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  • richardmitnick 5:26 am on June 17, 2017 Permalink | Reply
    Tags: , HIV AIDS, , ,   

    From Scripps: “Scientists Jump Hurdle in HIV Vaccine Design” 

    Scripps
    Scripps Research Institute

    June 19, 2017 issue
    Madeline McCurry-Schmidt

    1
    The new study shows the structure of an important HIV protein, called the envelope glycoprotein, on a common strain of the virus. (Image courtesy Javier Guenaga.)

    Scientists at The Scripps Research Institute (TSRI) have made another important advance in HIV vaccine design. The development was possible thanks to previous studies at TSRI showing the structures of a protein on HIV’s surface, called the envelope glycoprotein. The scientists used these structures to design a mimic of the viral protein from a different HIV subtype, subtype C, which is responsible for the majority of infections worldwide.

    The new immunogen is now part of a growing library of TSRI-designed immunogens that could one day be combined in a vaccine to combat many strains of HIV.

    “All of this research is going toward finding combinations of immunogens to aid in protecting people against HIV infection,” said TSRI Professor Ian Wilson, Hanson Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI.

    The research, published recently in the journal Immunity, was led by Wilson and TSRI Professor of Immunology Richard Wyatt, who also serves as Director of Viral Immunology for the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center at TSRI.

    The new study was published alongside a second study in Immunity, led by scientists at the Karolinska Institute in Stockholm, which showed that the vaccine candidate developed in the TSRI-led study can elicit neutralizing antibodies in non-human primates.

    “Together, the two studies reiterate how structure-based immunogen design can advance vaccine development,” said Wyatt.

    Solving the Clade C Structure

    HIV mutates rapidly, so there are countless strains of HIV circulating around the world. Of these strains, scientists tend to focus on the most common threats, called clades A, B and C.

    Like a flu vaccine, an effective HIV vaccine needs to protect against multiple strains, so researchers are designing a set of immunogens that can be given sequentially or as a cocktail to people so their immune systems can prepare for whatever strain they come up against.

    In 2013, TSRI scientists, led by Wilson and TSRI Associate Professor Andrew Ward, determined the structure of a clade A envelope glycoprotein, which recognizes host cells and contains the machinery that HIV uses to fuse with cells. Because this is the only antibody target on the surface of HIV, an effective HIV vaccine will have to trigger the body to produce antibodies to neutralize the virus by blocking these activities.

    Building on the previous original research, the scientists in the new study set out to solve the structure of the clade C glycoprotein and enable the immune system to fight clade C viruses.

    “Clade C is the most common subtype of HIV in sub-Saharan Africa and India,” explained study co-first author Javier Guenaga, an IAVI collaborator working at TSRI. “Clade C HIV strains are responsible for the majority of infections worldwide.”

    The scientists faced a big challenge: the clade C envelope glycoprotein is notoriously unstable, and the molecules are prone to falling apart.

    Guenaga needed the molecules to stay together as a trimer so his co-author Fernando Garces could get a clear image of the clade C glycoprotein’s trimeric structure. To solve this problem, Guenaga re-engineered the glycoprotein and strengthened the interactions between the molecules. “We reinforced the structure to get the soluble molecule to assemble as it is on the viral surface,” Guenaga said.

    The project took patience, but it paid off. “Despite all the engineering employed to produce a stable clade C protein, these crystals (of clade C protein) were grown in very challenging conditions at 4 degrees Celsius and it took the diffraction of multiple crystals to generate a complete dataset, as they showed high sensitivity to radiation damage,” said Garces. “Altogether, this highlights the tremendous effort made by the team in order to make available the molecular architecture of this very important immunogen.”

    With these efforts, the glycoprotein could then stay together in solution the same way it remains together on the virus itself. The researchers then captured a high-resolution image of the glycoprotein using a technique called x-ray crystallography.

    The researchers finally had a map of the clade C glycoprotein.

    Vaccine Candidate Shows Promise

    In a companion study, the scientists worked with a team at the Karolinska Institute to test an immunogen based on Guenaga’s findings. The immunogen was engineered to appear on the surface of a large molecule called a liposome—creating a sort of viral mimic, like a mugshot of the virus.

    This vaccine candidate indeed prompted the immune system to produce antibodies that neutralized the corresponding clade C HIV strain when tested in non-human primates.

    “That was great to see,” said Guenaga. “This study showed that the immunogens we made are not artificial molecules—these are actually relevant for protecting against HIV in the real world.”

    In addition to Wyatt, Wilson and Guenaga, the study, “Glycine substitution at helix-to-coil transitions facilitates the structural determination of a stabilized subtype C HIV envelope glycoprotein,” included co-first author Fernando Garces, Natalia de Val, Viktoriya Dubrovskaya and Brett Higgins of TSRI; Robyn L. Stanfield of TSRI and IAVI; Barbara Carrette of IAVI; and Andrew Ward of TSRI, IAVI and the Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID) at TSRI.

    This work was supported by the IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD; grants OPP1084519 and OPP1115782), CHAVI-ID (grant UM1 AI00663) and the National Institutes of Health (grants P01 HIVRAD AI104722, R56 AI084817 and U54 GM094586).

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG) From Scripps Research Institute.


    Scripps

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.


    My BOINC

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 8:37 am on November 21, 2016 Permalink | Reply
    Tags: , HIV AIDS, ,   

    From Science Alert: “Scientists have identified an antibody that neutralises 98% of HIV strains” 

    ScienceAlert

    Science Alert

    17 NOV 2016
    BEC CREW

    1
    WathanyuSowong/Shutterstock.com

    We’re closer than ever to an HIV vaccine.

    Scientists have discovered an antibody produced by an HIV-positive patient that neutralises 98 percent of all HIV strains tested – including most of the strains that are resistant to other antibodies of the same class.

    Due to HIV’s ability to rapidly respond to the body’s immune defences, an antibody that can block a wide range of strains has been very hard to come by. But now that we’ve found one, it could form the basis of a new vaccine against the virus.

    Researchers from the US National Institutes of Health (NIH) found that the antibody, called NG, was able to maintain its ability to recognise the HIV virus, even as the virus morphed and broke away from it.

    It’s also up to 10 times more potent than VRC01 – an antibody in the same class as N6, which has progressed to phase II clinical trials in human patients, after protecting monkeys against HIV for nearly six months.

    “The discovery and characterisation of this antibody with exceptional breadth and potency against HIV provides an important new lead for the development of strategies to prevent and treat HIV infection,” said Anthony S. Fauci from the US National Institute of Allergy and Infectious Diseases.

    An antibody is a protein produced by the immune system in response to harmful pathogens such as bacteria and viruses.

    Antibodies are responsible for identifying and destroying these pathogens by binding to them and either neutralising their biological effects on their own, or signalling to white blood cells to come and destroy them.

    When the researchers exposed N6 to 181 different strains of HIV, it managed to destroy 98 percent of them, including 16 of 20 strains resistant to other antibodies of the same class.

    That’s a significant step up from the VRC01 antibody, which stops up to 90 percent of HIV strains from infecting human cells.

    And, as the researchers report [Immunity], not only did N6 show extraordinary breadth – it’s coupled that with incredible potency:

    “Of those antibodies being considered for clinical development, there are examples of antibodies that are extremely broad but moderate in potency (e.g. 10E8 or VRC01) or extremely potent and less broad (e.g. PGT121 or PGDM1400).

    However, the discovery of the N6 antibody demonstrates that this new VRC01-class antibody can mediate both extraordinary breadth and potency even against isolates traditionally resistant to antibodies in this class.”

    So why is N6 so successful against HIV?

    The researchers tracked its evolution over time to see how it responded to the shape-shifting defences of the HIV virus, and found that it relied less on binding with parts of the virus that are prone to changing – known as the V5 region – and more on parts that change very little across different strains.

    By attaching to these more consistent parts of the virus, N6 is able to prevent HIV from attaching itself to a host’s immune cells and attacking them – which is what makes HIV-positive people so vulnerable to AIDS.

    “N6 evolved such that its binding was relatively insensitive to the absence or loss of individual contacts typically found in the VRC01 class,” the team reports.

    They also found that mutations of the HIV virus that happened to be resistant to N6 rarely cropped up, which suggests that the virus couldn’t respond to this antibody as quickly as it has with other treatments scientists have discovered recently.

    “The rare occurrence of N6 resistance mutations suggests that such mutations come at a relatively high fitness cost, which might represent a partial barrier to the selection of resistant mutants,” the team explains.

    Of course, these results have so far only been demonstrated in the lab, so until we see the same levels of success in actual human trials, we need to remain cautiously optimistic.

    But with a recent trial of a different treatment appearing to have erased HIV from a patient’s blood, and researchers honing in on whatever seems to be preventing one in 10 kids from catching the virus, we’re making real progress against the disease.

    Maybe this is how we end up beating it.

    See the full article here .

    Please help promote STEM in your local schools.

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    Stem Education Coalition

     
  • richardmitnick 8:00 am on October 1, 2016 Permalink | Reply
    Tags: , , , HIV AIDS,   

    From FightAIDS@ WCG: “FightAIDS@Home Team Expands Techniques, Refines Phase 1 Results, and Collaborates on a New Study” 

    New WCG Logo

    WCGLarge

    World Community Grid (WCG)

    30 Sep 2016
    By: The FightAIDS@Home research team

    Summary
    The FightAIDS@Home team is working with the World Community Grid technical team to create a new sampling protocol, which will more closely predict the binding strengths of potential drugs to their HIV protein targets as determined in real-life experiments. Read about this work, and other news, in this extensive update.

    1
    (Left to right) World Community Grid program manager Juan Hindo with some of the members of the Ron Levy group at Temple University: Ron Levy, Bill Flynn, Junchao Xia, Peng He, Nanjie Deng

    Creating a New Sampling Protocol

    Background

    The simulations running under FightAIDS@Home – Phase 2 have been using two new simulation methods (independent sampling and lambda scheduling) that we tailored for the unique computing environment of World Community Grid.

    faah-phase-ii

    While volunteers have been crunching away, we have been diligently analyzing the results returned to us to determine whether these new protocols are sufficient to both meet our scientific goals and provide the volunteers with efficient, worthwhile computing tasks. The results for the first 106 batches show qualitative agreement with prior benchmarks run on high-performance computing clusters, but some results demonstrate the new simulation protocols are not satisfactory for all types of analysis.

    With the support of our collaborators at the HIV Interaction and Viral Evolution Center (HIVE) and the World Community Grid team, we have been working closely with the World Community Grid software developers to implement a more rigorous simulation scheme that closely mimics the more algorithmically efficient simulations run on non-grid computing resources.

    faah-hive
    Scripps/HIVE

    This new sampling protocol is called asynchronous replica exchange.

    How Asynchronous Replica Exchange Works

    Our Current Process: Currently, multiple copies of a protein-ligand complex (the structure consisting of a drug candidate compound docked with a protein receptor) are sent out to many volunteers and are simulated with no interaction with one another. The collective information from all those simulations are combined during analysis at the very end.

    The New Process: Asynchronous replica exchange allows information from the different copies to be shared and exchanged among all copies dynamically after short periods of simulations, and this process yields the correct equilibrium statistical physics needed for our analysis.

    Benefits of the New Process: Replica exchange drastically increases the efficiency of the computations. This means that, in addition to being more valuable in terms of analysis, (a) future work units will have shorter runtimes, making Phase 2 computations accessible to more volunteers; (b) the number of batches running simultaneously can be increased; and (c) each batch will have shorter total simulation times.

    This new technique was first prototyped and then put to use on our local BOINC-powered grid at Temple University. Now, the World Community Grid software developers are working hard to implement the same technique on the World Community Grid platform. This effort would allow the largest replica exchange simulations (by two orders of magnitude) ever performed, and we anticipate testing to begin in the next few weeks. In the meantime, we will continue to run and extract valuable information from simulations using our current algorithms.

    For more information about this work, see these two articles:

    http://onlinelibrary.wiley.com/doi/10.1002/jcc.23996/abstract

    http://www.sciencedirect.com/science/article/pii/S0010465515002556

    Refining Results from FightAIDS@Home – Phase 1

    We are moving away from benchmarking simulations, and we are working closely with our collaborators and long-time FightAIDS@Home – Phase 1 research scientists at The Scripps Research Institute to collect the best hits from the many virtual screens performed over the last decade. We are in the process of preparing the input files for the top candidates from over 35 million compounds screened in Phase 1 from the ZINC library, a free database of commercially available compounds for virtual screening. Over the next set of batches, volunteers can expect to see research tasks that are geared toward refining the Phase 1 results.

    FAAH

    New Study on Computational Modeling of HIV

    3
    Figure: (Left) ALLINI KF116 (green) bound at the interface of two Catalytic Core Domain (CCD) subunits of HIV-integrase. (Right) ALLINI-2 (green) facilitating interactions between the CCD dimer and the C-Terminal Domain (CTD) of another HIV integrase molecule. Due to the presence of the ALLINI, the interaction between the CTD of one Integrase dimer and the CCD-CCD interface of another Integrase dimer is stabilized; chains of these inter-subunit interactions lead to aggregates.

    An exciting study regarding computational modeling of HIV has come out of a collaboration with our lab and experimentalists at the HIVE Center.

    HIV Integrase is a viral protein which plays a critical role in the replication of the HIV virus. A class of compounds, called allosteric Integrase inhibitors, or ALLINIs, has a unique inhibition mechanism targeting HIV Integrase. ALLINIs act like a glue that causes many Integrase molecules to become tangled together and make it difficult for them to complete their normal job, which is to incorporate HIV viral DNA into the cell’s own DNA.

    Research scientist Nanjie Deng, an associate research professor with the Ron Levy Group at Temple University, has demonstrated with molecular dynamics simulations of HIV Integrase dimers how this process, which is called multimerization, is promoted by the ALLINIs. Deng’s predictions appear to be confirmed by a high resolution crystal structure which will be available later this year. An accelerated publication of his work can be found here.

    We appreciate the support this project has received from World Community Grid volunteers around the globe.

    See the full article here.

    Please help promote STEM in your local schools.
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    Stem Education Coalition

    World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”
    WCG projects run on BOINC software from UC Berkeley.
    BOINCLarge

    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.

    BOINC WallPaper

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

    MyBOINC

    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-

    FightAIDS@home Phase II

    FAAH Phase II
    OpenZika

    Rutgers Open Zika

    Help Stop TB
    WCG Help Stop TB
    Outsmart Ebola together

    Outsmart Ebola Together

    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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  • richardmitnick 1:26 pm on September 13, 2016 Permalink | Reply
    Tags: , , HIV AIDS, ,   

    From Scripps: “TSRI Scientists Discover Antibodies that Target Holes in HIV’s Defenses” 

    Scripps
    Scripps Research Institute

    September 12, 2016

    New Findings Could Lead to New AIDS Vaccine Candidates

    A new study from scientists at The Scripps Research Institute (TSRI) shows that “holes” in HIV’s defensive sugar shield could be important in designing an HIV vaccine.

    It appears that antibodies can target these holes, which are scattered in HIV’s protective sugar or “glycan” shield, and the question is now whether these holes can be exploited to induce protective antibodies.

    “It’s important now to evaluate future vaccine candidates to more rapidly understand the immune response they induce to particular glycan holes and learn from it,” said 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 study, published recently in the journal Cell Reports, was co-led by Burton, TSRI Associate Professor Andrew Ward, also of CHAVI-ID, and Rogier W. Sanders of the University of Amsterdam and Cornell University.

    A Clue to Stopping HIV

    Every virus has a signature structure, like the architecture of a building. By solving these structures, scientists can put together a blueprint showing where HIV is vulnerable to infection-blocking antibodies.

    In the 1990s, scientists discovered that HIV can have random holes in its protective outer shell of glycan molecules. Until now, however, scientists weren’t sure if antibodies could recognize and target these holes.

    Researchers at Cornell and TSRI had previously designed a stabilized version of an important HIV protein, called the envelope glycoprotein (Env) trimer, to prompt rabbit models to produce antibodies against the virus. In the new study, the plan was to reveal HIV’s vulnerabilities by examining where the antibodies bound the virus.

    “From work on HIV-positive individuals, we knew that the best way to understand an antibody response is to isolate the individual antibodies and study them in detail,” said Laura McCoy, a TSRI, IAVI and CHAVI-ID researcher now at University College London, who served as co-first author of the study with TSRI Senior Research Associate Gabriel Ozorowski, also of TSRI and CHAVI-ID, and Marit J. van Gils of the University of Amsterdam.

    To their surprise, when the researchers examined the rabbits’ antibodies, they found three rabbits had produced antibodies that targeted the same hole in Env. It appeared that antibodies could indeed target holes in the glycan shield.

    “This opened up a whole new concept,” said Ozorowski.

    If the immune system was targeting this hole—preferring it to other vulnerable spots on Env—maybe holes would be especially important in designing vaccine candidates.

    Toward Better Antibodies

    By analyzing the genetic sequences of thousands of strains of HIV, the researchers found that 89 percent of strains appear to have a targetable hole in the Env. The virus has a defense mechanism though—it quickly mutates to fill in these gaps.

    The researchers speculate that future vaccines might prompt the immune system to create antibodies to target holes. “Targeting a hole could help the immune system get its foot in the door,” Ozorowski said. Alternatively, the holes may prove a distraction and should be filled in so the immune system can focus on targeting better sites for neutralizing the virus.

    Burton said researchers must investigate the different possibilities, but he emphasized that this new understanding of glycan holes could help researchers narrow down the field of molecules needed in potential HIV vaccines.

    Ward added that this same method of “rational” vaccine design—where researchers use a virus’s precise molecular details to prompt the immune system to produce specific antibodies—can also be applied to efforts to fight other viruses, such as influenza and Ebola viruses.

    In addition to Burton, Ward, Sanders, McCoy, Ozorowski and van Gils, authors of the study, “Holes in the glycan shield of the native HIV envelope are a target of trimer-elicited neutralizing antibodies,” were Terrence Messmer, Bryan Briney, James E. Voss, Daniel W. Kulp, Devin Sok, Matthias Pauthner, Sergey Menis and Jessica Hsueh of TSRI, IAVI and CHAVI-ID; Christopher A. Cottrell, Jonathan L. Torres and Ian A. Wilson of TSRI and CHAVI-ID; Matthew S. Macauley of TSRI; and William R. Schief of TSRI, IAVI, CHAVI-ID and the Ragon Institute.

    This study was supported by CHAVI-ID (grant UM1AI100663), the National Institutes of Health’s HIV Vaccine Research and Design (HIVRAD) Program (grant P01 AI110657), the IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD, grants OPP1084519 and OPP1115782), a Marie-Curie Fellowship (FP7-PEOPLE-2013-IOF), the Aids Fonds Netherlands (grant 2012041), EMBO (grant ASTF260-2013), the Netherlands Organization for Scientific Research (grant 917.11.314) and the European Research Council (grant ERC-StG- 2011-280829-SHEV).

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG) From Scripps Research Institute.

    Scripps

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    WCGLarge

    BOINCLarge

    MyBOINC

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    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 12:39 pm on September 9, 2016 Permalink | Reply
    Tags: , , HIV AIDS, ,   

    From Scripps: “Team Harnesses Antibody Evolution on the Path to an AIDS Vaccine” 

    Scripps
    Scripps Research Institute

    September 12, 2016
    Madeline McCurry-Schmidt

    1
    The new work shows the immune system can be prompted to mimic and accelerate a rare natural process during which antibodies slowly evolve to become better and better at targeting the constantly mutating HIV virus. Shown here is the molecule eOD-GT8 60mer, used in the team’s reductionist strategy.

    A series of new studies led by scientists at The Scripps Research Institute (TSRI) and the International AIDS Vaccine Initiative (IAVI) describe a potential vaccination strategy to jump-start the selection and evolution of broadly effective antibodies to prevent HIV infection. The researchers plan to test this strategy in an upcoming human clinical trial.

    The new studies, published September 8, 2016, in the journals Cell and Science, showed the immune system can be prompted to mimic and accelerate a rare natural process during which antibodies slowly evolve to become better and better at targeting the constantly mutating HIV virus.

    “Although we still have a long way to go, we’re making really good progress toward a human vaccine,” said William Schief, professor at TSRI and director of vaccine design for IAVI’s Neutralizing Antibody Center (NAC) at TSRI, whose lab developed many of the vaccine proteins tested in these studies.

    Schief co-led several of the new studies with TSRI Professor David Nemazee; Dennis Burton, James & Jessie Minor chair of the TSRI Department of Immunology and Microbial Science and scientific director of the IAVI NAC and the National Institutes of Health (NIH) Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID); and Ian Wilson, Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI.

    Developing a Blueprint

    A vaccine needs to elicit those rare antibodies, called “broadly neutralizing antibodies” (bnAbs), which fight a wide variety of strains of HIV—and it needs to elicit them quickly.

    One strategy to accomplish this, which scientists at TSRI have dubbed the “reductionist” strategy, is to find which antibody mutations are most important for making them effective against HIV, then to “prime” the immune system to start making antibody precursors. From there, scientists hope to prompt one important mutation after another with a series of different “booster” shots, deliberately building up a bnAb one step at a time.

    In a recent study in the journal PLOS Pathogens, the scientists created 3D maps of a structure on HIV known as the CD4 binding site. If antibodies successfully attack this site, scientists believe, most strains of HIV could be crippled. The researchers also created high-resolution maps of bnAbs that could bind to the CD4 binding site.

    “This is one of the most complete blueprints we’ve had for this target,” said Jean-Philippe Julien, a research associate in Wilson’s lab at the time of the study, who served as co-first author of the study with TSRI Research Associate Joseph Jardine, IAVI Research Scientist Devin Sok and Bryan Briney, assistant professor of immunology at TSRI.

    The scientists then studied stripped-down versions of the bnAbs to see exactly which components were important in targeting the CD4 binding site.

    With the results from the PLOS Pathogens study, the researchers finally had a guide to which mutations were the most important. They also had a better idea of which antibody-eliciting molecules, called immunogens, could be given in booster shots to trigger the right mutations at the right time.

    “We’re figuring how to boost antibodies to the next step—how to keep walking them along the path to increased breadth and potency after we get them started with a priming shot,” said Jardine.

    Training Promising Antibodies

    This finding set the stage for the three new studies. For the first one, published in Cell, researchers tested a priming immunogen, followed by a series of booster immunogens from the Schief lab. The immunogens were tested in a mouse model, developed by the Nemazee lab, which was engineered to have the genes (the raw materials) to make antibodies with the right mutations to target the CD4 binding site.

    The team found that the elicited antibodies more closely resembled mature antibodies. The sequence of immunogens had done their job.

    “The study showed that the immunogens are working,” said Nemazee. “They mutate the antibody-producing B cells in the right direction.”

    “The elicited antibodies share many genetic features with mature bnAbs and have the ability to neutralize one native HIV isolate as well as multiple other HIV isolates that we modified slightly to make them easier to neutralize,” added Briney, who served as first author of the study with Sok, Jardine, IAVI and TSRI Staff Scientist Daniel Kulp and TSRI Research Assistant Patrick Skog. “We will probably need additional booster immunogens to elicit antibodies that can broadly neutralize native HIV isolates, but our results suggest we are on the right track.”

    In the second Cell study, led by John R. Mascola at the NIH’s National Institute of Allergy and Infectious Disease (NIAID) Vaccine Research Center and Frederick W. Alt, a Howard Hughes Medical Institute (HHMI) researcher at Boston Children’s Hospital and Harvard Medical School, along with TSRI co-authors, took the reductionist approach a step further, showing that it could induce antibodies in mouse models with immune systems that can create an even wider range of antibodies—more similar to the human immune system.

    Results from the Science study further supported the reductionist vaccine approach. For the study, the researchers took on an even bigger challenge—to “prime” antibodies in a mouse model with a human-like immune system developed by Kymab Ltd, a UK-based company.

    The Kymab mouse model’s more complicated immune system made it more difficult for a vaccine protein to find and activate the “precursor” cells that have potential to produce bnAbs against the CD4 binding site. In fact, the researchers estimated that each Kymab mouse contained only one such precursor cell on average—with some mice containing none—among approximately 75 million antibody-producing cells.

    Despite this “needle-in-a-haystack” challenge, scientists found that their vaccine priming protein activated the appropriate antibody precursors in one-third to one-half of mice tested, suggesting this feat would also be possible in humans, where the targeted precursor cells are more plentiful. “This seems to be a much higher bar than we will face in humans,” Schief said.

    “The reductionist vaccine approach we’re undertaking will hopefully not only lead to an HIV vaccine, but also could potentially be applied to other challenging vaccine targets,” said Sok, who served as co-first author of the Science study with Briney, Jardine and Kulp.

    The researchers also gave credit to their strong international collaboration. “Our phenomenal results with the team at The Scripps Research Institute came from work at the interfaces—and boundaries—of vaccine technology, immunology, protein engineering and structural biology,” said Professor Allan Bradley, chief technical officer at Kymab and director emeritus of the Wellcome Trust Sanger Institute.

    IAVI and partners are planning for a clinical trial for next year to further develop and test whether the reductionist vaccine strategy—starting with activating the right precursors—will work in humans. If successful, the next step will be to test their booster immunogens.

    The first Cell study, Tailored Immunogens Direct Affinity Maturation Toward HIV Neutralizing Antibodies, included additional authors from the Ragon Institute. The study was supported by the IAVI through the NAC (grant SFP1849); NIAID grants; CHAVI-ID (grants UM1AI100663, P01AI081625 and R01AI073148); the Ragon Institute; and the Helen Hay Whitney Foundation.

    The second Cell study, Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires, included additional authors from HHMI; Boston Children’s Hospital; Harvard Medical School; the NIH’s NIAID Vaccine Research Center; Vanderbilt University; Columbia University; the Ragon Institute; Fred Hutchinson Cancer Center and the Duke University School of Medicine. This work was supported by the NIH (grants R01AI077595, AI020047, P01 AI094419, U19AI109632, P01-AI104722; CHAVI-ID (grants 5UM1 AI100645 and 1UM1 AI100663); the intramural research program of the NIAID Vaccine Research Center; the IAVI NAC Center; Collaboration for AIDS Vaccine Discovery funding for the IAVI NAC Center; the Ragon Institute and an HHMI Medical Student Fellowship.

    The Science study, Priming HIV-1 Broadly Neutralizing Antibody Precursors in Human Ig Loci Transgenic Mice, included additional authors from Kymab Ltd, the Wellcome Trust Sanger Institute and the Ragon Institute. The study was supported by IAVI, with the generous support of the United States Agency for International Development (USAID); Ministry of Foreign Affairs of the Netherlands; the Bill & Melinda Gates Foundation; the Ragon Institute; the Helen Hay Whitney Foundation; and NIAID (grants P01 AI094419 and CHAVI-ID 1UM1AI100663).

    See also additional Cell and Immunity studies on HIV/AIDS vaccine work led by TSRI scientists and published on September 8.

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG)

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

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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 9:04 am on August 24, 2016 Permalink | Reply
    Tags: , HIV AIDS,   

    From U Washington: “Novel strategy greatly reduces HIV transmission in couples” 

    U Washington

    University of Washington

    08.23.2016
    Brian Donohue

    Providing HIV medication to both members of a HIV-serodiscordant couple substantially reduced the risk of transmission within that couple, according to a study published Aug. 23 in PLOS Medicine.

    The researchers examined the feasibility and acceptability of a program in Kenya and Uganda to offer medications to 1,013 couples in which one member is HIV-positive and the other is HIV-negative.

    The model offered antiretroviral therapy (ART) to reduce the infectiousness of HIV-infected persons and pre-exposure prophylaxis (PrEP) to reduce susceptibility of their uninfected partners. PrEP was offered prior to ART initiation and for the first six months of ART, until the HIV-infected partner would have been expected to achieve viral suppression. Then PrEP was discontinued.

    “Our primary goals were to evaluate this delivery model, but partway through the span of the study, it became clear that HIV transmission rates were considerably lower than would have been anticipated,” said Jared Baeten, a UW Medicine global health specialist and professor in the University of Washington School of Public Health.

    ​He and colleagues at other schools conducted the research, whose preliminary findings were announced last year in Seattle. Couples’ infection status was followed for about one year per couple, on average. The observed rate of HIV transmission was 0.25 percent per year, Baeten said – significantly lower than the expected rate of transmission of 5.0 percent per year.

    Additionally, the study found high acceptance of, and adherence to, the therapy regimen.

    “We learned that the approach is desirable and highly cost-effective and could be delivered affordably to people in that setting,” he said. The researchers noted that this study does not include a concurrent comparison population for HIV transmission because it would have been unethical to enroll a control population and not offer access to therapies proven to work, Baeten said. Nevertheless, the findings suggest a promising strategy in the effort to reverse the HIV epidemic.

    “The results of this project demonstrate that an integrated strategy of ART and PrEP can be delivered feasibly to a high-risk African population and result in almost complete protection from HIV-1 transmission,” the researchers wrote.

    Partner collaborators were the Kenya Medical Research Institute, Makerere University and Kabwohe Clinical Research Centre, in Uganda, and Harvard University, Johns Hopkins University and Massachusetts General Hospital.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 8:16 am on August 3, 2016 Permalink | Reply
    Tags: , HIV AIDS, Researchers at Sandia Northeastern develop method to study critical HIV protein,   

    From Sandia: “Researchers at Sandia, Northeastern develop method to study critical HIV protein” 


    Sandia Lab

    August 3, 2016

    Mollie Rappe
    mrappe@sandia.gov
    (505) 844-8220

    More than 36 million people worldwide, including 1.2 million in the U.S., are living with an HIV infection. Today’s anti-retroviral cocktails block how HIV replicates, matures and gets into uninfected cells, but they can’t eradicate the virus.

    Mike Kent, a researcher in Sandia National Laboratories’ Biological and Engineering Sciences Center, is studying a protein called Nef involved in HIV progression to AIDS with the ultimate goal of blocking it. He and his collaborators have developed a new hybrid method to study this HIV protein that compromises the immune system. The method also could work on many other proteins that damage cellular processes and cause diseases.

    Nef goes to the membrane of the infected cell and tricks the cell into destroying its own immune system signaling receptors, allowing the infected cell to evade the immune system. Nef also hijacks cellular communications to make it easier for the virus to reproduce. In order to interact with the host proteins, Nef needs to change shape.

    This shape-changing protein is so important that rhesus monkeys infected with a version of the closely related Simian immunodeficiency virus that lacks the Nef protein don’t develop immune deficiency symptoms.

    “Nef is a protein essential for AIDS. It accomplishes its missions by altering signaling and receptor trafficking. It binds to critical immune system receptors and then signals your cells to destroy them. If you know how this protein works, you have a better shot at developing drugs to stop it,” said Kent.

    Combining two techniques reveals Nef structure and function

    Kent and Bioanalytical Chemistry professor John Engen’s team at Northeastern University combined two known biophysical techniques to discover how Nef changes structure to perform its functions.

    Kent is an expert at neutron reflectometry, a technique that gets nanometer-scale structural information about films and biological membranes. His team used this technique to compare the global structure of Nef in its membrane-bound form versus its inactive, membrane-free form.

    Engen’s forte is hydrogen-deuterium exchange mass spectrometry, a technique that measures the local structure and flexibility of proteins. The team used it to get information on the local structure and dynamics of Nef when it’s bound to the membrane.

    The global information from the neutron reflectometry shows only the average location of Nef relative to the membrane. The local dynamics from hydrogen-deuterium exchange mass spectrometry are acquired for many small portions of the protein, showing the flexibility of 30 overlapping sections that collectively cover 90 percent of Nef. Together they construct a more complete picture of Nef and its structural changes.

    The global and local, peptide-specific information supported a widely held assumption that, in binding to the membrane, Nef changes its structure to interact with signaling receptors and other host proteins: a hypothesis without support, until now.

    “People have been studying Nef for a long time and there was a model of what people thought the protein might look like and might do. Nef is a difficult protein to study because you can only crystalize the folded part of the protein, and about half of the protein is unstructured. In addition, you can’t study the membrane-bound form by crystallography,” said Kent.

    “It’s the first time anybody had measured these kinds of structural changes and the results were consistent with the hypothetical model,” Kent continued. “Details of these shape changes provide important new molecular insights into how Nef functions.” This method could lead to new assays for drug screening.

    To combine the two techniques, the team first needed to make a special apparatus. It needed to contain a flat lipid monolayer, made of saturated fats, which mimicked the biological membrane. It also had to be integrated with equipment at neutron sources for neutron reflection measurements, and allow rapid exchange of the watery support layer for the hydrogen-deuterium exchange experiments.

    Another challenge was correctly producing the Nef protein. In infected cells, Nef is tagged with a special lipid that serves to anchor Nef to the cell membrane. Engen’s team had to produce Nef that contained this essential lipid, known as a myristate group.

    This work was supported by the National Institutes of Health. The neutron reflection measurements were performed at the Center for Neutron Research at the National Institute of Standards and Technology and the Spallation Neutron Source at Oak Ridge National Laboratory.

    1
    Nef – a critical HIV protein – changes shape. When it is bound to the lipid membrane, it is “open” and able to trick the cell into destroying its own immune system signaling receptors and enhance the replication of the virus. When it is not bound to the lipid membrane, it is “closed” and not able to interact with host proteins. (Image courtesy Sandia National Laboratories)

    New method could answer many questions about HIV, other diseases

    With the hybrid method and unique apparatus in hand, the team is seeking funds to answer additional questions about Nef.

    “We studied it alone; now we want to study it with its binding partners, with the host proteins and the complexes that it forms, and in the presence of drug molecules or inhibitors,” Kent said. “Stopping it from binding with its partners or inhibiting it from adopting the conformation that leads to receptor degradation would have important medical implications.”

    Tom Smithgall of the University of Pittsburgh School of Medicine, a co-author on one of the team’s papers, is currently screening for potential drugs that might block Nef’s actions.

    Kent also hopes to apply this hybrid method to other important structural problems of membrane-associated proteins, including virus maturation; the fusion of viruses with host cell membranes; the workings of bacterial toxins such as botulinum, tetanus and diphtheria; and cell-signaling dysfunctions ranging from cancer to regulating cholesterol levels.

    “There is a lot of potential for combining these two techniques in a more general sense. There are no other ways to get this kind of specific, direct information about essential membrane proteins. This is a significant niche of biological problems that could not be addressed before our work, and we’ve made some big steps forward. The future benefit depends on how broadly we can apply the method beyond just this one HIV protein,” said Kent.

    See the full article here .

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    Sandia Campus
    Sandia National Laboratory

    Sandia National Laboratories is a multiprogram laboratory operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy’s National Nuclear Security Administration. With main facilities in Albuquerque, N.M., and Livermore, Calif., Sandia has major R&D responsibilities in national security, energy and environmental technologies, and economic competitiveness.
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  • richardmitnick 4:35 pm on July 25, 2016 Permalink | Reply
    Tags: , , HIV AIDS, ,   

    From Rockefeller: ” New antibody drug continues to show promise for treatment of HIV” 

    Rockefeller U bloc

    Rockefeller University

    July 25, 2016
    Katherine Fenz
    kfenz@rockefeller.edu
    212-327-7913

    1
    Halting HIV: Antibody treatment delayed the virus (above) from rebounding in patients taken off their anti-retroviral medications.

    Great strides have been made in recent years to develop treatment options for HIV, and the disease can now be controlled with anti-retroviral drugs. But a cure remains elusive and current medications have limitations: they must be taken daily, for life, and can cause long-term complications.

    Now, Rockefeller scientists report that they are one step closer to an alternative treatment that utilizes antibodies. This therapy has the potential for long-acting effects and would allow for less frequent dosing.

    Recently published in Nature, the findings suggest that an antibody called 3BNC117 can effectively delay the virus from rebounding in patients who temporarily suspended their anti-retroviral medications, currently the standard treatment for HIV.

    “These are very positive results,” says Marina Caskey, Assistant Professor of Clinical Investigation in the Laboratory of Molecular Immunology, headed by Michel Nussenzweig. “This is the longest any antibody has been able to delay virus rebound.”

    Keeping HIV at bay

    The 3BNC117 antibody was isolated in the Nussenzweig lab several years ago by guest investigator Johannes Scheid, co-first author of this most recent publication. It was cloned from cells of an HIV-infected patient whose immune system was able to fight HIV particularly well. The virus primarily infects CD4 T cells, part of the immune system that helps protect the body from infection. 3BNC117 stops multiple strains of HIV from hijacking these cells.

    Anti-retroviral drugs suppress HIV by preventing its replication, but the virus remains dormant in the body, mostly in reservoirs within CD4 cells. If a patient stops taking anti-retroviral drugs, the virus is released from these reservoirs, and quickly rebounds.

    This small study, called a Phase IIa clinical trial, builds on a previous study from the Nussenzweig lab, in which HIV-infected patients were given the antibody without receiving other treatment. This time, the researchers tested 13 HIV-infected patients who had been treated successfully with antiviral therapy. The goal of the study was to determine whether the antibody alone would be able to maintain virus suppression in patients that were taken off anti-retroviral drugs.

    Caskey and colleagues found that the antibody was able to delay when the virus came back to about 10 weeks, compared to about 3 weeks in controls.

    Virus under pressure

    One of the many challenges in treating HIV is that the virus quickly mutates. As a result, patients carry many different strains that cannot be eliminated with a single medication, and each person’s virus repertoire is different. An advantage of 3BNC117 is that is has the ability to fight a wide range of HIV strains, but not all; some studies suggest it can neutralize about 80 percent of viral isolates taken from patients.

    In this study, the researchers tried to select participants whose viral strains were likely to be a good target for 3BNC117. However, current testing methods are not very precise in predicting exactly which strains are present, and patients had varied responses.

    “In one-third of participants, rebound happened very late, when the antibody levels were low,” says co-first author and former graduate student in the Nussenzweig lab, Josh Horwitz. “This means that the antibody was effective at suppressing the viruses that are sensitive to it, but it’s also clear that for the remaining patients with different strains of HIV, this antibody is not sufficient.”

    The researchers also found that the antibody was able to reduce the assortment of viral strains that rebounded, which tends to be very diverse in patients taken off antiretroviral medications. “We were excited to see a significant delay in rebound,” says Sheid, “but the reduced diversity of viruses that we saw is also promising because it will take fewer additional antibodies to target them.”

    The next step will be to test 3BNC117 in combination with another HIV-specific antibody, such as 10-1074, which targets the virus from a different angle, and has also been shown to decrease virus levels when given to HIV patients not on treatment.

    “There are a lot of factors at play here, part of which is that we are working with a diverse reservoir of viruses with different sensitivities to different antibodies,” says Caskey. “However, we are hopeful that testing the antibodies in combination will be successful in bringing us closer to better strategies to prevent and treat HIV.”

    This study was supported by the Collaboration for AIDS Vaccine Discovery, the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program, NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Bill and Melinda Gates Foundation, the Robertson Foundation, the Ruth L. Kirschstein National Research Service Award, and other sources.

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG)

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

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    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

     
  • richardmitnick 2:47 pm on July 21, 2016 Permalink | Reply
    Tags: , HIV AIDS,   

    From Princeton: “Study Models How the Immune System Might Evolve to Conquer HIV (PLOS Genetics)” 

    Princeton University
    Princeton University

    July 21, 2016
    Katherine Unger Baillie, courtesy of the University of Pennsylvania

    It has remained frustratingly difficult to develop a vaccine for HIV/AIDS, in part because the virus, once in our bodies, rapidly reproduces and evolves to escape being killed by the immune system.

    “The viruses are constantly producing mutants that evade detection,” said Joshua Plotkin, a professor in the University of Pennsylvania’s Department of Biology in the School of Arts & Sciences. “A single person with HIV may have millions of strains of the virus circulating in the body.”

    Yet the body’s immune system can also evolve. Antibody-secreting B-cells compete among themselves to survive and proliferate depending on how well they bind to foreign invaders. They dynamically produce diverse types of antibodies during the course of an infection.

    In a new paper in PLOS Genetics, Plotkin, along with postdoctoral researcher Jakub Otwinowski and Armita Nourmohammad, an associate research scholar at Princeton University’s Lewis-Sigler Institute for Integrative Genomics, mathematically modeled these dueling evolutionary processes to understand the conditions that influence how antibodies and viruses interact and adapt to one another over the course of a chronic infection.

    Notably, the researchers considered the conditions under which the immune system gives rise to broadly neutralizing antibodies, which can defeat broad swaths of viral strains by targeting the most vital and immutable parts of the viral genome. Their findings, which suggest that presenting the immune system with a large diversity of viral antigens may be the best way to encourage the emergence of such potent antibodies, have implications for designing vaccines against HIV and other chronic infections.

    “This isn’t a prescription for how to design an HIV vaccine,” Plotkin said, “but our work provides some quantitative guidance for how to prompt the immune system to elicit broadly neutralizing antibodies.”

    The biggest challenge in attempting to model the co-evolution of antibodies and viruses is keeping track of the vast quantity of different genomic sequences that arise in each population during the course of an infection. So the researchers focused on the statistics of the binding interactions between the virus and antibodies.

    “This is the key analytical trick to simplify the problem,” said Otwinowski. “It would otherwise be impossible to track and write equations for all the interactions.”

    The researchers constructed a model to examine how mutations would affect the binding affinity between antibodies and viruses. Their model calculated the average binding affinities between the entire population of viral strains and the repertoire of antibodies over time to understand how they co-evolve.

    “It’s one of the things that is unique about our work,” said Nourmohammad. “We’re not only looking at one virus binding to one antibody but the whole diversity of interactions that occur over the course of a chronic infection.”

    What they saw was an S-shaped curve, in which sometimes the immune system appeared to control the infection with high levels of binding, but subsequently a viral mutation would arise that could evade neutralization, and then binding affinities would go down.

    “The immune system does well if there is active binding between antibodies and virus,” Plotkin said, “and the virus does well if there is not strong binding.”

    Such a signature is indicative of a system that is out of equilibrium where the viruses are responding to the antibodies and vice versa. The researchers note that this signature is likely common to many antagonistically co-evolving populations.

    To see how well their model matched with data from an actual infection, the researchers looked at time-shifted experimental data from two HIV patients, in which their antibodies were collected at different time points and then “competed” against the viruses that had been in their bodies at different times during their infections.

    They saw that these patient data are consistent with their model: Viruses from earlier time points would be largely neutralized by antibodies collected at later time points but could outcompete antibodies collected earlier in infection.

    Finally, the researchers used the model to try to understand the conditions under which broadly neutralizing antibodies, which could defeat most strains of virus, would emerge and rise to prominence.

    “Despite the effectiveness of broadly neutralizing antibodies, none of the patients with these antibodies has been cured of HIV,” Plotkin said. “It’s just that by the time they develop them, it’s too late and their T-cell repertoire is depleted. This raises the intriguing idea that, if only they could develop these antibodies earlier in infection, they might be prepared to combat an evolving target.”

    “The model that we built,” Nourmohammad said, “was able to show that, if viral diversity is very large, the chance that these broadly neutralizing antibodies outcompete more specifically targeted antibodies and proliferate goes up.”

    The finding suggests that, in order for a vaccine to elicit these antibodies, it should present a diverse set of viral antigens to the host. That way no one specialist antibody would have a significant fitness advantage, leaving room for the generalist, broadly neutralizing antibodies to succeed.

    The researchers said that there has been little theoretical modeling of co-evolutionary systems such as this one. As such, their work could have implications for other co-evolution scenarios.

    “Our theory can also apply to other systems, such as bacteria-phage co-evolution,” said Otwinowski, in which viruses infect bacteria, a process that drives bacterial evolution and ecology.

    “It could also shed light on the co-evolution of the influenza virus in the context of evolving global immune systems,” Nourmohammad said.

    The work was supported by funding from the U.S. National Science Foundation, James S. McDonnell Foundation, David and Lucile Packard Foundation, U.S. Army Research Office and National Institutes of Health.

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG)

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

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    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

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  • richardmitnick 8:23 am on July 21, 2016 Permalink | Reply
    Tags: , HIV AIDS, , UW team finding is integral to HIV drug-effectiveness puzzle   

    From U Washington: “UW team finding is integral to HIV drug-effectiveness puzzle” 

    U Washington

    University of Washington

    07.19.2016
    Sarah C.B. Guthrie

    1
    Microscopic picture of vaginal epithelial clue cells coated with Gardnerella vaginalis, magnified 400 times. Wikimedia Commons | Dr. F.C. Turner

    Increasingly, people at risk for HIV infection are turning to preventive drug measures to help stave off the virus. Researchers from the University of Washington School of Pharmacy found that one such drug, Tenofovir, in the form of a topical vaginal gel, is metabolized, or broken down, by the common bacterium Gardnerella vaginalis.

    This negative effect counteracts the gel’s intended protection. Women who apply the drug but who have that bacterium are more vulnerable to HIV infection.

    The good news, however, is that Gardnerella, commonly associated with bacterial vaginosis, is relatively easy to detect and treat.

    The finding emerged in the lab of Nichole Klatt, UW assistant professor of pharmaceutics and pathobiology. Grad student Ryan Cheu and postdoctoral fellow Alex Zevin uncovered the mechanism. “These findings open up a whole new field of research in drug efficacy,” Klatt said.

    Their analysis looked at 3,334 genital bacterial proteins from 688 women in the Centre for the AIDS Programme of Research in South Africa trial. The trial, a collaboration of the UW team and lead investigator Dr. Adam Burgener of the University of Manitoba and Public Health Agency of Canada, assessed the ability of Tenofovir gel to block new HIV infection.

    Analysis showed the drug was less effective for a relatively large population of women, and Burgener and Klatt wanted to understand why. In most of the women, lactobacillus was the dominant vaginal bacterium. Burgener discovered that women who have a predominance of “good” lactobacillus in their reproductive tract were better protected by the Tenofovir gel but hadn’t figured out why until Klatt’s team identified Gardnerella’s role.

    Clinics can screen women with a readily available, simple and cheap pH test to quickly discern the greater presence of lactobacillus or Gardnerella, and resolve any imbalance with antibiotic treatment before Tenofovir gel use begins.

    In most of southern and eastern Africa, about 380,000 new HIV infections occur each year in females 16-24 years old. These young women experience HIV rates several-fold higher than their male peers, making the reduction of infection among young women one of the most crucial challenges in HIV prevention in Africa.

    Klatt said the team is following up with studies of other prophylactic drugs administered orally and rectally to learn whether they have the same vulnerability.

    “It is incredibly exciting to have this breakthrough, knowing that it will make a difference in the lives of hundreds of thousands of women at risk for HIV,” she said.

    The research was presented July 19 as part of the AIDS 2016 Conference in Durban, South Africa.

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG)

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    WCGLarge
    WCG Logo New

    BOINCLarge
    BOINC WallPaper

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
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