on samples from circulating viruses found in ailing patients. The RNA fragments were prepared in Kantor’s lab by Dr. Mia Coetzer, assistant professor of medicine and a co-author on the paper.

    “The next steps are to continue the development of LRA and other methods on patient samples to detect additional mutations and address specific HIV challenges related to mutation detection, such as enormous genomic diversity,” Kantor said, “and work on incorporation of such methods onto a point-of-care device that would satisfy the infrastructure and low-cost needs of resource limited settings.”

    Lei Zhang, a biomedical engineering graduate student in Tripathi’s lab is the lead author on the paper. In addition to Zhang, Coetzer, Tripathi, and Kantor, the paper’s other authors are Jingjing Wang (now at PerkinElmer) and Stephanie Angione (now at Massachusetts General Hospital). within one solution (purple droplet).

    See the full article here .

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    Welcome to Brown

    Brown U Robinson Hall
    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.

     
    • serodiscordant canuck 9:06 pm on October 15, 2015 Permalink | Reply

      Great News….It took my partner 2months for his genotype/drug resistance test here in Canada. We are in NS and it is shipped to the other side of the country! Great news…

      Like

  • richardmitnick 6:58 am on October 9, 2015 Permalink | Reply
    Tags: , AIDS, ,   

    From AAAS: “AIDS pioneer finally brings AIDS vaccine to clinic” 

    AAAS

    AAAS

    8 October 2015
    Jon Cohen

    1
    HIV’s gp120 (brown triangle) docking onto a CD4 receptor (grey finger) that studs a white blood cell. Subramaniam Lab/CCR/NCI/NIH. © 2014 Veronica Falconieri.

    Human trials of more than 100 different AIDS vaccines have taken place since researchers proved in 1984 that HIV caused the disease. Robert Gallo, whose U.S. National Cancer Institute laboratory published the four landmark papers in Science that convinced the world of the link between this recently discovered retrovirus and the growing epidemic, has closely monitored—and often sharply critiqued—the AIDS vaccine search since it began. But Gallo, who now runs the Institute of Human Virology (IHV) in Baltimore, Maryland, has always been a spectator—until today.

    Gallo’s team has been developing a vaccine with an unusual method of protection for 15 years and is now launching the first clinical trial of it in collaboration with Profectus BioSciences, a biotech that spun off from IHV recently. Known as a phase I study, the trial expects to enroll 60 people and will simply assess safety and immune responses of the full-length single chain vaccine. “It’s a terrible name,” says Gallo, who is not one to mince words.

    The vaccine contains a version of HIV’s surface protein, gp120, engineered so that it links to a few portions of a protein called the CD4 receptor. When HIV infects cells, gp120 first binds to the CD4 receptor on white blood cells and then “transitions” in such a way that hidden parts of the virus are exposed, allowing it to bind to a second receptor on the immune cells called CCR5. Once bound to both receptors, HIV can enter the white blood cell and establish an infection. The IHV vaccine aims to generate antibodies that bind to HIV’s gp120 when it’s in this transitional state, ultimately blocking attachment to CCR5, aborting the infection process. The development of the vaccine is being led by IHV’s George Lewis, whose team includes Antonio DeVico and Timothy Fouts.

    Gallo, 78, says it has taken a long time to move this vaccine into the clinic because he and his group have done extensive testing in monkeys, faced the typical vaccine challenges of manufacturing a human-grade product, and have had to scramble for funding. “Was anything a lack of courage?” asks Gallo, who frequently asks and answers his own questions. “Sure. We wanted more and more answers before going into people.”

    See the full article here .

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

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  • richardmitnick 8:47 am on October 5, 2015 Permalink | Reply
    Tags: AIDS, , , , Pegivirus   

    From COSMOS: “The virus that could help stop HIV” 

    Cosmos Magazine bloc

    COSMOS

    5 Oct 2015
    Viviane Richter

    Researchers are starting to unravel the secrets of a virus that not only doesn’t make you sick, but can help you fight off other diseases.

    1
    Macaque monkeys can become infected with the primate version of the pegivirus Credit: egortupikov/gettyimages

    We’ve all heard of friendly bacteria, but a friendly virus? Called the pegivirus, catching it doesn’t make you sick. Instead, it can help the immune system to keep HIV infections in check. Discovered in 1995, scientists do not understand how it works, but that could soon change. Researchers at the Wisconsin National Primate Research Centre recently discovered baboons have their own pegivirus strain, offering a new way to study the oddball virus. Their investigation, published in Science Translational Medicine in September, may inspire new ways to tackle HIV.

    The pegivirus is found in about one in every six people, with infections lasting up to a decade before being cleared from the body. It can be transmitted from mother to child, through contact with an infected person’s blood, or sexually. In the US, where the virus is not included in routine blood bank screens, an estimated 1,000 people receive pegivirus-positive blood or blood products each day.

    While the pegivirus is genetically related to the hepatitis C virus, it doesn’t cause disease. On the contrary, researchers discovered in 2001 that the pegivirus appeared to protect some HIV-positive patients from developing AIDS. An 11-year study of 362 patients found 56% of HIV-positive people who did not carry pegivirus died. But among those patients infected with the pegivirus, the death rate was only 29%.

    How pegivirus thwarts HIV “has really been a bit confusing”, says Stephen Kent, an immunologist at the University of Melbourne. “But if you could mimic that with something that’s more potent – that would be good.”

    So what’s the pegivirus’ secret? “That’s the million-dollar question,” says Adam Bailey, lead author of the new study. Researchers need to study the pegivirus in an animal before it can be answered – one where the virus behaves much as it does in humans, happily cohabiting with its host without causing disease. Macaques failed the test: after being given human pegivirus they quickly cleared the infection. Maybe it was a matter of finding a money-version of the virus? Primates are known to carry viruses closely related to those we carry. For instance many primate species carry a virus closely related to HIV, called Simian Immunodeficiency Virus (SIV)
    .

    So Bailey’s team hunted for a pegivirus that had struck up a long-term relationship with a non-human primate. They found it in 30-year-old samples of baboon blood stashed in a colleague’s freezer. Although that virus was genetically similar to the human strain, when it was injected into macaques it stayed in their blood for up to 200 days without causing harm, long enough for the researchers to study it.

    The researchers euthanised some infected monkeys, analysed their tissues for pegivirus RNA, and found most of the virus nestled in the spleen and bone marrow. These are also the tissues where HIV holes up. Pegivirus appeared to be actively replicating only in bone marrow, since removing the spleen of an infected monkey did not change the blood levels of the virus.

    The fact that pegivirus and HIV are replicating in the same tissues – though not necessarily in the same cells – offers a further a clue to how pegivirus may thwart HIV, says the study’s senior author, David O’Connor.

    When the immune system detects an invading virus, it pumps out more T cells – the infantry of the immune army. Alas that strategy plays right into the enemy’s hands since HIV replicates in and destroys those very cells. More T cells are produced to make up the casualties, giving HIV more cells to exploit. This vicious cycle decimates the immune system.

    2
    Cell infected with HIV. HIV attacks T cells, which are crucial in the body’s immune system. The pegivirus helps the body resist HIV.Credit: THOMAS DEERINCK / NCMIR / getty images

    The researchers found pegivirus seems to slow the recruitment of new T cells from bone marrow. Kent speculates the pegivirus might prompt T cells to make molecules that lock HIV out. For instance the anti-HIV drug Maraviroc acts this way by blocking the CCR5 receptor on T cells.

    The Wisconsin team’s next step will be to co-infect macaques with pegivirus and SIV, the monkey form of HIV, to see how the viruses interact. They hope that once they discover how the pegivirus blocks HIV, they’ll be able to mimic the action with a drug.

    Today’s antiretroviral drugs are good at keeping HIV at bay – it’s estimated they’ve lowered the number of HIV deaths by two-thirds. But as O’Connor says “there’s a lot of space to help people even further”

    See the full article here .

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  • richardmitnick 10:31 am on August 2, 2015 Permalink | Reply
    Tags: AIDS, ,   

    From Technion: “New Strategy for HIV” 

    Technion bloc

    Technion

    02/08/2015
    No Writer Credit

    In light of the limitations of existing drugs for AIDS:
    Researchers at the Technion Faculty of Biology offer a new strategy to combat the HIV-1 virus

    1
    The illustration appearing on the cover of the Journal of Virology

    The AIDS epidemic continues to take the lives of millions around the world. Despite the resistance of the body cells that are attacked, and despite the use of dedicated drugs, HIV-1 virus manages to survive and reproduce in the living cell and is displaying increasing resistance.

    In light of the partial failure of existing drugs, the strategy of medical research in this field is changing: instead of focusing on the proteins of the virus (and the development of drugs that target them), the new strategy focuses on the interactions of the virus proteins with the host cell.

    This strategy is far more effective, since the virus cannot survive and reproduce without relying on the cellular mechanisms of the host cell. However, the new strategy also has its weaknesses.

    Assistant Prof. Akram Alian of the Technion Faculty of Biology explains that when the virus encounters a barrier on its way into a cell, it looks for ‘detours’ that will enable it to take advantage of the cell nevertheless. Since there is redundancy in the host cell – various mechanisms leading to the same operation – the virus may exploit a self-mutation that could enable it to make use of that detour. “Our hypothesis is that the redundancy in the cellular pathways may represent a survival mechanism that allows the virus to take advantage of a wide variety of similar processes,” says Assistant Prof. Alian. “The virus can use these detours when the favored route is blocked by natural cellular mechanisms or artificial drugs and under other circumstances in which it is better for the virus to circumvent the obstacles of the cellular environment and the various stages of replication.”

    Assistant Prof. Alian and research assistant Dr. Ailie Marx present an abstract of the innovative concept in a paper that was published in the May issue of the Journal of Virology. Janine McCaughey, a visiting student in the lab, illustrates this idea with a drawing of HIV-1 as an octopus whose arms represent takeover paths. The illustration appears on the cover of the issue (http://jvi.asm.org/content/89/12.cover-expansion).

    2
    Assistant Prof. Akram Alian

    An earlier article, published in the journal Cell Structure in October 2014, reviewed a new approach to AIDS research developed by scientists at Assistant Prof. Alian’s laboratory. The researchers conducted a comparison of an important viral protein (integrase) that exists in both HIV-1 and FIV, the AIDS pathogen in cats, and discovered new differences

    that could aid in the understanding and prediction of the development of resistance. With both viruses, the integrase inserts the viral DNA into the DNA of the infected cell, and then replicates itself in a manner that enables it to spread throughout the body.

    “The virus is a kind of Trojan horse, which uses the host’s genome in order to replicate,” explains Assistant Prof. Alian. “Now we are studying this issue in depth and trying to develop this idea of ‘multiple route reproduction of the HIV virus,’ as a new strategy in the treatment of AIDS.”

    See the full article here.

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    Technion Campus

    A science and technology research university, among the world’s top ten,
    dedicated to the creation of knowledge and the development of human capital and leadership,
    for the advancement of the State of Israel and all humanity.

     
  • richardmitnick 3:00 am on March 12, 2015 Permalink | Reply
    Tags: AIDS, , ,   

    From New Scientist: “HIV’s hiding places at last revealed by simple scan” 

    NewScientist

    New Scientist

    09 March 2015
    Clare Wilson

    1
    (Image: medicalrf.com/Getty)

    It’s like using heat cameras to catch criminals on the run, but it finds HIV instead. A novel scanning technique is enabling researchers to pinpoint where in the body HIV is lurking.

    “This could really help with the research for a functional cure,” says Alan Winston of Imperial College London, who was not involved in the study.

    Today’s potent drug treatments can eradicate HIV from the blood, but the virus must survive elsewhere in the body, because it returns when people stop taking these drugs.

    It has been assumed that the virus hides out in immune cells at various “sanctuary sites”, either replicating very slowly or becoming completely dormant. Supporting this, biopsies reveal the virus in sites such as patches of immune tissue in the gut.

    Sanctuary sites

    One strategy to eradicate HIV completely might be to somehow wake up the hiding virus and then kill it. Research into this “kick and kill” strategy is ongoing, but little is known about which sanctuary sites are the most important, what the virus is doing there and whether existing drugs can reach the sites.

    Francois Villinger of Emory University in Atlanta and colleagues wondered if a PET scanning approach, which is also used to show the spread of cancer, could reveal the location of the virus. This idea was prompted by the discovery of an antibody that binds strongly to SIV, the monkey version of HIV.

    To test the idea, the team injected radioactive antibodies into three monkeys with SIV that were being treated with antiviral drugs. PET scanning, which can detect the location of radiation sources within the body, revealed the viral protein, called gp120, in a range of sites including the nose, lungs, gut, genitals and lymph nodes in the armpits and groin. The antibody could not get into the brain, however, which is thought to be another sanctuary site.

    The scans were not detailed enough to reveal which specific cells the virus protein was in, but tests after the monkeys were killed confirmed that the virus was present in the immune cells of the areas identified by the scan.

    Kick and kill

    Although the technique won’t show up a virus that is completely dormant, just being able to see where there is low viral replication is a major advance, says Winston. “It’s the first paper that has allowed us to visualise viral reservoirs.”

    The next step would be to develop antibodies that can recognise the gp120 protein made by the human strain of the virus. Scans made using these could aid researchers working on kick-and-kill strategies, and help investigate the rare cases where people seem to have been cured of HIV.

    This has been claimed for a handful of people who were given bone marrow transplants from donors whose immune cells are resistant to HIV, as well as for an infant who was given antiviral drugs straight after birth.

    Initially after that child – the so-called Mississippi baby – was taken off the drugs, there was no virus detectable in her blood, and her doctor claimed a cure. Unfortunately, after four years the virus returned and she had to restart drug treatment.

    The PET scanning technique could help in such cases, Villinger speculates, by revealing if the virus is present in sanctuary sites.

    See the full article here.

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  • richardmitnick 3:40 pm on February 20, 2015 Permalink | Reply
    Tags: AIDS, , ,   

    From FightAIDS@Home at WCG: “The end of the beginning is near for FightAIDS@Home” 

    WCGLarge
    WCG new
    World Community Grid

    FAAH
    FightAIDS@home

    20 Feb 2015
    The FightAIDS@Home research team

    Summary
    Thanks to the incredible generosity of World Community Grid volunteers, the FightAIDS@Home project team has finished with an important stage of their project. The research team has refocused on analyzing their existing results and preparing for the end of this historic grid computing stage.

    ________________________________________________________________

    FightAIDS@Home has been running on World Community Grid in some form almost since the beginning of World Community Grid itself: our project launched in 2005. Thanks to the enormous and ongoing support of our worldwide community of volunteers, we have expanded the scope of our research and explored new targets and drug candidates that we simply could not imagine at the outset. It hardly seems sufficient to say thank you for donating over 330,000 years of processing time to support our research, but once again, from all of us to all of you: thank you. Clearly we could not do this research without you.

    With your help, we have reached a new milestone: no new AutoDock (AD) or AD Vina docking experiments are currently being generated. Put another way: we’re done creating new work tasks. The AutoDock queue is now empty, and the AD Vina queue has more than a year’s worth of jobs left. Most of our efforts have shifted towards analysis.

    The analysis of the FightAIDS@Home data has several levels of difficulty due to the sheer amounts of data, which are comprised of several structures of any drug target as well as millions of small molecules, resulting in hundreds of millions of data points. We are attempting to use a couple of approaches to mine this data, one of which includes examining amino-acids involved in top-ranked dockings. Another approach is to investigate the atomic coordinates of important interactions (pharmacophore) between the protein and the small molecule that was docked. Figures 1 and 2 (below) illustrate a simple example of inhibitor TL3 (Figure 1) and the predictions of 1 experiment (Figure 2, ~5.5 million dockings on 1 protein structure). Of course, these evaluations must be done with a large set of known inhibitors and across myriad protein structures. Once these methods pass a high level of confidence, molecules will be bought and sent to collaborators to be tested.

    1
    Figure 1. Docked pose of known HIV-1 protease inhibitor TL3 in an HIV-1 protease structure (not shown). Spherical representations (accompanied with dots, orange for TL3, green for a water molecule) represent important locations for protein-ligand interactions that are used to evaluate if a molecule may be a good drug candidate. The green sphere represents the location of an important (“flap”) water molecule often observed in HIV-1 protease co-crystal structures. The 2 orange spheres directly below the green sphere represent two locations of an interaction with significant amino acids (Asp25) of HIV-1 protease.

    3
    Figure 2. Same docked pose of TL3 in HIV-1 protease as Figure 1 with top percentage of interactions from 1 experiment (pink spheres) and several predictions (transparent surfaces) for important protein-ligand interactions. Note that the water molecule (green) and the 2 orange interactions below it are always predicted.

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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.

     
  • 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
    ibm

    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.

    ScienceSprings relies on technology from

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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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