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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.

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  • richardmitnick 10:20 am on July 18, 2016 Permalink | Reply
    Tags: , , HIV AIDS   

    From CNN: “HIV cure study provides insight into 2008 case” 

    1
    CNN

    July 18, 2016
    Meera Senthilingam

    In 2008, one man, Timothy Ray Brown, was cured of HIV.

    Also known as the “Berlin patient,” Brown was considered cured of his infection after receiving two bone-marrow transplants to treat a separate disease he had been diagnosed with a few years earlier: acute myeloid leukemia.

    The bone marrow he received came from a donor whose genes carried a rare mutation that made them resistant to HIV, known as CCR5-delta 32, which was transferred on to Brown.

    Traces of the virus were seen in his blood a few years later, but remained undetectable despite him not being on antiretroviral treatment, meaning he was still clinically cured of his infection, according to his clinicians.

    Despite various attempts on patients after him by scientists using this same approach, including a similar transplant in two Boston patients, Brown remains the only person known about who has been cured of HIV.

    But a new study presented Sunday at the 2016 Towards an HIV Cure Symposium — ahead of the 21st International AIDS conference in Durban, South Africa, this week — revealed data on a new set of HIV positive patients whose reservoirs of HIV have fallen to very low levels after receiving a range of stem cell transplants similar to Brown’s.

    The study is part of the EPISTEM project, a European project to investigate the potential for an HIV cure using stem cell transplantation, and provides further insight into the science underlying Brown’s success.
    Everyone included in the project is in need of stem cell transplantation to cure severe blood disorders, in addition to being infected with HIV.

    Can stem cells bear a cure?

    The 15 patients monitored in the study to date are still on antiretroviral treatment, unlike Brown, but have received stem cell transplants. Three of them had their operations three years ago and have been studied in detail since.
    “In two of the three patients we were unable to detect infectious virus in the blood of the patients,” said Annemarie Wensing, a virologist at the University Medical Center Utrecht who led the study. Tissue samples were also studied and one patient also had just traces of the virus hiding there.

    “All HIV-infected patients that received a stem cell transplantation had a significant reduction of the viral reservoir in their body. This has not been demonstrated with other cure strategies,” Wensing said.
    The minute levels of the virus that have been seen to date were not considered competent enough to replicate, according to the team.
    “[This] will help us shape future HIV eradication strategies that could be applied at a larger scale than stem cell transplantation,” said Wensing.

    But there’s a long road ahead.

    “What’s interesting is that these patients have survived more than a year,” said Sharon Lewin, director of the Peter Doherty Institute for Infection and Immunity and co-chairwoman of the symposium. “There was concern that maybe when you take a CCR5-delta32 bone marrow it doesn’t engraft as well, but these patients have survived to 12 months.”
    The next step will have to explore how they fare without treatment, Lewin added.

    How the transplant works

    The process of transferring resistance to HIV is extremely complicated — and rare.
    Firstly, only 1% of Caucasians are estimated to carry the CCR5-delta 32 mutation that confers resistance to HIV, with other races having even fewer numbers. The genetic change means people lack a protein needed by HIV to enter blood cells.

    The team also cannot be 100% sure whether the mutation is the only cause of the resistance to HIV or whether the many other stages of the transplant process play a role.

    These include the body being totally cleared of its immune system using chemotherapy and irradiation ahead of it being rebuilt by the donor stem cells, and the potential for the newly formed immune cells to attack any remaining old ones that may be harboring HIV. Patients can also have one or two transplants.

    “All those factors may be really important and we’re trying to tease it out,” said Monique Nijhuis, also from the Utrecht Medical Center who works on the project.

    The unique and rare nature of the blood disorders affecting the patients also means they receive different treatments rather than everyone receiving the same treatment for comparison.

    “Each person is like a micro-clinical trial in himself or herself,” said Asier Saez-Cirion from the Institut Pasteur, also involved in the project.

    What the team does know, however, is that monitoring these patients and the new participants being recruited globally will help them understand where the virus hides within the body — known as reservoirs — and the biology involved in clearing these reservoirs to leave levels of the virus undetectable.

    “We want to know the mechanisms behind HIV cure … to understand [what] is important for the decline in HIV and why there was a cure in the Berlin patient,” said Nijhuis. “This will give us a sense of biomarkers … for the HIV reservoirs and to predict what will happen after we stop treatment.”

    The main drawback, however, is the impracticality of applying this process to more than a handful of people and the resulting unlikelihood of it becoming a generic cure.

    In 2015, almost 37 million people were living with HIV, of which only 46% were receiving antiretroviral therapy, and 2,1 million were newly infected.

    Not feasible

    “It’s impractical to think we’re going to do that for millions of people,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Disease. “It’s the practicality of saying what is better: a single or two pills a day, or getting chemotherapy, getting a stem cell transplant and then having chemotherapy for a period of time after you get the transplant versus just taking a drug,” he said.

    What Fauci instead feels may be more feasible, and scalable, is using this insight to inform future therapies that involve gene editing, where people may have the CCR5 gene edited out of their cells so HIV can no longer invade them.

    “It’s interesting science and what it might do is serve as the proof of concept that you can do gene editing of someone, as opposed to stem cell transplantation,” said Fauci. He highlighted the fact that the HIV community currently does not have enough budget to provide pills to everyone who needs them, let alone transplants.

    Saez-Cirion agreed. “Bone marrow transplant won’t be applied widely … it’s extremely complex,” he said.

    But with so few cases to date showing either a cure or remission, the EPISTEM team hopes its group of patients will at least provide data to build on the existing — and limited — body of evidence.

    Targeting remission instead

    Fauci does believe the possibility of HIV remission, where levels of HIV are brought down to undetectable levels when people are not taking antiretroviral drugs, is realistic, but by other means. He presented updates on the use of broadly neutralizing antibodies, which as their name suggests could neutralize HIV reservoirs hiding in cells, at the symposium.

    The consensus among HIV cure experts attending the conference was for remission to be the end goal — at least for now.

    “We should not give up on eradication … but I would put my major emphasis on sustained virological remission … to keep people suppressed as low as they can possible be.” Fauci said.

    Remission has been shown in other groups of patients, including one known as the VISCONTI cohort where 14 adults treated for HIV soon after infection stopped taking their drugs three years later and showed no resurgence in the amount of virus found in their blood. The group is considered to be post-treatment controllers of the virus.

    Last year a French teenager was also reported to have similar control, 12 years after stopping treatment. Both groups are monitored by Saez-Cirion’s team at the Institut Pasteur.

    “Remission will be the first step in any case,” said Saez-Cirion. “Then when we get more data on survival in this remission period and more sensitive techniques we can being to talk about a cure.

    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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  • richardmitnick 7:05 am on July 15, 2016 Permalink | Reply
    Tags: , , HIV AIDS   

    From EMBL: “How new HIV drugs lock virus in immaturity” 

    EMBL European Molecular Biology Laboratory bloc

    European Molecular Biology Laboratory

    14 July 2016
    Sonia Furtado Neves

    1
    For HIV to mature, a crucial cutting point has to be exposed. IMAGE: Florian Schur/EMBL

    Study provides insights into workings of new HIV drugs and how virus becomes resistant

    A new type of HIV drug currently being tested works in an unusual way, scientists in the Molecular Medicine Partnership Unit, a collaboration between EMBL and Heidelberg University Hospital, have found. They also discovered that when the virus became resistant to early versions of these drugs, it did not do so by blocking or preventing their effects, but rather by circumventing them. The study, published online today in Science, presents the most detailed view yet of part of the immature form of HIV.

    HIV, the virus that causes AIDS, comes in two forms: immature and mature. The immature form is assembled inside an infected person’s cells. After an immature virus particle has left the cell, it has to change into the mature form before it can infect other human cells. A new group of drugs that inhibit this maturation is currently undergoing clinical trials, but so far it was unclear how exactly these drugs act.

    To go from immature to mature, HIV has to cut the connections between its main building blocks, and rearrange those pieces. John Briggs’ lab at EMBL and Hans-Georg Kräusslich’s lab at Heidelberg University Hospital looked at a particularly important cutting point. It connects building blocks known as the capsid protein and the spacer peptide 1, and if it is not cut, the virus cannot mature. The scientists used a combination of cryo-electron tomography and subtomogram averaging to reveal exactly what this part of the immature form of HIV looks like in 3D. They found that the cutting site is hidden in a position where the virus’ cutting machinery can’t sever it. So for the virus to mature, the structure first has to change, to expose that cutting point.

    “When we looked at the virus with one of these inhibitor drugs on it, we found that the inhibitor doesn’t prevent the cutting machinery from getting in, as you might expect,” says Florian Schur, who carried out the work in Briggs’ lab. “Rather, the drug locks the immature virus structure in place, so that it can’t be cut.”

    2
    The scientists determined the cutting site’s 3D structure in whole HIV particles. IMAGE: Florian Schur/EMBL

    When the new inhibitor drugs were first developed, scientists found that HIV viruses with certain mutations in their genetic sequence were unaffected by the drugs – they were resistant. Having determined what the cutting point looks like and how the drugs act, Briggs and colleagues are now able to understand the effects of those mutations.

    “Rather than stopping the drug from binding, the virus becomes resistant through mutations that destabilise the immature structure,” says Kräusslich. “This allows it to rearrange and be cut even when the drug is in place.”

    The researchers would now like to probe the virus and the inhibitor drugs in even greater detail, to understand exactly how the drugs attach themselves to the viral proteins, and potentially gather data that could help to search for better drugs – or to design them.

    The method used in this study – combined cryo-electron tomography and subtomogram averaging – enables scientists to study structures inside irregular viruses like HIV, or within cells. In essence, the scientists use an electron microscope to obtain a 3D image of the sample – in this case, whole HIV-1 particles. They then identify all the copies of the object they want to study – all the instances of the capsid protein-spacer peptide 1 cutting point – and use software to rotate the 3D image of each copy so that they are all facing the same way. By repeating this procedure with thousands of images, the scientists can obtain an accurate picture. With this approach, researchers can study such samples without having to purify them in a test-tube, which means that they see them in their real state. The EMBL scientists’ work now proves that the method can provide the level of detail that is crucial to understanding how molecular machines work and to informing drug design.

    See the full article here .

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    EMBL European Molecular Biology Laboratory campus

    EMBL is Europe’s flagship laboratory for the life sciences, with more than 80 independent groups covering the spectrum of molecular biology. EMBL is international, innovative and interdisciplinary – its 1800 employees, from many nations, operate across five sites: the main laboratory in Heidelberg, and outstations in Grenoble; Hamburg; Hinxton, near Cambridge (the European Bioinformatics Institute), and Monterotondo, near Rome. Founded in 1974, EMBL is an inter-governmental organisation funded by public research monies from its member states. The cornerstones of EMBL’s mission are: to perform basic research in molecular biology; to train scientists, students and visitors at all levels; to offer vital services to scientists in the member states; to develop new instruments and methods in the life sciences and actively engage in technology transfer activities, and to integrate European life science research. Around 200 students are enrolled in EMBL’s International PhD programme. Additionally, the Laboratory offers a platform for dialogue with the general public through various science communication activities such as lecture series, visitor programmes and the dissemination of scientific achievements.

     
  • richardmitnick 5:46 am on July 15, 2016 Permalink | Reply
    Tags: , HIV AIDS, , ,   

    From UCLA: “Cancer-fighting gene immunotherapy shows promise as treatment for HIV” 

    UCLA bloc

    UCLA

    July 14, 2016
    Enrique Rivero

    1
    Researchers find that potent antibodies can be used to generate a specific type of cell that can be used to kill cells infected with HIV-1. An HIV-infected T cell is shown here. NIAID/Flickr

    A type of immunotherapy that has shown promising results against cancer could also be used against HIV, the virus that causes AIDS.

    In a study published July 11 in the peer-reviewed Journal of Virology, researchers from the UCLA AIDS Institute and Center for AIDS Research found that recently discovered potent antibodies can be used to generate a specific type of cell called chimeric antigen receptors, or CARs, that can be used to kill cells infected with HIV-1.

    CARs are artificially created immune T cells that have been engineered to produce receptors on their surface that are designed to target and kill specific cells containing viruses or tumor proteins. Chimeric receptors are the focus of ongoing research into how gene immunotherapy can be used to fight cancer. But they could also be used to create a strong immune response against HIV, said Dr. Otto Yang, professor of medicine in the division of infectious diseases at the David Geffen School of Medicine at UCLA and the study’s corresponding author.

    Although the human body’s immune system does initially respond to and attack HIV, the sheer onslaught of the virus — its ability to hide in different T cells and to rapidly replicate — eventually wears out and destroys the immune system, leaving the body vulnerable to a host of infections and diseases. Researchers have been looking for ways to strengthen the immune system against HIV, and it now appears CARs could be a weapon in that fight.

    “We took new generation antibodies and engineered them as artificial T-cell receptors, to reprogram killer T cells to kill HIV-infected cells,” said Yang, who is also director of vaccine and pathogenesis research at the AIDS Institute and Center for AIDS Research. “Others have used antibodies against cancer antigens to make artificial T-cell receptors against cancer and shown this to be helpful in cancer treatment.” UCLA is the first to design this strategy for HIV.

    While the receptors approach has been in use for almost 10 years to fight cancer, this is the first attempt to use the technique to treat HIV since 15 years ago, when experiments proved unsuccessful. The new research differs because it takes advantage of new antibodies that have been discovered in the past few years. In the previous trials, researchers had used an early type that was not antibody-based. That approach, however, was abandoned because it was clinically ineffective.

    Here the researchers used seven recently discovered “broadly neutralizing antibodies” that have the ability to bind multiple strains of invading viruses, unlike earlier isolated antibodies that tend to bind few strains. These antibodies were re-engineered as artificial CAR-T cell receptors to have activity against broad strains of HIV. In lab tests, the researchers found that all seven had varying degrees of ability to direct killer T cells to proliferate, kill and suppress viral replication in response to HIV-infected cells.

    Yang notes that “what works in a test tube doesn’t necessarily work in a person,” so the next step is to find strategies to put these receptors into humans. But this therapy shows enough promise to move forward with further research.

    Grants funding this study are the California Institute for Regenerative Medicine (#TR4-06845), the AIDS Healthcare Foundation, and the UCLA AIDS Institute and Center for AIDS.

    Study co-authors, all of UCLA, are Ayub Ali, who was the lead author, Scott Kitchen, Irvin Chen, Hwee Ng and Jerome Zack.

    See the full article here .

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  • richardmitnick 10:34 am on March 28, 2016 Permalink | Reply
    Tags: , HIV AIDS,   

    From Scripps: “Team Uses CRISPR to Hit Hibernating HIV” 

    Scripps
    Scripps Research Institute

    March 28, 2016
    Elie Diner

    HIV is especially difficult to eliminate because it can hibernate in infected patients, eluding current antiretroviral drug therapy.

    Researchers at The Scripps Research Institute (TSRI) have now developed a new method to switch on, or reactivate, hibernating viruses and force them out of hiding. The breakthrough uses the CRISPR/Cas9 system, a genetic engineering tool that can be easily programmed, to target HIV and advance a potential cure.

    “Cas9 has been transformative for biology and in using it we’ve found a more specific and potent way of activating HIV,” said Kevin Morris, associate professor at TSRI and the University of New South Wales.

    1
    “Cas9 has been transformative for biology and in using it we’ve found a more specific and potent way of activating HIV,” says Associate Professor Kevin Morris.

    Morris was a senior author on the study, published recently in Molecular Therapy, with Marc Weinberg, adjunct assistant professor of molecular and experimental medicine at TSRI and professor of molecular medicine and haematology at the University of the Witwatersrand in Johannesburg, South Africa.

    Draining the HIV Reservoir

    HIV infections are currently treated with a combination of antiretroviral therapies (cART) that inhibit different stages in the viral life cycle. Use of these drugs has led to a large reduction in the morbidity, mortality and transmission associated with having HIV.

    However, cART is unable to target hibernating, or latent, HIV. Latency occurs when the viral genome integrates into the genome of an infected cell and enters an inactive state. In this state, there is a reduction in a cellular process called transcription, which is important for making HIV RNA, and no viral genes are produced.

    Cells carrying integrated HIV genomes act as a “reservoir” that enables HIV to come out of latency at any time, begin transcription of the viral genome and produce active virus. Reactivation is poorly understood, but can force many patients to continue cART for the duration of their lives.

    Several latency-reversing agents (LRAs) have been investigated to drive HIV out of hibernation by activating transcription of the HIV genome, yet many have nonspecific and unpredictable effects on cells, leading to a disruption of normal cell division or toxicity and making them unfavorable as therapeutics.

    “We wanted to find a potential LRA that could be as effective as the current therapeutics, but more specific,” said Weinberg of the group’s effort. To do this, the team investigated the use of the “dead” Cas9 (dCas9) system, a variant of the popular CRISPR gene editing system. dCas9 can be programmed to activate transcription at almost any sequence by using small guide RNAs (sgRNAs) that match a given DNA sequences. In this case, the group directed dCas9 to a region of the HIV genome where transcription normally begins.

    dCas9 Marks HIV ‘Hotspot’

    Morris, Weinberg and colleagues designed and tested 23 sgRNAs and analyzed their ability with dCas9 to activate transcription in several cell culture models for latent HIV. They found that targeting a small 20-30 nucleotide window led to strong activation of transcription, about 20-fold better than any of the other sequences targeted.

    The group went on to compare their dCas9 system to several LRAs, some of which have been investigated clinically. By targeting dCas9 to the “hotspot” region the researchers identified, they found that they could activate HIV better than many other methods.

    In addition, the team found its dCas9 system could specifically activate HIV with few off-target effects.

    As with this and other Cas9 therapies, the process of moving this proof-of-concept treatment into the clinic is in its infancy. “The million-dollar question with any of these types of approaches is the cellular delivery, and there are a lot of options for the use of CRISPR that should be looked at when applying these technologies,” said Weinberg.

    In addition to Weinberg and Morris, authors of the study, Potent and Targeted Activation of Latent HIV-1 Using the CRISPR/dCas9 Activator Complex, were co-first authors Sheena M. Saayman and Daniel C. Lazar, and Jonathan R. Hart of TSRI; Tristan A. Scott of the University of the Witwatersrand; Mayumi Takahashi and John C. Burnett of the Beckman Research Institute at the City of Hope; and Vicente Planelles of the University of Utah School of Medicine.

    2
    Key authors of the new paper include (left to right) Marc Weinberg, Daniel Lazar and Sheena Saayman. (Photo by Cindy Brauer.)

    The research was supported by the Strategic Health Innovation Partnerships Unit of South African Medical Research Council with funds received from the South African Medical Research Council, the National Institutes of Health (grants P01 AI099783-01, R01 AI111139-01 and R01 DK104681-01) and the Australian Research Council.

    See the full article here .

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    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.

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  • richardmitnick 2:17 pm on March 25, 2016 Permalink | Reply
    Tags: , HIV AIDS,   

    From Scripps: ” New Findings in Humans Provide Encouraging Foundation for Upcoming AIDS Vaccine Clinical Trial” 

    Scripps
    Scripps Research Institute

    March 28, 2016

    Some people infected with HIV naturally produce antibodies that effectively neutralize many strains of the rapidly mutating virus, and scientists are working to develop a vaccine capable of inducing such “broadly neutralizing” antibodies that can prevent HIV infection.

    An emerging vaccine strategy involves immunizing people with a series of different engineered HIV proteins as immunogens to teach the immune system to produce broadly neutralizing antibodies against HIV. This strategy depends on the ability of the first immunogen to bind and activate special cells, known as , which have the potential to develop into broadly neutralizing antibody-producing B cells.

    A research team has now found that the right precursor (germline) cells for one kind of HIV broadly neutralizing antibody are present in most people, and has described the design of an HIV vaccine germline-targeting immunogen capable of binding those B cells. The findings by scientists from The Scripps Research Institute (TSRI), the International AIDS Vaccine Initiative (IAVI) and the La Jolla Institute for Allergy and Immunology were published in Science on March 25.

    “We found that almost everybody has these broadly neutralizing antibody precursors, and that a precisely engineered protein can bind to these cells that have potential to develop into HIV broadly neutralizing antibody-producing cells, even in the presence of competition from other immune cells,” said the study’s lead author, William Schief, TSRI professor and director, Vaccine Design of the IAVI Neutralizing Antibody Center at TSRI, in whose lab the engineered HIV vaccine protein was developed.

    The body’s immune system contains a large pool of different precursor B cells so it can respond to a wide variety of pathogens. But that also means that precursor B cells able to recognize a specific feature on a virus surface are exceedingly rare within the total pool of B cells.

    “The challenge for vaccine developers is to determine if an immunogen can present a particular viral surface in a way that distinct B cells can be activated, proliferate and be useful,” said study co-author Shane Crotty, professor at the La Jolla Institute. “Using a new technique, we were able to show—well in advance of clinical trials—that most humans actually have the right B cells that will bind to this vaccine candidate. It is remarkable that protein design can be so specific as to ‘find’ one in a million cells, demonstrating the feasibility of this new vaccine strategy.”

    The work offers encouraging insights for a planned Phase 1 clinical trial to test a nanoparticle version of the engineered HIV vaccine protein, the “eOD-GT8 60mer.” “The goal of the clinical study will be to test safety and the ability of this engineered protein to elicit the desired immune response in humans that would look like the start of broadly neutralizing antibody development,” Schief said. “Data from this new study was also important for designing the clinical trial, including the size and the methods of analysis.”

    In June, scientists from TSRI, IAVI and The Rockefeller University reported that the eOD-GT8 60mer produced antibody responses in mice that showed some of the traits necessary to recognize and inhibit HIV. If the eOD-GT8 60mer performs similarly in humans, additional boost immunogens are thought to be needed to ultimately induce broadly neutralizing antibodies that can block HIV.

    The new work also provides a method for researchers to assess whether other new vaccine proteins can bind their intended precursor B cells. This method is a valuable tool in the design of more targeted and effective vaccines against AIDS, providing the ability to vet germline-targeting immunogens before testing them in large, time-consuming and costly clinical trials.

    Looking at blood donated by healthy volunteers, the scientists found B cells that were capable of creating “VRC01-class” antibodies that recognized a critical surface patch, or epitope, of HIV. VRC01-class broadly neutralizing antibodies are a group of antibodies isolated from different individuals that appear to have developed in a very similar way, and it has been hypothesized that the starting VRC01-class B cells were very similar in the different people. The eOD-GT8 60mer is designed to engage these precursor B cells to initiate HIV broadly neutralizing antibody development.

    Other contributors to the paper, HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen, included Joseph Jardine, Daniel Kulp, Colin Havenar-Daughton, Anita Sarkar, Bryan Briney, Devin Sok, Fabian Sesterhenn, June Ereno-Orbea, Oleksandr Kalyuzhniy, Isaiah Deresa, Xiaozhen Hu, Skye Spencer, Meaghan Jones, Erik Georgeson, Jumiko Adachi, Michael Kubitz, Allan decamp, Jean-Philippe Julien, Ian Wilson and Dennis Burton. This work was supported by the International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center; the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard; the Bayer Science and Education Foundation; the Helen Hay Whitney Foundation; Howard Hughes Medical Institute; Bill & Melinda Gates Foundation; and the National Institute of Allergy and Infectious Diseases (P01 AI094419, Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI- ID) 1UM1AI100663, P01 AI82362 and R01 AI084817.)

    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 4:52 pm on March 3, 2016 Permalink | Reply
    Tags: , HIV AIDS,   

    From Scripps: “New TSRI Study Shows HIV Structure in Unprecedented Detail” 

    Scripps
    Scripps Research Institute

    March 3, 2016
    Office of Communications
    Tel: 858-784-2666
    Fax: 858-784-8136
    press@scripps.edu

    A new study from scientists at The Scripps Research Institute (TSRI) describes the high-resolution structure of the HIV protein responsible for recognition and infection of host cells.

    The study, published today in the journal Science, is the first to show this HIV protein, known as the envelope (Env) trimer, in its natural or “native” form. The findings also include a detailed map of a vulnerable site at the base of this protein, as well as the binding site of an antibody that can neutralize HIV.

    HIV trimer
    HIV trimer. No image credit.

    “This structure has been elusive because its fragility typically causes it to fall apart before it can be imaged,” said TSRI Associate Professor Andrew Ward, senior author of the study. “Now that we know what the native state looks like, the next step is to look at vaccine applications.”

    Studying HIV’s Defenses

    Imagine an airplane going in for a landing. Now imagine the airport runway is covered with heaps of barbed wire.

    This is the kind of challenge human antibodies face when they attempt to neutralize HIV.

    “The immune system can generate a response, but those responses can’t effectively hit the virus,” said Ward.

    Ideally, antibodies would be able to target HIV’s Env trimer—three loosely connected proteins that stick out of the virus’s membrane and enable the virus to fuse with and infect host cells. This “fusion machinery” is also a valuable target because its structure is highly conserved, meaning the same vulnerabilities exist on many strains of the virus, and antibodies against these sites could be “broadly neutralizing.” Unfortunately, a “shield” of sugar molecules, called glycans, blocks many antibodies from reaching this region.

    To develop a vaccine against HIV, researchers need a detailed map of these glycans to reveal the small holes in the shield where antibodies might penetrate and neutralize the underlying viral machinery.

    The HIV trimer is notoriously unstable, however, making it hard for scientists to capture a good image. Partly due to this limitation, previous studies at TSRI and other institutions had shown only truncated trimers or high-resolution models of mutation-stabilized trimers. No one had a clear view of the trimer and its glycan defenses in their native form.

    New Techniques Lead to Detailed Map

    In the new study, the researchers employed cryo-electron microscopy (EM)—a 3D imaging technique that enables resolution of atomic-level details. TSRI maintains a state-of-the-art cryo-EM suite that includes a powerful Titan Krios cryo-electron microscope and a new generation of digital camera, the Gatan K2 Summit.

    The researchers devised a strategy to extract and purify the fragile HIV Env trimer from its membrane environment and load it into the microscope for imaging. The process involved the use of an HIV broadly neutralizing antibody, PGT151, previously discovered in the lab of TSRI Professor Dennis Burton (also scientific director of the International AIDS Vaccine Initiative’s (IAVI) Neutralizing Antibody Center and the National Institutes of Health (NIH)-sponsored Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), both at TSRI).

    The resulting images included a more-complete trimer structure than ever seen before. Researchers could see the complete fusion machinery, complex glycans and a vaccine target called the membrane proximal external region (MPER). The structures also demonstrated that the trimer is malleable and can subtly alter its shape. This shape-shifting is both part of its fusion machinery and a way to dodge neutralizing antibody responses.

    The structure also includes a highly detailed picture of the PGT151 site of vulnerability, the most complex and extensive broadly neutralizing epitope (site that antibodies can recognize) yet described. In addition to targeting several glycans on the surface of Env, PGT151 binds to the fusion peptide—rendering the virus unable to infect host cells.

    In addition, the researchers used this more complete trimer to study an antibody that binds to MPER. In the past, 3D structures of this region had only been studied using trimer fragments.

    The findings give researchers a better idea of the antibody traits needed to negotiate the glycan shield. “That’s extremely important to know when you’re trying to develop a vaccine against HIV,” said Jeong Hyun Lee, a graduate student in the Ward lab and first author of the study.

    Ward said the newly solved structure is similar to the Env trimer-mimicking structures being developed for an HIV vaccine and confirms that vaccine strategies are on target. Researchers can now build on that work to develop superior vaccine candidates.

    In addition to Ward and Lee, the other author of the study, “Cryo-EM structure of a native, fully glycosylated, cleaved HIV-1 envelope trimer,” was Gabriel Ozorowski of TSRI.

    This work was supported by the National Institutes of Health (grant UM1 AI100663), the National Institutes of Health (NIH)-sponsored Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI, the International AIDS Vaccine Initiative’s (IAVI) Neutralizing Antibody Consortium through the Bill & Melinda Gates Foundation’s Collaboration for AIDS Vaccine Discovery (grants OPP1084519 and OPP1115782) and the California HIV/AIDS Research Program Dissertation Award. IAVI’s support for the study was made possible in part by the generous support of the American people through the United States Agency for International Development (USAID), which administers the U.S. foreign assistance program providing economic and humanitarian assistance in more than 120 countries worldwide

    See the full article here .

    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.

     
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