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Hiv and broadly neutralizing antibody

Daniela Fera, Matthew S Lee, Kevin Wiehe, R Ryan Meyerhoff, Alessandro Piai, Mattia Bonsignori, Baptiste Aussedat, William E Walkowicz, Therese Ton, Jeffrey O Zhou, Samuel Danishefsky, Barton F Haynes, Stephen C Harrison
HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide ("Man9 -V3") for structural studies of an HIV Env third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage ("DH270"), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man9 -V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs-the conserved GDIR motif and the N332 glycan...
March 16, 2018: Nature Communications
Hao D Cheng, Sebastian K Grimm, Morgan Sa Gilman, Luc Christian Gwom, Devin Sok, Christopher Sundling, Gina Donofrio, Gunilla B Karlsson Hedestam, Mattia Bonsignori, Barton F Haynes, Timothy P Lahey, Isaac Maro, C Fordham von Reyn, Miroslaw K Gorny, Susan Zolla-Pazner, Bruce D Walker, Galit Alter, Dennis R Burton, Merlin L Robb, Shelly J Krebs, Michael S Seaman, Chris Bailey-Kellogg, Margaret E Ackerman
Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth...
March 8, 2018: JCI Insight
Jesse L Huang, Attila Nagy, Vera B Ivleva, Daniel Blackstock, Frank Arnold, Cindy X Cai
One approach to mitigate product clipping during HIV mAb CAP256-VRC26.25 cell culture development is the addition of protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF) to the cell culture media. AEBSF can undergo hydrolysis to form an inactive compound, 4-(2-aminoethyl) benzenesulfonic acid. Using mass spectrometry detection, a kinetic profiling of AEBSF hydrolysis was generated for conditions simulating that of cell culture at pH 7.0/37 C. It was found that increasing pH and/or temperature could accelerate AEBSF hydrolysis...
March 6, 2018: Analytical Chemistry
Kshitij Wagh, Michael S Seaman, Marshall Zingg, Tomas Fitzsimons, Dan H Barouch, Dennis R Burton, Mark Connors, David D Ho, John R Mascola, Michel C Nussenzweig, Jeffrey Ravetch, Rajeev Gautam, Malcolm A Martin, David C Montefiori, Bette Korber NCT02960581.
March 5, 2018: PLoS Pathogens
Vani G S Narasimhulu, Anna K Bellamy-McIntyre, Annamarie E Laumaea, Chan-Sien Lay, David N Harrison, Hannah A D King, Heidi E Drummer, Pantelis Poumbourios
HIV-1 is spread by cell-free virions and by cell-cell viral transfer. We asked whether the structure and function of a broad neutralizing antibody (bNAb) epitope, the membrane-proximal ectodomain region (MPER) of the viral gp41 transmembrane glycoprotein, differ in cell-free and cell-cell transmitted viruses and whether this difference could be related to Ab neutralization sensitivity. Whereas cell-free viruses bearing W666A and I675A substitutions in the MPER lacked infectivity, cell-associated mutant viruses were able to initiate robust spreading infection...
March 1, 2018: Journal of Biological Chemistry
James J Steinhardt, Javier Guenaga, Hannah L Turner, Krisha McKee, Mark K Louder, Sijy O'Dell, Chi-I Chiang, Lin Lei, Andrey Galkin, Alexander K Andrianov, Nicole A Doria-Rose, Robert T Bailer, Andrew B Ward, John R Mascola, Yuxing Li
HIV-1 broadly neutralizing antibodies (bNAbs) are being explored as passively administered therapeutic and preventative agents. However, the extensively diversified HIV-1 envelope glycoproteins (Env) rapidly acquire mutations to evade individual bNAbs in monotherapy regimens. The use of a "single" agent to simultaneously target distinct Env epitopes is desirable to overcome viral diversity. Here, we report the use of tandem single-chain variable fragment (ScFv) domains of two bNAbs, specific for the CD4-binding site and V3 glycan patch, to form anti-HIV-1 bispecific ScFvs (Bi-ScFvs)...
February 28, 2018: Nature Communications
Manickam Ashokkumar, Shambhu G Aralaguppe, Srikanth P Tripathy, Luke Elizabeth Hanna, Ujjwal Neogi
Adequate information on the precise molecular and biological composition of the viral strains that establish HIV-infection in the human host will provide effective means of immunization against HIV-infection. In an attempt to identify and differentiate the biological properties and infectious potential of the transmitted founder (TF) virus from the population of the early transmitted virus, patient-derived 250 envelope glycoprotein, gp120 were cloned in pMN-K7-Luc-IRESs-NefΔgp120 to obtain chimeric viruses...
February 28, 2018: Journal of Virology
Victoria Oakes, Johana Torralba, Edurne Rujas, José L Nieva, Carmen Domene, Beatriz Apellaniz
The 10E8 antibody achieves near-pan neutralization of HIV-1 by targeting the remarkably conserved gp41 membrane-proximal external region (MPER) and the connected transmembrane domain (TMD) of the HIV-1 envelope glycoprotein (Env). Thus, recreating the structure that generates 10E8-like antibodies is a major goal of the rational design of anti-HIV vaccines. Unfortunately, high-resolution information of this segment in the native Env is lacking, limiting our understanding of the behavior of the crucial 10E8 epitope residues...
February 22, 2018: Biochimica et Biophysica Acta
Xilin Wu, Jia Guo, Mengyue Niu, Minghui An, Li Liu, Hui Wang, Xia Jin, Qi Zhang, Ka Shing Lam, Tongjin Wu, Hua Wang, Qian Wang, Yanhua Du, Jingjing Li, Lin Cheng, Hang Ying Tang, Hong Shang, Linqi Zhang, Paul Zhou, Zhiwei Chen
The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral drug therapy (cART). Here, we investigate the potential of an engineered tandem bi-specific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving two scFv binding domains of each parental bnAb, a single-gene-encoded tandem bs-bnAb, namely BiIA-SG, displayed significantly improved breadth and potency...
February 20, 2018: Journal of Clinical Investigation
Paneerselvam Nandagopal, Jayanta Bhattacharya, Aylur K Srikrishnan, Rajat Goyal, Chinnambedu Ravichandran Swathirajan, Shilpa Patil, Shanmugam Saravanan, Suprit Deshpande, Ramachandran Vignesh, Sunil Suhas Solomon, Nikhil Singla, Joyeeta Mukherjee, Kailapuri G Murugavel
Broadly neutralizing antibodies (bnAbs) have been considered to be potent therapeutic tools and potential vaccine candidates to enable protection against various clades of human immunodeficiency virus (HIV). The generation of bnAbs has been associated with enhanced exposure to antigen, high viral load and low CD4+ T cell counts, among other factors. However, only limited data are available on the generation of bnAbs in viraemic non-progressors that demonstrate moderate to high viraemia. Further, since HIV-1 subtype C viruses account for more than 50 % of global HIV infections, the identification of bnAbs with novel specificities is crucial to enable the development of potent tools to aid in HIV therapy and prevention...
February 5, 2018: Journal of General Virology
Robyn L Stanfield, Jeremy Haakenson, Thaddeus C Deiss, Michael F Criscitiello, Ian A Wilson, Vaughn V Smider
Antibodies are the key circulating molecules that have evolved to fight infection by the adaptive immune system of vertebrates. Typical antibodies of most species contain six complementarity-determining regions (CDRs), where the third CDR of the heavy chain (CDR H3) has the greatest diversity and often makes the most significant contact with antigen. Generally, the process of V(D)J recombination produces a vast repertoire of antibodies; multiple V, D, and J gene segments recombine with additional junctional diversity at the V-D and D-J joints, and additional combinatorial possibilities occur through heavy- and light-chain pairing...
2018: Advances in Immunology
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
Francis Barin, Karl Stefic
No abstract text is available yet for this article.
February 2018: Médecine Sciences: M/S
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
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
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
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
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
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
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
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