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  • richardmitnick 4:14 pm on July 14, 2017 Permalink | Reply
    Tags: , HIV/AIDS, , TSRI   

    From TSRI: ” San Diego Team Tests Best Delivery Mode for Potential HIV Vaccine” 

    Scripps
    Scripps Research Institute

    July 17, 2017
    Gina Kirchweger

    For decades, HIV has successfully evaded all efforts to create an effective vaccine but researchers at The Scripps Research Institute (TSRI) and the La Jolla Institute for Allergy and Immunology (LJI) are steadily inching closer. Their latest study, published in a recent issue of Immunity, demonstrates that optimizing the mode and timing of vaccine delivery is crucial to inducing a protective immune response in a preclinical model.

    More than any other factors, administering the vaccine candidate subcutaneously and increasing the time intervals between immunizations improved the efficacy of the experimental vaccine and reliably induced neutralizing antibodies. Neutralizing antibodies are a key component of an effective immune response. They latch onto and inactive invading viruses before they can gain a foothold in the body and have been notoriously difficult to generate for HIV.

    “This study is an important staging point on the long journey toward an HIV vaccine,” says TSRI Professor Dennis R. Burton, Ph.D, 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 vaccine candidates we worked with here are probably the most promising prototypes out there, and one will go into people in 2018,” says Burton.

    “There had been a lot of big question marks and this study was designed to get as many answers as possible before we go into human clinical trials,” adds senior co-author Shane Crotty, Ph.D., a professor in LJI’s Division of Vaccine Discovery. “We are confident that our results will be predictive going forward.”

    HIV has faded from the headlines, mainly because the development of antiretroviral drugs has turned AIDS into a chronic, manageable disease. Yet, only about half of the roughly 36.7 million people currently infected with HIV worldwide are able to get the medicines they need to control the virus. At the same time, the rate of new infections has remained stubbornly high, emphasizing the need for a preventive vaccine.

    The latest findings are the culmination of years of collaborative and painstaking research by a dozen research teams centered around the development, improvement, and study of artificial protein trimers that faithfully mimic a protein spike found on the viral surface. At the core of this effort is the CHAVI-ID immunogen working group, comprised of TSRI’s own William R. Schief, Ph.D., Andrew B. Ward, Ph.D., Ian A. Wilson, D.Phil. and Richard T. Wyatt, Ph.D., in addition to Crotty and Burton. This group of laboratories in collaboration with Darrell J. Irvine, Ph.D., professor at MIT, and Rogier W. Sanders, Ph.D., professor at the University of Amsterdam, provided the cutting-edge immunogens tested in the study.

    The recombinant trimers, or SOSIPs as they are called, were unreliable in earlier, smaller studies conducted in non-human primates. Non-human primates, and especially rhesus macaques, are considered the most appropriate pre-clinical model for HIV vaccine studies, because their immune system most closely resembles that of humans.

    “The animals’ immune responses, although the right kind, weren’t very robust and a few didn’t respond at all,” explains Colin Havenar-Daughton, Ph.D., a scientific associate in the Crotty lab. “That caused significant concern that the immunogen wouldn’t consistently trigger an effective immune response in all individuals in a human clinical trial.”

    In an effort to reliably induce a neutralizing antibody response, the collaborators tested multiple variations of the trimers and immunization protocols side-by-side to determine the best strategy going forward. Crotty and Burton and their colleagues teamed up with Professor Dan Barouch, M.D., Ph.D., Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, who coordinated the immunizations.

    The design of the study was largely guided by what the collaborators had learned in a previous study via fine needling sampling of the lymph nodes, where the scientists observed follicular helper T cells help direct the maturation steps of antibody-producing B cells. Administering the vaccine subcutaneously versus the more conventional intramuscular route, and spacing the injection at 8 weeks instead of the more common 4-6 weeks, reliably induced a strong functional immune response in all animals.

    Using an osmotic pump to slowly release the vaccine over a period of two weeks resulted in the highest neutralizing antibody titers ever measured following SOSIP immunizations in non-human primates. While osmotic pumps are not a practical way to deliver vaccines, they illustrate an important point. “Depending on how we gave the vaccine, there was a bigger difference due to immunization route than we would have predicted,” says Matthias Pauthner, a graduate student in Burton’s lab and the study’s co-lead author. “We can help translate what we know now into the clinic.”

    See the full article here .

    Please help promote STEM in your local schools.

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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 3:55 pm on July 13, 2017 Permalink | Reply
    Tags: A new three-dimensional snapshot of HIV, , Env trimer, HIV/AIDS, HIV’s Env is a protein complex made up of three identical mushroom-shaped structures that each contain a stalk-like subunit gp41 and a cap-like region called gp120, ,   

    From Scripps: “TSRI Scientists Capture First High Resolution Image of Key HIV Protein Transitional State” 

    Scripps
    Scripps Research Institute

    July 12, 2017

    A new, three-dimensional snapshot of HIV demonstrates the radical structural transformations that enable the virus to recognize and infect host cells, according to a new study led by scientists at The Scripps Research Institute (TSRI).

    The atomic-scale close-up image reveals an intricate dance between different parts of a key HIV protein complex, known as the envelope (Env) trimer, that takes place just moments before the virus would normally fuse itself to an immune cell’s plasma membrane.

    1
    CD4 and b12 both trap Env in an open, pre-fusion conformation but only CD4 exposes the co-receptor binding site required for entry.

    “One could consider this a ‘missing link’ between HIV’s previously known prefusion and the post-fusion states,” said Andrew Ward, an associate professor at TSRI who led the study.

    The image also gives scientists their clearest glimpse yet at the plastic nature of Env, which constantly shifts between different configurations before latching on to human cells.

    “Several other studies have shown evidence of trimer ‘breathing,’ and here we are able to capture two different conformational states of Env at high resolution,” said study co-first author Gabriel Ozorowski, a senior research associate at TSRI.

    Findings from the study, published online on July 12 in the journal Nature, could provide new potential targets for HIV vaccine designs.

    “By understanding the molecular details of this fusion intermediate state, we can infer how the trimer transitions between states and engineer mutations or molecules to block those transitions,” Ward said.

    An Elusive Target

    HIV, the human immunodeficiency virus, currently infects about 37 million people worldwide. The development of a vaccine that can prevent—as opposed to just manage—HIV infections has been largely stymied by the complex and elusive structure of Env.

    HIV’s Env is a protein complex made up of three identical, mushroom-shaped structures that each contain a stalk-like subunit, gp41, and a cap-like region called gp120. The structures are only loosely connected to one another, enabling the trimer to change shape and making it notoriously difficult to study and target with drugs. In addition, the trimer also frequently mutates its outermost “variable loop” regions to evade immune attack, and its surfaces are coated with complex sugar molecules (called glycans) that obscure potential drug-binding sites.

    But by capturing Env in a configuration that exposes previously unknown patches on the trimer’s surfaces, the snapshot presents interesting new prospects for drug developers.

    “If we can target the newly found pockets with small molecules, then there is the potential to create new fusion inhibitor drugs,” Ward said.

    Help from a Substitute

    The team’s ultra-detailed image of Env is actually a composite picture digitally stitched together from thousands of images taken with a cryo-electron microscope.

    For HIV infection to occur, Env must first bind with two proteins on an immune T cell’s outer surface, a membrane receptor known as CD4, and then to a coreceptor, either CXCR4 or CCR5. For the new study, the scientists created a protein that included a modified form of Env—genetically engineered for stability—that is bound to CD4 and 17b, a human antibody that resembles CXCR4/CCR5 and is used as a stand-in for the coreceptors. The trimer complexes are then embedded into a thin layer of ice and placed under the microscope for imaging.

    “The electron beam is scattered by the protein atoms, leading to detailed two-dimensional images,” said study co-first author Jesper Pallesen, also a senior research associate at TSRI. “We take about 2,000 images, each one containing thousands of complexes frozen in random orientations, and we computationally align them to create a high-resolution, three-dimensional snapshot.”

    A New State

    The new snapshot of Env in its “fusion intermediate” state reveals that upon binding to CD4, the V1 and V2 variable loops of gp120 flip away from the center of the trimer, exposing the coreceptor binding site. CD4 binding also triggers parts of the gp41 “stalk” to rearrange themselves to create a small pocket of space inside the trimer. This pocket acts to stabilize the fusion peptide—an amino acid sequence that anchors itself in the host cell—as it moves from the base of the trimer toward the interior in preparation for membrane fusion.

    Due to its critical role in infection, the fusion peptide region of HIV is particularly resistant to mutation and thus a sought-after drug target. “If you can target this particular stretch of amino acids, then the virus has a hard time escaping,” Pallesen said.

    However, actually hitting this target has proven difficult because the fusion peptide rarely stays still. “Prior to CD4 binding, the fusion peptide is floating and flopping around outside of the trimer,” Ozorowski said. “What we see for the first time in our structure is that when Env binds CD4, the fusion peptide moves closer to the trimer’s interior and adopts a more stable state as it prepares to anchor into the host cell’s membrane.”

    Breathing

    The team also conducted a second antibody-substitute experiment to obtain the clearest picture yet of Env’s shapeshifting abilities. “Because Env is a metastable fusion machine, it has been long understood that it must be a malleable structure,” Ward said.

    Swapping out CD4 for a similarly shaped antibody, b12, the team was able to show that in addition to a “closed” state, in which the CD4 binding site is hidden, and an “open” state that is ready for CD4 binding, Env also contorts into a partially open configuration that accommodates b12 but not CD4.

    “For infection to happen, the trimer must transition from a closed state to an open state that brings the fusion peptide in close proximity to the host cell,” Ozorowski said. “Sampling various states could make it easier for Env to switch from one to the next. We show that despite these different conformations, each one still exhibits some degree of stability.”

    This stable meta-state is yet another path that drug makers can explore. “We can now probe this new conformation to discover new druggable pockets on the surface of Env,” Pallesen said. “So, it opens up yet another arsenal of weapons in the fight against infection.”

    The article, Open and Closed Structures Reveal Allostery and Pliability in the HIV-1 Envelope Spike, also included study co-authors Natalia de Val, Christopher Cottrell, Jonathan Torres, Jeffrey Copps, Robyn Stanfield and Ian Wilson of TSRI; Dmitry Lyumkis of the Salk Institute for Biological Studies; and Albert Cupo, Pavel Pugach and John Moore of the Weill Medical College of Cornell University.

    This work was supported by funds from the Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (grant UM1AI100663) and the National Institutes of Health (grants P01 AI110657 and P50 GM103368).

    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.

     
  • richardmitnick 4:11 pm on May 15, 2017 Permalink | Reply
    Tags: , Dexter Holland, HIV/AIDS, ,   

    From INVERSE: “The Offspring’s Dexter Holland Earns Ph.D. in Molecular Biology” 

    INVERSE

    INVERSE

    Dedicated to M.F.T. and his Mother and Father, I hope they see it.

    1
    Just a scientist with low self-esteem.

    May 13, 2017
    Grace Lisa Scott

    The Offspring lead singer and former braids enthusiast Dexter Holland can now add a Ph.D. to his list of accomplishments.

    On Thursday, the 51-year-old graduated from the University of Southern California with a doctorate in molecular biology. His final thesis, focused on HIV research, is titled “Discovery of Mature MicroRNA Sequences within the Protein-Coding Regions of Global HIV-1 Genomes: Predictions of Novel Mechanisms for Viral Infection and Pathogenicity.”

    In an emailed statement to Rolling Stone, Holland said:

    “My research focused on the human immunodeficiency virus, or HIV, the virus which causes AIDS. I am interested in virology and wanted to contribute in some small way to the knowledge which has been learned about HIV and AIDS. This terrible disease remains a worldwide epidemic – over 35 million people worldwide are currently infected and living with the HIV virus. Over 1 million people a year die from this disease.”

    The achievement has been a long time coming. Holland began pursuing his Ph.D. at the University of Southern California in the early ‘90s, but when The Offspring’s touring schedule picked up following the success of their album Smash, he decided to put his academic career on hold to focus on the band. He returned to his studies a few years ago and has been steadily working away at his degree in between recording and touring.

    Holland isn’t the only musician to hold a pedigree from an institution other than the school of rock. Queen’s Brian May earned his Ph.D. in astrophysics in 2008, Greg Graffin, of Bad Religion, has a Ph.D. in zoology from Cornell, Ladytron’s Mira Aroyo has a Ph.D. in genetics from Oxford, and the Descendents singer Milo Aukerman has a Ph.D. in biochemistry from the University of Wisconsin-Madison.

    You can take a look at Holland’s thesis here, which also reveals his email address is 7715x@gofarkid.com.
    Photos via Getty Images / Kevin Winter

    See the full article here .

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  • richardmitnick 2:03 pm on January 23, 2017 Permalink | Reply
    Tags: , , HIV/AIDS, HIVE, , ,   

    From FAAH at WCG: “Virtual Screening of the HIV-1 Mature Capsid Protein” 

    New WCG Logo

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    World Community Grid (WCG)

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    faah-hive

    Scripps Institute

    This webpage is dedicated to the virtual screening of the HIV-1 capsid protein in her mature form. This project is part of the HIVE Center and the FA@H initiative in collaboration with IBM and their World Community Grid (WCG).

    People involved in the project come from the Olson Lab in The Scripps Research Institute, and from all over the world as volunteers of the WCG. Meet them here.

    FightAidsOlsonLab@home

    For any question about the project or this webpage, please contact
    Dr. Pierrick Craveur : pcraveur@scripps.edu

    Background

    During the maturation of the HIV virus, the HIV-1 capsid protein (CA) assembles with thousands of copies to forms the capsid core [ref 1] with a characteristic conical shape (see Figure 1 and Figure 2C). This core encloses the RNA viral genome. Upon the entry of the HIV in host cells, the capsid core is released into the cytoplasm, and it dissociates in connection with the reverse transcription in a not completely understood process. This leads to the importation of DNA viral genome in the host cell’s nucleus, where it is integrated in the host DNA to finalize the infection.

    2
    Figure 1: The early phase of the HIV-1 replication cycle.
    (credit: Nature Reviews Microbiology 13, 471–483 (2015) | doi:10.1038/nrmicro3503)

    The critical role of CA protein, in early and late stages of the viral replication life cycle, has led to recent efforts on drug development, targeting the mature form of the protein. Currently, none of these molecules are used in clinic, and some face natural polymorphism and resistant mutations [ref 2]. Therefore, continued development of drugs targeting the CA protein is still needed.

    The critical role of CA protein, in early and late stages of the viral replication life cycle, has led to recent efforts on drug development, targeting the mature form of the protein. Currently, none of these molecules are used in clinic, and some face natural polymorphism and resistant mutations [ref 2]. Therefore, continued development of drugs targeting the CA protein is still needed.

    3
    Figure 2: The HIV-1 mature capsid assembly.
    (credit: Pierrick Craveur)

    Different level of the capsid protein structure

    CA protein consist of a sequence of 231 amino acids which folds into 3 different domains (Figure 2A): The N-terminal domain (N-ter), the linker, and the C-terminal domain (C-ter). This protein chain complexes with other chains to form hexamers (Figure 2B) or pentamers; which assemble together to form the fullerene-cone shape of the capsid core (Figure 2C). There are several models of the core assembly, but all are composed of ~200 hexamers, and exactly 12 pentamers.

    High Throughput Virtual Screening

    The FightAIDS@Home team is working with World Community Grid to find active compounds which could attach to the CA proteins and mediate the assembly of the capsid core. This computational experiment will be performed using the docking software AutoDock VINA [ref 3].
    Thanks to the volunteers, around 2 million molecules will be screened across ~50 conformations of the capsid protein, and hopefully lead to a reduced selection of molecules. This will be the starting point of a drug discovery process targeting the HIV-1 capsid protein.
    This computational experiment will be performed using the docking software AutoDock VINA [ref 3].
    With the support of our collaborators from the HIV Interaction and Viral Evolution (HIVE), experimental biding assays and infectivity assays will be conducted to determine if the selected compounds could be optimized as a promising drug candidate.

    4
    Figure 3: The four pockets of interest.
    (credit: Pierrick Craveur)

    Four pockets of interest

    Based on X-ray structures of CA protein, models of the core, and computational analysis of their flexibility, four pockets of interest have been selected on the surface of the hexamer assembly (see Figure 3).
    These pockets involve either one monomer (as pocket 2 along the linker domain), at the interface of two monomers (pocket 1 & 4), or at the six-fold interface (pocket 3).
    Mutagenesis experiments revealed that core stability is fine-tuned to allow ordered disassembly during early stage of virus replication cycle [ref 4]. This is why selection of compounds will be done either for molecules which could stabilize or destabilize the hexamer; assuming that both actions could have impacts on the equilibrium of the core.

    References

    Briggs, J. A. and H. G. Krausslich (2011). “The molecular architecture of HIV.” J Mol Biol 410(4): 491-500.
    Thenin-Houssier, S. and S. T. Valente (2016). “HIV-1 Capsid Inhibitors as Antiretroviral Agents.” Curr HIV Res 14(3): 270-282.
    Trott, O. and A. J. Olson (2010). “AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.” J Comput Chem 31(2): 455-461.
    Forshey, B. M., U. von Schwedler, et al. (2002). “Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication.” J Virol 76(11): 5667-5677.

    See the full article here.

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  • richardmitnick 9:45 am on July 17, 2016 Permalink | Reply
    Tags: , , HIV/AIDS,   

    From Science Alert: “Scientists just discovered where HIV began” 

    ScienceAlert

    Science Alert

    19 JUN 2016 [JUst now in social media]
    NEIL C. BHAVSAR, FUTURISM

    1
    R. Dourmashkin/Cell Image Library

    Birthplace of the disease that won’t die.

    Diseases, while disastrous, often come and go in the public eye. We hear about ebola, but then another one quickly grabs national monitors and TV screens for its fifteen minutes.

    However, one condition that seems to not fit into his norm is the Human Immunodeficiency Virus (HIV). The spread of HIV is a story that would have most television dramas pale in comparison – combining elements of intrigue, suspense, and mystery into one cohesive nightmare that has blanketed the globe since the 1920s.

    It all began in Kinshasha, the capital of the Democratic Republic of Congo. However, in the 1920s, it was better known as the Belgian colony of Leopoldville.

    A high profile location for young men to sojourn to in hopes of making a fortune, as it was the capital of Belgian Congo. Therefore, with them came railroads and sex workers. Two forms of transportation that respectively spread people and infection. With a flourishing location, HIV found many opportunities to grow into the pandemic it is today.

    The irony of it all is that HIV-1 group M, the type of HIV that originated in the colony, is responsible for about 90 percent of all infections, while HIV-1 group O, another type of HIV originating nearby is still quietly confined to West Africa. Thereby suggesting it may have been the opportunities, and not the function, of that disease that enabled it to roar globally.

    “Ecological rather than evolutionary factors drove its rapid spread,” says Nuno Faria at the University of Oxford in the UK, in an interview with the BBC.

    Faria and his colleagues were able to make this determination after they built a family tree of HIV by looking at a host of HIV genomes collected from about 800 infected people from central Africa.

    Notably, by comparing two genome sequences and counting the differences in them, the team was able to figure out when the two last shared a common ancestor.

    Ultimately, Faria determined that the HIV genomes all shared a common ancestor… one that existed no more than 100 years ago. To that end, they assert that it all likely began around 1920.

    And with this information, they were able to place the virus to a specific city of origin – Kinshasa, which is now the capital of the Democratic Republic of Congo.

    All in all, the genetic assays that helped us localise the origin of the disease are still underway to help us identify points of public health intervention that may help us reduce the spread of the infection. Because, although we may know where it came from, we have yet to figure out where it will end.

    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 1:52 pm on July 1, 2016 Permalink | Reply
    Tags: , HIV/AIDS,   

    From Scripps: “Researchers Stabilize HIV Structure, Design Potential AIDS Vaccine Candidates” 

    Scripps
    Scripps Research Institute

    July 04, 2016
    Madeline McCurry-Schmidt

    Want to catch a criminal? Show a mugshot on the news.

    Want to stop HIV infections? Get the immune system to recognize and attack the virus’s tell-tale structure.

    1
    “We’ve figured out one of the fundamental reasons why HIV is metastable,” says Assistant Professor Jiang Zhu (left), here with some co-authors of the new studies, Charles Morris (back), Parisa Azadnia (center) and Linling He. (Photo by Cindy Brauer.)

    2
    In a feat of bioengineering, the team designed nanoparticles that could mimic HIV.

    That’s part of the basic approach behind efforts at The Scripps Research Institute (TSRI) to design an AIDS vaccine. This strategy may hinge on finding new ways to stabilize proteins called HIV-1 surface antigens and in designing HIV-like particles to prompt the body to fight the real virus.

    Now two new studies led by TSRI scientists advance these efforts. The first describes a strategy to stabilize an important HIV structure and potentially create HIV lookalikes for large-scale vaccine production. The second study engineers novel nanoparticles as vaccine candidates, using this new knowledge.

    “This is a big accomplishment in terms of engineering and design,” said TSRI biologist Jiang Zhu.

    Zhu co-led the first study with Ian Wilson, Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI, and co-led the second with TSRI Associate Professor Andrew Ward.

    The findings were published June 28, 2016 in the journal Nature Communications.

    Stabilizing HIV

    In the first publication, Zhu and researcher Leo Kong (a study first author now at the National Institutes of Health) built on previous structural studies from the Ward and Wilson labs to investigate a trait called “metastability.” Metastability describes the tense state of the HIV Envelope glycoprotein (Env) trimer when it is poised like a loaded spring to undergo the dramatic changes that allow the virus to enter cells.

    Metastability poses a problem for scientists who want to create a precise image of this viral target and see what the human immune system is up against.

    Metastability also stands in the way of naturally occurring immunity and vaccine production. For the adaptive immune system to work in either case, it needs to recognize a functional, stable version of a virus’s proteins—a sort of mugshot—so it can produce antibodies and attack the actual virus upon encountering it.

    Unfortunately, because of the virus’s metastability, or shape-shifting tendency, structures of HIV’s proteins have proven difficult to establish for use in vaccine design. The Ward and Wilson groups at TSRI have previously determined cryo-EM and x-ray structures for other Env constructs; however, current methods to stabilize Env in one strain of HIV won’t necessarily stabilize it in another, making it hard to design an arsenal of Env proteins to help elicit “broadly neutralizing antibodies” that could fight many types of HIV.

    To advance the vaccine effort, TSRI researchers wanted to track down the root cause of metastability, and Jiang and Kong hypothesized that altering a key region of Env would improve its overall properties.

    They hypothesized that a region of the Env called HR1 could be linked to metastability.

    “The HR1 basically resembles a highly bent twig that is ready to spring back straight,” said Kong. “This small bend in the HR1 region is likely ground zero for metastability. In most published Env structures, this region appears disordered when mutated or loosely packed when in its native form. From these observations, it seemed reasonable that rewiring the HR1 bend could greatly stabilize Env.”

    Indeed, when the scientists tweaked HIV’s genetic sequence, they were able to shorten the HR1 region, preventing its transformation and keeping the rest of the structure stable.

    “We’ve figured out one of the fundamental reasons why HIV is metastable,” said Zhu.

    The researchers then demonstrated that their stabilized Env trimers also almost perfectly mimicked the structure of the real HIV trimer, suggesting they could be useful in vaccines. Since rewiring the HR1 should prevent Env undergoing its necessary shape-shifting changes to infect cells, the stabilization strategy also could lead to protein or DNA-based vaccines. Furthermore, the modified trimer also has the potential to be produced in reasonably large quantities and at high purity—important considerations in industrial-scale vaccine production.

    Finally, since many viruses contain metastable Env proteins with HR1-like regions, this TSRI-developed engineering approach may be applicable in the design of vaccines against other viral pathogens such as influenza and Ebola virus.

    New Vaccine Candidates

    In the second paper, the researchers looked into designing nanoparticles that could mimic HIV.

    Particles aren’t new in vaccine design. They provide the backbone of successful vaccines against human papillomavirus (HPV), hepatitis B and hepatitis E—“the most efficacious human vaccines ever made,” according to Zhu.

    These nanoparticles are called virus-like particles (VLPs) and are hollow shells of other proteins found in nature. Scientists have found that they can add viral proteins to the outside of a shell, creating a phony virus. The imposter then prompts the body to produce antibodies for long-term protection against the real virus.

    But as Zhu and his colleagues focused on creating HIV-like VLPs, the Env trimer, once again, presented a challenge.

    The trimer is made of three subunits that come together to form a base with a crown shape on top. The top of the crown is where the tips of the three subunits meet.

    Scientists have found that the immune system cannot produce broadly neutralizing antibodies when a vaccine contains only one part of the trimer. The immune system needs to see intact HIV proteins—also called antigens when they stimulate the immune system to create antibodies—in their native trimeric context.

    To construct an artificial virus, in the new study the researchers added HIV trimers to nanoparticles that naturally lock their own subunits together in clusters of three. As the three subunits come together, the researchers hypothesized, they could bring the HIV antigens together to form a trimer.

    “Our idea was to ‘fuse’ a trimeric HIV-1 antigen to a nanoparticle subunit, so when the subunits ‘self-assemble’ they bring three attached HIV-1 antigens together,” said TSRI Staff Scientist Linling He, who served as co-first author of the study with Natalia de Val, a researcher at TSRI at the time of the study.

    It was a feat of geometry and engineering—and it worked. “It has been really challenging to properly present HIV Env on nanoparticles while keeping its natural trimeric form—but we did it,” said Zhu, “Multiple copies of Env are now displayed on the nanoparticle surface, just like what a real virus would do.”

    The team then tested different nanoparticles and versions of the trimer, including one based on the stabilized Env in the first study, to find the best combinations. Six designs worked well in laboratory tests and now await trials in animal models.

    “We are still pushing hard to find new vaccine candidates to elicit a protective response in humans,” said Wilson. “The challenges going forward are to understand how to use these new vaccine candidates to induce a protective broadly neutralizing antibody response and to develop the appropriate regimens to initiative this response.”

    In addition to Zhu, Wilson, Ward, Kong, He and de Val, authors of the first study, “Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability,” were Nemil Vora, Charles D. Morris, Parisa Azadnia and Bin Zhou of TSRI; Devin Sok of TSRI, the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), and TSRI Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID); and Dennis R. Burton of TSRI, IAVI, CHAVI-ID and the Ragon Institute.

    This study was supported by the NIH National Institute of General Medical Sciences (NIGMS) (grants P41GM103393, U54 GM094586 and AI084817), the NIH National Center for Research Resources (grant P41RR001209), the IAVI Neutralizing Antibody Center and CAVD (grants OPP1084519 and OPP1115782), CHAVI-ID (grant CHAVI-ID UM1 AI100663), the HIV Vaccine Research and Design (HIVRAD) program (grant P01 AI110657), and American Foundation for AIDS Research Mathilde Krim Fellowship in Basic Biomedical Research. Use of the Advanced Photon Source (APS) beamline 23ID-B and Stanford Synchrotron Radiation Lightsource (SSRL) BL12-2 for this study was supported by the U.S. Department of Energy (DOE), Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357 and the DOE Office of Biological and Environmental Research.

    In addition to the authors listed above, authors of the second study, “Presenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles,” were Therese C. Thinnes and David Nemazee of TSRI.

    This study was supported by the IAVI Neutralizing Antibody Center and CAVD, CHAVI-ID (grant UM1 AI00663), the HIV Vaccine Research and Design (HIVRAD) program (grant P01 AI110657) and the Joint Center of Structural Genomics, funded by the NIGMS Protein Structure Initiative (grants U54 GM094586, AI073148 and AI084817).

    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 8:24 am on June 30, 2016 Permalink | Reply
    Tags: , , HIV/AIDS   

    From AAAS: “South Africa’s bid to end AIDS” 

    AAAS

    AAAS

    Jun. 29, 2016
    Jon Cohen

    1
    Lesego Kgaladi, 20, who lives in Soweto, South Africa, was infected with HIV at birth. At school, she speaks out about stigma and misunderstandings about HIV. James Oatway

    On a Wednesday morning in April, a line of 600 HIV-infected people snakes through the hallways to the first waiting room of the Themba Lethu Clinic, a wing of the Helen Joseph Hospital in Johannesburg, South Africa. In most places in the country, where clinics are overtaxed, this would presage a wait of up to 10 hours. But here something different is happening. Staffers at computer monitors swiftly log in people and dispatch them for triage or, if they have tuberculosis, a special area away from others. Those who only need their antiretroviral (ARV) drugs walk directly to the pharmacists, who retrieve each patient’s electronic medical record and use a robotic system to pull drugs from shelves and fill orders. The average wait time is 30 minutes to 2 hours to complete a doctor or nurse visit and 15 minutes at the pharmacy. A prototype ATM promises to further speed visits by directly dispensing ARV pills; one day, it is hoped, similar pill machines in shopping malls could make some clinic visits unnecessary.

    “This is an awesomely efficient place,” says Ian Sanne, who heads Right to Care, a nongovernmental organization that runs this and several other clinics in collaboration with the health department. In developed countries, where patients complain about much shorter waits, this boast might seem absurd. But in South Africa, the Themba Lethu Clinic is celebrated as an example of what can be done to care for large numbers of HIV-infected people. This is at once a compliment to the clinic and a hint of the country’s overwhelming HIV/AIDS challenge.

    South Africa has pledged to ramp up efforts to end its massive HIV/AIDS epidemic, the world’s largest. Come September, it will offer every infected person ARVs, which both stave off disease and make people less infectious. The immediate goal is to reach what is known as 90-90-90 by 2020: to have 90% of infected people aware of their status, 90% of known positives start ARVs, and 90% of that group drive the amount of virus in their bloodstream down to un-detectable levels. The theory is that as viral levels drop, transmission will, too, leading the epidemic to spiral downward. This 90-90-90 target is the cornerstone of a grand campaign, articulated by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and widely embraced by world leaders, to end the AIDS epidemic “as a global public health threat” by 2030.

    In a nation estimated to have at least 6.6 million HIV-infected people—18% of the world’s total—the drive to hit 90-90-90 by 2020 seems overly ambitious to many experts. And the obstacles faced by South Africa provide a sobering reality check to the lofty, laudable aspiration of ending AIDS, a topic that promises to occupy center stage later this month in Durban at the biannual International AIDS Conference.

    Models and reality

    2
    South African HIV and TB Investment Case, SANAC and National Department of Health

    South Africa has already made enormous gains against its HIV/AIDS epidemic. When it last hosted this international gathering in 2000, then-President Thabo Mbeki and his health minister questioned whether HIV even causes AIDS, triggering widespread outrage. At the time, only the wealthiest South Africans had access to ARVs, which cost about $5000 per person for an annual supply. But by the end of 2015, the price had dropped to $100, and 3.4 million HIV-infected South Africans were receiving ARVs—more than in any other country in the world. South Africa, in fact, consumes the same amount of the life-saving drugs as Asia and the Pacific, North America, and western and central Europe combined.

    As a result, life expectancy jumped 9 years between 2005, when ARVs started to become widely available, and 2014. The country has pioneered innovative ways to deliver the drugs and help people stay on them. And South Africa’s strong cadre of HIV/AIDS investigators has made the country a hub of cutting-edge basic research and clinical trials. “Given our resources, we’ve done amazing things,” says Glenda Gray, an HIV/AIDS researcher who heads South Africa’s Medical Research Council in Cape Town.

    3
    This family tree is derived from the DNA of thousands of HIV isolates from South Africa and it shows how the virus has evolved in 5-year periods. The darkest blue dots represent sequences from 2010 to 2015 and the lightest dots are from 1989. Andrew Rambaut, Univ. of Edinburgh, and Tulio de Oliveira, Africa Centre for Population Health.

    Yet almost half the infected population today is still untreated. Some have not suffered enough immune damage from the virus to merit ARVs under current government policy. Many other infected people don’t know their status or never seek care, and still others who start treatment have difficulty taking their daily pills for years on end. Estimates suggest that because of failures in this “care continuum,” only about one in four HIV-infected South Africans has fully suppressed the virus. “We have to ride two horses at the same time,” says Fareed Abdullah, who heads the quasi-governmental South African National AIDS Council (SANAC) in Pretoria. “One is to improve our system so that the more than 3 million on treatment are retained in care and properly managed, and we also have to expand to a group that is largely asymptomatic and well.”

    Adding to those challenges is South Africa’s alarming HIV incidence—the percentage of the population that becomes infected each year. The government reports that HIV incidence has dropped from a high of 1.67% in adults in 2005 to 1.22% last year, but that still translates into 330,000 new infections a year. The rate is shockingly high in women under 25, especially in the hardest hit province, KwaZulu-Natal, where incidence tops 6% in some communities.

    Health Minister Aaron Motsoaledi, who acknowledges that the country’s aggressive HIV/AIDS program got off to a late start because of Mbeki, is confident that South Africa has the willpower and the money to hit 90-90-90. “Can we afford not to treat people?” Motsoaledi asks. “Surely, we’re going to pay much more dearly socially, politically, and economically if you can’t.” To that end, the government, which already spends $1.2 billion a year on HIV/AIDS and receives another $300 million in foreign aid, is adding $65 million annually through 2019.

    4
    As part of an exercise to determine what it could afford, the South African government put price tags on the many interventions now proven to work. South African HIV and TB Investment Case, SANAC and National Department of Health

    But a new report concludes that meeting the UNAIDS target will require an additional $8 billion over the next 5 years. “UNAIDS is pushing very hard on our health ministry, which doesn’t want to be caughtshort again and wants to make the case that we can reach 90-90-90,” says Linda-Gail Bekker, who co-runs the Desmond Tutu HIV Foundation (DTHF) in Cape Town and is one of the co-authors of the report. The cost of drugs is just one part of the equation, she says. Reaching the target will also require massive HIV testing and the costly delivery of ARVs to patients who must be monitored and then helped if they’re not suppressing the virus. “I’m really, really anxious about the resources it’s going to take.”
    There are scientific questions, too. The assumption that reaching the 90-90-90 target will end AIDS is based on mathematical models that factor in ARV “coverage” in combination with other proven prevention strategies like male circumcision, condom promotion, and behavior change efforts. Researchers note that in large epidemics like the one in South Africa, which has spread far beyond “concentrated” populations such as men who have sex with men and sex workers, such strategies could prove less effective than expected, allowing HIV to continue spreading at high rates even after the country reaches 90-90-90.

    Epidemiologist Salim Abdool Karim, who runs the Centre for the AIDS Programme of Research in South Africa (CAPRISA) in Durban, points to recent data from Botswana that call into question the model’s assumptions. Botswana, which is relatively wealthy and has a tiny population of 2 million, has nearly reached 90-90-90, as shown in a study published online on 23 March in The Lancet. But incidence has barely budged, in part because the missing 10-10-10 continue to spread the virus. “For a country that’s close to 90-90-90, the incidence is ridiculously high,” Karim says. “It’s scandalous.” A report published by SANAC and the health department further questions the 90-90-90 mathematical modeling. Even if 90-90-90 leads to big declines in new infections by 2030, that report suggests that incidence in South Africa’s population of 53 million will not quite drop below 0.1%—the level that UNAIDS says it must reach for an epidemic to end.

    The bottom line is that it remains an open question whether the 90-90-90 treatment goal really can stop the spread of HIV in South Africa. Some of the world’s largest controlled trials of treatment as prevention (TasP) are underway in the country to try to answer it.

    In an area known as Mfekayi in rural KwaZulu-Natal, two dozen people are sitting on the shaded porch of a plywood shack waiting their turn to see a counselor. The shack is the Egedeni Clinic, and the people are participants in a 28,000-person, multisite clinical trial that will assess the precise relationship between increased levels of HIV suppression in a community and drops in incidence. At Egedeni and 10 other clinics across the province, the TasP study offers ARVs to all infected participants. Another 11 TasP clinics instead offer treatment in keeping with current government recommendations, meaning that people start ARVs only after their immune systems show signs of damage.

    One by one, the participants hand bottles of ARVs they received a month earlier to the counselors, who count the remaining pills. This ritual, which is a crude way to monitor adherence, underscores an obvious limitation of the underlying strategy: Even if ARVs make people less infectious, TasP relies on the fickle relationship humans have with taking daily medications.

    Run by the Africa Centre for Population Health in nearby Mtubatuba, TasP is the furthest along of four similar large trials in sub-Saharan Africa that are examining the care continuum and the real-world outcome of “universal treatment.” Early analysis of TasP results found that fewer than 40% of the people who tested positive sought care within 3 months, as recommended. This first step still has remained a major stumbling block on the road to 90-90-90.

    At the International AIDS Conference later this month, the researchers plan to reveal whether their intervention has reduced incidence. “This will be the first opportunity to assess whether, in fact, the bio-logical rationale is actually true in practice,” says Deenan Pillay, a clinical virologist who heads the Africa Centre. But Pillay says the study already has made clear that ending AIDS is not simply a matter of “let’s just treat everyone and everything will be OK.” In the final analysis, he says, the power of TasP depends as much on human behavior as it does on biology.

    Jacqualine Ncube, a 19-year-old restaurant worker, first took an HIV test when she was in high school. At the time, Ncube spent many hours after school hanging out at DTHF’s Youth Centre, which abuts the struggling township of Masiphumelele outside of Cape Town. The Youth Centre offers teens internet access, holds soccer matches, loans surfboards, and provides care at a health clinic. Kids also earn “Tutus,” good for shopping vouchers or food, for every-thing from helping the community to taking an HIV test. When Ncube got her first results, she was overwhelmed. “I really screamed,” she says. She was negative.

    Ncube has repeatedly tested negative, and in April 2015 she joined the Youth Centre’s Pillsplus, a study of what’s known as pre-exposure prophylaxis, or PrEP, in 150 teens. With PrEP, uninfected people take daily ARV pills to prevent infection. Although PrEP is a proven strategy, South Africa recommends its use only in sex workers, and Ncube is one of the first hetero-sexual teens in the world to take ARVs for prevention. She still uses condoms with her boyfriend, but says she wanted to try PrEP because “no protection is 100%.”

    DTHF’s Bekker, who is heading Pillsplus to assess PrEP’s acceptability in teens, contends that PrEP should be provided to all people at high risk of infection. “When I sit opposite a 17-year-old young woman, I have nothing to offer her,” Bekker says.

    CAPRISA’s Karim says using PrEP in young women could be key to breaking the epidemic’s back. About 30% of new infections in South Africa occur in young women between 15 and 24 years of age. The new infection rate in men in the same age bracket is more than four times lower. In some districts of KwaZulu-Natal, a woman has a 60% chance of becoming infected by age 34.

    Sex and age

    HIV infects far more girls and young women than boys and men of the same age in South Africa. The sex difference shrinks by age 35, then prevalence drops.

    5
    Rachael Dellar et al., CAPRISA

    To understand the pattern of viral spread, CAPRISA and the Africa Centre mapped out the infection cycle between men and women of different ages in KwaZulu-Natal. The study analyzed the genetic sequences of HIV isolated from 858 men and women, all between 16 and 35 years old, who belonged to the same sexual networks. The viral genetics linked different isolates and indicated which ones were older, allowing the researchers to infer who infected whom. Teenage girls were infected by men who were, on average, 8 years older. After the age of 24, people typically became infected by partners their own age, with transmission more frequently moving from woman to man. “They are trying to find lifetime partners at this age,” Karim says. These older men are the same group having sex with the youngest women. “We have to break the chain between men in their late 20s and teen girls,” he says.

    PrEP can help address shortcomings of TasP, Karim says. In the infection-cycle study, men who infected younger women had extremely high HIV levels, indicating they recently acquired the virus and thus would not appear infected on standard antibody-based tests. “If your strategy is to test and treat these people, you’re not going to catch them,” Karim says. Men are also less connected to the health care system and often migrate for work, he adds, making it more difficult to help those who know they are infected fully suppress the virus. Giving PrEP to young women sidesteps the male dilemma. “We just have to protect girls for 5 years in that critical risk period until they find their partners,” he says.

    Karim says new biomedical interventions on the horizon may bolster prevention efforts. His group plans to report at the Durban meeting that it has identified an unusual microbe linked to vaginal inflammation in women in KwaZulu-Natal. Treating it could potentially lower their risk of HIV infection. Injectable ARVs that last for 2 months are also being tested in South Africa and elsewhere, and those could eliminate the challenge of taking daily pills—a key problem for both treatment and PrEP. Next fall, South Africa plans to launch the world’s only efficacy trial of an AIDS vaccine—the strongest preventive medicine of all.

    For now, 90-90-90 is the most powerful tool available to South Africa in its quest to end its epidemic, even if PrEP and other new strategies ultimately are needed. SANAC’s Abdullah takes a pragmatic view of meeting the UNAIDS deadline. “I think we should plan for it, because if we don’t hit it by 2020, we’ll do it by 2022,” he predicts. “What we’re really after is bringing down new infections to low levels,” along with getting as many HIV-infected people as possible on treatment and living longer lives. The virus itself, Abdullah says, “will be with us for the next 100 years.”

    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 10:20 am on June 16, 2016 Permalink | Reply
    Tags: , HIV/AIDS, Simulations describe HIV’s ‘diabolical delivery device’,   

    From U Chicago: “Simulations describe HIV’s ‘diabolical delivery device’ “ 

    U Chicago bloc

    University of Chicago

    June 14, 2016
    Carla Reiter

    1
    UChicago scientists have developed a simulation to show steps of the HIV-1 capsid assembly, which the virus needs to mature and become infective. The scale bar represents 20 nanometers.

    From a virus’s point of view, invading our cells is a matter of survival. The virus makes a living by hijacking cellular processes to produce more of the proteins that make it up.

    From our point of view, the invasion can be a matter of survival too: surviving the virus. To combat viral diseases like HIV-AIDS, Ebola and Zika, scientists need to understand the “life cycle” of the virus and design drugs to interrupt it. But seeing what virus proteins do inside living cells is extremely difficult, even with the most powerful imaging technologies.

    Now University of Chicago scientists and their colleagues have developed an innovative computer model of HIV that gives real insight into how a virus “matures” and becomes infective. In doing so, it offers the prospect of developing new anti-viral drugs and greatly extends what has been possible with computer simulations of biological systems. Their findings appeared in the May 13 edition of Nature Communications.

    “Understanding the details of viral maturation is considered a holy grail,” said Gregory Voth, the Haig P. Papazian Distinguished Service Professor in Chemistry, who built the model with research scientist John Grime. “It has a set of processes that are incredibly hard to stop. With our model, we’ve discovered a key set of dynamical steps in the maturation process. And we think we’ve identified two core aspects of HIV.”

    To mature and become infective, a virus must grow a little pear-shaped capsule called the capsid, which is made of proteins that wrap themselves around the RNA that will allow the virus to replicate. “This is the thing that’s going to get shot into a new cell and release its contents,” said Voth. “The capsid is like a little armor-plated container that carries with it the genetic material of the virus. And it is a diabolical delivery device.”

    Capsid growth details

    Voth and Grime’s model illuminates in detail how the capsid grows in HIV, something difficult to examine in real life because the capsid is tiny and surrounded by other material. “That’s where computer simulations are so powerful,” Voth said. “And in computer simulations you can turn things on and off, which you can’t do in reality. It makes a huge difference in what you learn. It’s not reality, but if the model’s good it can be pretty darn close.”

    Voth and Grime worked with data and real-world images from experimental collaborators at the University of Virginia and the California Institute of Technology to make sure that their model was consistent with experimental findings. “Their important work helped us to build the model and validate it,” Voth said.

    After the HIV virus infects a cell, it forms a “bud” on the cell’s surface—a virus particle that contains some cell membrane, proteins and the virus’s RNA. The bud breaks free of the cell as the “virion” and travels in the body. During that travelling period, critical proteins inside the bud are cut into bits by the enzyme HIV protease—the target of many of today’s anti-HIV drugs. Some 1,200 of these protein bits pair up and assemble themselves into the capsid, enclosing the RNA.

    Conditions inside the virion are crowded. And that crowding turns out to be critical to whether a capsid can form or not. “With our simulations we can make it more and less crowded and you see a remarkable sensitivity to that,” Voth said. Too little crowding, and the proteins are likely to speed past each other without interacting. Too much, and they grow useless bits and pieces.

    But Voth and Grime found that even with a Goldilocks-like “just right” amount of crowding in their model, the capsid didn’t grow properly. “We’d grow too much, or we’d start growing multiple pieces of the shell and they wouldn’t stick together in the right way, so you’d get a bunch of crazy-looking structures,” Voth said. “We were fundamentally missing something.”

    Flipping and dancing

    After a year of further work, they realized that before the protein bits pair up and add themselves to the growing capsid shell they are in constant motion, flipping and dancing around. For them to connect to each other and to the capsid they had to be oriented properly. This meant that only a few of them could participate in building the structure at any given time.

    “We discovered that the contortions of these proteins are very important to limiting how fast these structures can grow, so it’s just right,” Voth said. “When we built that into the model, guided by published experimental data, that was the secret.”

    A large part of building a computer model is deciding what to leave out of it so that it is computationally tractable. “We develop methods to simplify the calculations while retaining their physical essence,” said Voth. “And that opens up very broad frontiers of what can be studied that hasn’t been possible before.”

    But even though it is simpler than what exists in nature, the HIV capsid model is tremendously complex. It took millions of hours of computer time on the National Science Foundation supercomputer Blue Waters in Urbana-Champaign to run the simulations.

    “I don’t think anyone’s got close to simulating something of this complexity before,” said Grime, who did most of the nuts-and-bolts construction. “I think it’s a very significant advance in terms of what you can do with these sorts of models.”

    Voth envisions making similar models for other dangerous viruses, helping scientists discern the points in the cycle that might be good prospects for disruption by a drug.

    “We could do this for Zika virus, for Ebola,” he said. “Viruses have a capsid, and that capsid contains their genetic material. So these sets of methodologies could be applied to any of them. We just need enough information and computer power.”

    Citation: Coarse-grained simulation reveals key features of HIV-1 capsid self­assembly,” by John M.A. Grime, James F. Dama, Barbie K. Ganser-Pronillas, Cora L. Woodward, Grant J. Jensen, Mark Yeager and Gregory A. Voth, Nature Communications, published May 13, 2016, DOI: 10.1038/NCOMMS11568.

    See the full article here .

    Please help promote STEM in your local schools.

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    U Chicago Campus

    An intellectual destination

    One of the world’s premier academic and research institutions, the University of Chicago has driven new ways of thinking since our 1890 founding. Today, UChicago is an intellectual destination that draws inspired scholars to our Hyde Park and international campuses, keeping UChicago at the nexus of ideas that challenge and change the world.

     
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