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Broadly neutralizing antibody

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https://www.readbyqxmd.com/read/29451898/integrating-linear-optimization-with-structural-modeling-to-increase-hiv-neutralization-breadth
#1
Alexander M Sevy, Swetasudha Panda, James E Crowe, Jens Meiler, Yevgeniy Vorobeychik
Computational protein design has been successful in modeling fixed backbone proteins in a single conformation. However, when modeling large ensembles of flexible proteins, current methods in protein design have been insufficient. Large barriers in the energy landscape are difficult to traverse while redesigning a protein sequence, and as a result current design methods only sample a fraction of available sequence space. We propose a new computational approach that combines traditional structure-based modeling using the Rosetta software suite with machine learning and integer linear programming to overcome limitations in the Rosetta sampling methods...
February 16, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29451475/-trispecific-broadly-neutralizing-antibodies-for-hiv-immunoprophylaxis-and-immunotherapy
#2
Francis Barin, Karl Stefic
No abstract text is available yet for this article.
February 2018: Médecine Sciences: M/S
https://www.readbyqxmd.com/read/29449847/potential-epigenetic-regulation-in-the-germinal-center-reaction-of-lymphoid-tissues-in-hiv-siv-infection
#3
REVIEW
Xiaolei Wang, Huanbin Xu
The production of high-affinity and broadly neutralizing antibodies plays a key role in the defense against pathogens. These antibody responses require effective germinal center (GC) reaction within anatomical niches of GCs, where follicular helper T (Tfh) cells provide cognate help to B cells for T cell-dependent antibody responses. Emerging evidences indicate that GC reaction in normal state and perhaps establishment of latent Tfh cell reservoir in HIV/SIV infection are tightly regulated by epigenetic histone modifications, which are responsible for activating or silencing chromatin...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29449842/pan-influenza-a-protection-by-prime-boost-vaccination-with-cold-adapted-live-attenuated-influenza-vaccine-in-a-mouse-model
#4
Yo Han Jang, Joo Young Kim, Young Ho Byun, Ahyun Son, Jeong-Yoon Lee, Yoon Jae Lee, Jun Chang, Baik Lin Seong
Influenza virus infections continually pose a major public health threat with seasonal epidemics and sporadic pandemics worldwide. While currently licensed influenza vaccines provide only strain-specific protection, antigenic drift and shift occasionally render the viruses resistant to the host immune responses, which highlight the need for a vaccine that provides broad protection against multiple subtypes. In this study, we suggest a vaccination strategy using cold-adapted, live attenuated influenza vaccines (CAIVs) to provide a broad, potent, and safe cross-protection covering antigenically distinct hemagglutinin (HA) groups 1 and 2 influenza viruses...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29444432/surface-matrix-screening-identifies-semi-specific-interactions-that-improve-potency-of-a-near-pan-reactive-hiv-1-neutralizing-antibody
#5
Young D Kwon, Gwo-Yu Chuang, Baoshan Zhang, Robert T Bailer, Nicole A Doria-Rose, Tatyana S Gindin, Bob Lin, Mark K Louder, Krisha McKee, Sijy O'Dell, Amarendra Pegu, Stephen D Schmidt, Mangaiarkarasi Asokan, Xuejun Chen, Misook Choe, Ivelin S Georgiev, Vivian Jin, Marie Pancera, Reda Rawi, Keyun Wang, Rajoshi Chaudhuri, Lisa A Kueltzo, Slobodanka D Manceva, John-Paul Todd, Diana G Scorpio, Mikyung Kim, Ellis L Reinherz, Kshitij Wagh, Bette M Korber, Mark Connors, Lawrence Shapiro, John R Mascola, Peter D Kwong
Highly effective HIV-1-neutralizing antibodies could have utility in the prevention or treatment of HIV-1 infection. To improve the potency of 10E8, an antibody capable of near pan-HIV-1 neutralization, we engineered 10E8-surface mutants and screened for improved neutralization. Variants with the largest functional enhancements involved the addition of hydrophobic or positively charged residues, which were positioned to interact with viral membrane lipids or viral glycan-sialic acids, respectively. In both cases, the site of improvement was spatially separated from the region of antibody mediating molecular contact with the protein component of the antigen, thereby improving peripheral semi-specific interactions while maintaining unmodified dominant contacts responsible for broad recognition...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29443078/chemo-enzymatic-synthesis-of-n-glycans-for-array-development-and-hiv-antibody-profiling
#6
Sachin S Shivatare, Vidya S Shivatare, Chung-Yi Wu, Chi-Huey Wong
We present a highly efficient way for the rapid preparation of a wide range of N-linked oligosaccharides (estimated to exceed 20,000 structures) that are commonly found on human glycoproteins. To achieve the desired structural diversity, the strategy began with the chemo-enzymatic synthesis of three kinds of oligosaccharyl fluoride modules, followed by their stepwise α-selective glycosylations at the 3-O and 6-O positions of the mannose residue of the common core trisaccharide having a crucial β-mannoside linkage...
February 5, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29442996/role-of-framework-mutations-and-antibody-flexibility-in-the-evolution-of-broadly-neutralizing-antibodies
#7
Victor Ovchinnikov, Joy E Louveau, John P Barton, Martin Karplus, Arup K Chakraborty
Eliciting antibodies that are cross reactive with surface proteins of diverse strains of highly mutable pathogens (e.g., HIV, influenza) could be key for developing effective universal vaccines. Mutations in the framework regions of such broadly neutralizing antibodies (bnAbs) have been reported to play a role in determining their properties. We used molecular dynamics simulations and models of affinity maturation to study specific bnAbs against HIV. Our results suggest specific classes of evolutionary lineages: if germline B cells that initiate affinity maturation have high affinity for the conserved residues of the targeted epitope, framework mutations increase antibody rigidity as affinity maturation progresses to evolve bnAbs...
February 14, 2018: ELife
https://www.readbyqxmd.com/read/29439644/potential-hiv-1-fusion-inhibitors-mimicking-gp41-specific-broadly-neutralizing-antibody-10e8-in-silico-discovery-and-prediction-of-antiviral-potency
#8
Alexander M Andrianov, Ivan A Kashyn, Alexander V Tuzikov
An integrated computational approach to in silico drug design was used to identify novel HIV-1 fusion inhibitor scaffolds mimicking broadly neutralizing antibody (bNab) 10E8 targeting the membrane proximal external region (MPER) of the HIV-1 gp41 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb 10E8 active towards the gp41 MPER segment, (ii) shape and pharmacophore-based identification of the 10E8-mimetic candidates by a web-oriented virtual screening platform pepMMsMIMIC, (iii) high-throughput docking of the identified compounds with the gp41 MPER peptide, and (iv) molecular dynamics simulations of the docked structures followed by binding free energy calculations...
January 15, 2018: Journal of Bioinformatics and Computational Biology
https://www.readbyqxmd.com/read/29429810/envelope-proteins-of-two-hiv-1-clades-induced-different-epitope-specific-antibody-response
#9
Tripti Shrivastava, Sweety Samal, Ashish K Tyagi, Sandeep Goswami, Naresh Kumar, Gabriel Ozorowski, Andrew B Ward, Bimal K Chakrabarti
Using HIV-1 envelope protein (Env)-based immunogens that closely mimic the conformation of functional HIV-1 Envs and represent the isolates prevalent in relevant geographical region is considered a rational approach towards developing HIV vaccine. We recently reported that like clade B Env, JRFL, membrane bound Indian clade C Env, 4-2.J41 is also efficiently cleaved and displays desirable antigenic properties for plasmid DNA immunization. Here, we evaluated the immune response in rabbit by injecting the animals with plasmid expressing membrane bound efficiently cleaved 4-2...
February 8, 2018: Vaccine
https://www.readbyqxmd.com/read/29420040/integrity-of-glycosylation-processing-of-a-glycan-depleted-trimeric-hiv-1-immunogen-targeting-key-b-cell-lineages
#10
Anna-Janina Behrens, Abhinav Kumar, Max Medina-Ramirez, Albert Cupo, Kevin Marshall, Victor M Cruz Portillo, David J Harvey, Gabriel Ozorowski, Nicole Zitzmann, Ian A Wilson, Andrew B Ward, Weston B Struwe, John P Moore, Rogier W Sanders, Max Crispin
Broadly neutralizing antibodies (bNAbs) that target the trimeric HIV-1 envelope glycoprotein spike (Env) are tools that can guide the design of recombinant Env proteins intended to engage the predicted human germline precursors of bNAbs (gl-bNAbs). The protein components of gl-bNAb epitopes are often masked by glycans, while mature bNAbs can evolve to accommodate or bypass these shielding glycans. The design of germline-targeting Env immunogens therefore includes the targeted deletion of specific glycan sites...
February 8, 2018: Journal of Proteome Research
https://www.readbyqxmd.com/read/29414440/induction-of-broadly-neutralizing-antibodies-in-germinal-centre-simulations
#11
REVIEW
Philippe A Robert, Andrea Lj Marschall, Michael Meyer-Hermann
Vaccines against mutating pathogens such as influenza, HIV, or plasmodium are poorly protective towards new evolving strains. Rare individuals naturally mount broadly neutralizing antibodies covering most strains, but the requirements for their induction are unknown. The antibody response to vaccination has been recapitulated by in silico models that proposed two opposite schemes: A theory of 'frustration' where one epitope at a time leads to optimal antibody breadth through sequential immunizations, that was proven successful for HIV vaccination in primates...
February 1, 2018: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/29410416/broad-and-long-lasting-immune-protection-against-various-chikungunya-genotypes-demonstrated-by-participants-in-a-cross-sectional-study-in-a-cambodian-rural-community
#12
Heidi Auerswald, Camille Boussioux, Saraden In, Sokthearom Mao, Sivuth Ong, Rekol Huy, Rithea Leang, Malen Chan, Veasna Duong, Sowath Ly, Arnaud Tarantola, Philippe Dussart
Chikungunya virus (CHIKV) is an alphavirus circulating worldwide. Its presence in Asia has been reported since the 1950s, constituting the Asian genotype. Since 2005, strains from the Eastern, Central, and Southern African (ECSA) genotype have caused several outbreaks across Asia. Viruses from the ECSA genotype were also detected in Cambodia in late 2011 and led to an outbreak in a rural community in 2012. A former investigation from 2012 found a higher risk of infection in people younger than 40 years, suggesting a pre-existing herd immunity in the older Cambodian population due to infection with an Asian genotype...
February 7, 2018: Emerging Microbes & Infections
https://www.readbyqxmd.com/read/29408442/porcine-reproductive-and-respiratory-syndrome-virus-neutralizing-antibodies-provide-in-vivo-cross-protection-to-prrsv1-and-prrsv2-viral-challenge
#13
Sally R Robinson, Michael C Rahe, Diem K Gray, Kyra V Martins, Michael P Murtaugh
Vaccine control and prevention of porcine reproductive and respiratory syndrome (PRRS), the most important disease of swine, is difficult to achieve. However, the discovery of broadly neutralizing antibody activity against porcine reproductive and respiratory syndrome virus (PRRSV) under typical field conditions opens the door to new immunologic approaches for robust protection. We show here that passive administration of purified immunoglobulins with neutralizing antibodies reduced PRRSV2 infection by up to 96%, and PRRSV1 infection by up to 87%, whereas immune immunoglobulins lacking neutralizing activity had no effect on viral infection...
February 3, 2018: Virus Research
https://www.readbyqxmd.com/read/29398272/development-of-a-high-growth-enterovirus-71-vaccine-candidate-inducing-cross-reactive-neutralizing-antibody-responses
#14
Min-Yuan Chia, Wan-Yu Chung, Chun-Hsiung Wang, Wei-Hau Chang, Min-Shi Lee
Although Enterovirus 71 (EV71) has only one serotype based on serum neutralization tests using hyperimmune animal antisera, three major genogroups (A, B and C) including eleven genotypes (A, B1-B2, and C1-C5) can be well classified based on phylogenetic analysis. Since 1997, large-scale EV71 epidemics occurred cyclically with different genotypes in the Asia-Pacific region. Therefore, development of EV71 vaccines is a national priority in several Asian countries. Currently, five vaccine candidates have been evaluated in clinical trials in China (three C4 candidates), Singapore (one B2 candidate), and Taiwan (one B4 candidate)...
February 2, 2018: Vaccine
https://www.readbyqxmd.com/read/29396418/structural-insights-into-the-design-of-novel-anti-influenza-therapies
#15
REVIEW
Nicholas C Wu, Ian A Wilson
A limited arsenal of therapies is currently available to tackle the emergence of a future influenza pandemic or even to deal effectively with the continual outbreaks of seasonal influenza. However, recent findings hold great promise for the design of novel vaccines and therapeutics, including the possibility of more universal treatments. Structural biology has been a major contributor to those advances, in particular through the many studies on influenza hemagglutinin (HA), the major surface antigen. HA's primary function is to enable the virus to enter host cells, and structural work has revealed the various HA conformational forms generated during the entry process...
February 2, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29386288/hiv-1-envelope-glycoproteins-from-diverse-clades-differentiate-antibody-responses-and-durability-among-vaccinees
#16
Nicole L Yates, Allan C deCamp, Bette T Korber, Hua-Xin Liao, Carmela Irene, Abraham Pinter, James Peacock, Linda J Harris, Sheetal Sawant, Peter Hraber, Xiaoying Shen, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Phillip W Berman, Merlin L Robb, Giuseppe Pantaleo, Susan Zolla-Pazner, Barton F Haynes, S Munir Alam, David C Montefiori, Georgia D Tomaras
Induction of broadly cross-reactive anti-viral humoral responses with the capacity to target globally diverse circulating strains is a key goal for HIV-1 immunogen design. A major gap in the field is the identification of diverse HIV-1 envelope antigens to evaluate vaccine regimens for binding antibody breadth. In this study, we define unique antigen panels to map HIV-1 vaccine-elicited antibody breadth and durability. Diverse HIV-1 envelope glycoproteins were selected based on genetic and geographic diversity to cover the global epidemic, with a focus on sexually acquired transmitted/founder viruses with a tier-2 neutralization phenotype...
January 31, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29386285/functional-optimization-of-broadly-neutralizing-hiv-1-antibody-10e8-by-promoting-membrane-interactions
#17
Edurne Rujas, Daniel P Leaman, Sara Insausti, Lei Ortigosa-Pascual, Lei Zhang, Michael B Zwick, José L Nieva
The 10E8 antibody targets a helical epitope in the membrane-proximal external region (MPER) and transmembrane domain (TMD) of the envelope glycoprotein (Env) subunit gp41, and is among the broadest known neutralizing antibodies against HIV-1. Accordingly, this antibody and its mechanism of action valuably inform the design of effective vaccines and immunotherapies. 10E8 exhibits unusual adaptations to attain specific, high-affinity binding to the MPER at the viral membrane interface. Reversing charge of the basic paratope surface (from net positive to net negative) reportedly lowered its neutralization potency...
January 31, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29370298/phenotypic-deficits-in-the-hiv-1-envelope-are-associated-with-the-maturation-of-a-v2-directed-broadly-neutralizing-antibody-lineage
#18
Lucia Reh, Carsten Magnus, Claus Kadelka, Denise Kühnert, Therese Uhr, Jacqueline Weber, Lynn Morris, Penny L Moore, Alexandra Trkola
Broadly neutralizing antibodies (bnAbs) to HIV-1 can evolve after years of an iterative process of virus escape and antibody adaptation that HIV-1 vaccine design seeks to mimic. To enable this, properties that render HIV-1 envelopes (Env) capable of eliciting bnAb responses need to be defined. Here, we followed the evolution of the V2 apex directed bnAb lineage VRC26 in the HIV-1 subtype C superinfected donor CAP256 to investigate the phenotypic changes of the virus populations circulating before and during the early phases of bnAb induction...
January 25, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29367243/immunogenicity-in-rabbits-of-sosip-trimers-from-clades-a-b-and-c-given-individually-sequentially-or-in-combinations
#19
Alba Torrents de la Peña, Steven W de Taeye, Kwinten Sliepen, Celia C LaBranche, Judith A Burger, Edith E Schermer, David C Montefiori, John P Moore, Per Johan Klasse, Rogier W Sanders
Recombinant soluble HIV-1 envelope glycoprotein (Env) SOSIP trimers are a design platform for inducing broadly neutralizing antibodies (bNAbs) by vaccination. To date, these and alternative designs of native-like trimers given singly or in pairs, have not induced bNAbs in test animals such as rabbits or macaques. Here, we have evaluated whether trivalent and tetravalent combinations of SOSIP trimers from clades A, B and C, delivered simultaneously or sequentially, induce better neutralizing antibody responses in rabbits than when given alone...
January 24, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29366547/hiv-reactivation-after-partial-protection-by-neutralizing-antibodies
#20
REVIEW
Matthew S Parsons, Deborah Cromer, Miles P Davenport, Stephen J Kent
It is widely thought that generating broadly neutralizing anti-HIV antibodies (BnAbs) will protect humans against HIV, given promising data from in vitro experiments and in vivo macaque studies. The primary action of BnAbs is preventing cell-free virus from entering cells. Recent in vitro and macaque data suggest that BnAbs are less potent against cell-associated virus exposure. We speculate that BnAb-based suppression of HIV transmission, particularly if mediated by cell-cell transmission, may result in some exposed subjects carrying a form of latent (or 'occult') HIV infection...
January 20, 2018: Trends in Immunology
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