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https://www.readbyqxmd.com/read/27905530/structural-basis-for-broad-neutralization-of-hiv-1-through-the-molecular-recognition-of-10e8-helical-epitope-at-the-membrane-interface
#1
Edurne Rujas, Jose M M Caaveiro, Angélica Partida-Hanon, Naveed Gulzar, Koldo Morante, Beatriz Apellániz, Miguel García-Porras, Marta Bruix, Kouhei Tsumoto, Jamie K Scott, M Ángeles Jiménez, José L Nieva
The mechanism by which the HIV-1 MPER epitope is recognized by the potent neutralizing antibody 10E8 at membrane interfaces remains poorly understood. To solve this problem, we have optimized a 10E8 peptide epitope and analyzed the structure and binding activities of the antibody in membrane and membrane-like environments. The X-ray crystal structure of the Fab-peptide complex in detergents revealed for the first time that the epitope of 10E8 comprises a continuous helix spanning the gp41 MPER/transmembrane domain junction (MPER-N-TMD; Env residues 671-687)...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27849170/hiv-1-envelope-mimicry-of-host-enzyme-kynureninase-does-not-disrupt-tryptophan-metabolism
#2
Todd Bradley, Guang Yang, Olga Ilkayeva, T Matt Holl, Ruijun Zhang, Jinsong Zhang, Sampa Santra, Christopher B Fox, Steve G Reed, Robert Parks, Cindy M Bowman, Hilary Bouton-Verville, Laura L Sutherland, Richard M Scearce, Nathan Vandergrift, Thomas B Kepler, M Anthony Moody, Hua-Xin Liao, S Munir Alam, Roger McLendon, Jeffrey I Everitt, Christopher B Newgard, Laurent Verkoczy, Garnett Kelsoe, Barton F Haynes
The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross-reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host proteins by pathogens can lead to autoimmune disease. In this article, we demonstrate that neither the 2F5 bnAb nor HIV MPER-KYNU cross-reactive Abs elicited by immunization with an MPER peptide-liposome vaccine in 2F5 bnAb VHDJH and VLJL knock-in mice and rhesus macaques modified KYNU activity or disrupted tissue tryptophan metabolism...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27795431/broadly-neutralising-antibodies-display-superior-potential-over-non-neutralising-antibodies-in-preventing-hiv-1-infection-of-mucosal-tissue
#3
Hannah M Cheeseman, Natalia J Olejniczak, Paul M Rogers, Abbey B Evans, Deborah F L King, Paul Ziprin, Hua-Xin Liao, Barton F Haynes, Robin J Shattock
: Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralisation is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Non-neutralising antibodies (nnAbs) may also impact on mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27731975/lytic-inactivation-of-hiv-1-by-dual-engagement-of-gp120-and-gp41-domains-in-the-virus-env-protein-trimer
#4
Bibek Parajuli, Kriti Acharya, Reina Yu, Brendon Ngo, Adel A Rashad, Cameron F Abrams, Irwin M Chaiken
We recently reported discovery of a recombinant chimera, denoted DAVEI (Dual Acting Virucidal Entry Inhibitor), which is able to selectively cause specific and potent lytic inactivation of both pseudotyped and fully infectious HIV-1 virions. The chimera is composed of the lectin cyanovirin-N (CVN) fused to the 20-residue membrane-proximal external region (MPER) of HIV-1 gp41. Since the Env gp120-binding CVN domain on its own is not lytic, we sought here to determine how the MPER(DAVEI) domain is able to endow the chimera with virolytic activity...
October 12, 2016: Biochemistry
https://www.readbyqxmd.com/read/27612593/amino-acid-changes-in-the-hiv-1-gp41-membrane-proximal-region-control-virus-neutralization-sensitivity
#5
Todd Bradley, Ashley Trama, Nancy Tumba, Elin Gray, Xiaozhi Lu, Navid Madani, Fatemeh Jahanbakhsh, Amanda Eaton, Shi-Mao Xia, Robert Parks, Krissey E Lloyd, Laura L Sutherland, Richard M Scearce, Cindy M Bowman, Susan Barnett, Salim S Abdool-Karim, Scott D Boyd, Bruno Melillo, Amos B Smith, Joseph Sodroski, Thomas B Kepler, S Munir Alam, Feng Gao, Mattia Bonsignori, Hua-Xin Liao, M Anthony Moody, David Montefiori, Sampa Santra, Lynn Morris, Barton F Haynes
Most HIV-1 vaccines elicit neutralizing antibodies that are active against highly sensitive (tier-1) viruses or rare cases of vaccine-matched neutralization-resistant (tier-2) viruses, but no vaccine has induced antibodies that can broadly neutralize heterologous tier-2 viruses. In this study, we isolated antibodies from an HIV-1-infected individual that targeted the gp41 membrane-proximal external region (MPER) that may have selected single-residue changes in viral variants in the MPER that resulted in neutralization sensitivity to antibodies targeting distal epitopes on the HIV-1 Env...
October 2016: EBioMedicine
https://www.readbyqxmd.com/read/27513582/insights-into-the-conformation-of-the-membrane-proximal-regions-critical-to-the-trimerization-of-the-hiv-1-gp41-ectodomain-bound-to-dodecyl-phosphocholine-micelles
#6
John M Louis, James L Baber, Rodolfo Ghirlando, Annie Aniana, Ad Bax, Julien Roche
The transitioning of the ectodomain of gp41 from a pre-hairpin to a six-helix bundle conformation is a crucial aspect of virus-cell fusion. To gain insight into the intermediary steps of the fusion process we have studied the pH and dodecyl phosphocholine (DPC) micelle dependent trimer association of gp41 by systematic deletion analysis of an optimized construct termed 17-172 (residues 528 to 683 of Env) that spans the fusion peptide proximal region (FPPR) to the membrane proximal external region (MPER) of gp41, by sedimentation velocity and double electron-electron resonance (DEER) EPR spectroscopy...
2016: PloS One
https://www.readbyqxmd.com/read/27466419/generation-of-long-lived-bone-marrow-plasma-cells-secreting-antibodies-specific-for-the-hiv-1-gp41-membrane-proximal-external-region-in-the-absence-of-polyreactivity
#7
Luke R Donius, Yuxing Cheng, Jaewon Choi, Zhen-Yu J Sun, Melissa Hanson, Michael Zhang, Todd M Gierahn, Susanna Marquez, Mohammed Uduman, Steven H Kleinstein, Darrell Irvine, J Christopher Love, Ellis L Reinherz, Mikyung Kim
UNLABELLED: An effective preventive vaccine is highly sought after in order to stem the current HIV-1 pandemic. Both conservation of contiguous gp41 membrane-proximal external region (MPER) amino acid sequences across HIV-1 clades and the ability of anti-MPER broadly neutralizing antibodies (BNAbs) to block viral hemifusion/fusion establish the MPER as a prime vaccination target. In earlier studies, we described the development of an MPER vaccine formulation that takes advantage of liposomes to array the MPER on a lipid bilayer surface, paralleling its native configuration on the virus membrane while also incorporating molecular adjuvant and CD4 T cell epitope cargo...
October 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27411313/live-attenuated-salmonella-displaying-hiv-1-10e8-epitope-on-fimbriae-systemic-and-mucosal-immune-responses-in-balb-c-mice-by-mucosal-administration
#8
Qing-Hai Li, Gang Jin, Jia-Ye Wang, Hai-Ning Li, Huidi Liu, Xiao-Yun Chang, Fu-Xiang Wang, Shu-Lin Liu
The HIV-1 membrane proximal external region (MPER) that is targeted by several broadly neutralizing antibodies (BNAbs) has been considered a potential immunogen for vaccine development. However, to date the immunogenicity of these BNAb epitopes has not been made sufficiently adequate. In the present work, we used live attenuated Salmonella as a platform to present the HIV-1 MPER 10E8 epitope in the fimbriae. The insertion of the 10E8 epitope into the fimbriae had no significant influence on the expression and the absorption capacity of bacterial fimbriae, nor on the virulence and invasiveness of the attenuated Salmonella...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27329850/an-immunogen-containing-four-tandem-10e8-epitope-repeats-with-exposed-key-residues-induces-antibodies-that-neutralize-hiv-1-and-activates-an-adcc-reporter-gene
#9
Zhiwu Sun, Yun Zhu, Qian Wang, Ling Ye, Yanyan Dai, Shan Su, Fei Yu, Tianlei Ying, Chinglai Yang, Shibo Jiang, Lu Lu
After three decades of intensive research efforts, an effective vaccine against HIV-1 remains to be developed. Several broadly neutralizing antibodies to HIV-1, such as 10E8, recognize the membrane proximal external region (MPER) of the HIV-1 gp41 protein. Thus, the MPER is considered to be a very important target for vaccine design. However, the MPER segment has very weak immunogenicity and tends to insert its epitope residues into the cell membrane, thereby avoiding antibody binding. To address this complication in vaccine development, we herein designed a peptide, designated 10E8-4P, containing four copies of the 10E8 epitope as an immunogen...
2016: Emerging Microbes & Infections
https://www.readbyqxmd.com/read/27303748/engineering-recombinant-reoviruses-to-display-gp41-membrane-proximal-external-region-epitopes-from-hiv-1
#10
Karl W Boehme, Mine' Ikizler, Jason A Iskarpatyoti, J Denise Wetzel, Jordan Willis, James E Crowe, Celia C LaBranche, David C Montefiori, Gregory J Wilson, Terence S Dermody
The gp41 membrane-proximal external region (MPER) is a target for broadly neutralizing antibody responses against human immunodeficiency virus type 1 (HIV-1). However, replication-defective virus vaccines currently under evaluation in clinical trials do not efficiently elicit MPER-specific antibodies. Structural modeling suggests that the MPER forms an α-helical coiled coil that is required for function and immunogenicity. To maintain the native MPER conformation, we used reverse genetics to engineer replication-competent reovirus vectors that displayed MPER sequences in the α-helical coiled-coil tail domain of viral attachment protein σ1...
May 2016: MSphere
https://www.readbyqxmd.com/read/27299673/developmental-pathway-of-the-mper-directed-hiv-1-neutralizing-antibody-10e8
#11
Cinque Soto, Gilad Ofek, M Gordon Joyce, Baoshan Zhang, Krisha McKee, Nancy S Longo, Yongping Yang, Jinghe Huang, Robert Parks, Joshua Eudailey, Krissey E Lloyd, S Munir Alam, Barton F Haynes, James C Mullikin, Mark Connors, John R Mascola, Lawrence Shapiro, Peter D Kwong
Antibody 10E8 targets the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes >97% of HIV-1 isolates, and lacks the auto-reactivity often associated with MPER-directed antibodies. The developmental pathway of 10E8 might therefore serve as a promising template for vaccine design, but samples from time-of-infection-often used to infer the B cell record-are unavailable. In this study, we used crystallography, next-generation sequencing (NGS), and functional assessments to infer the 10E8 developmental pathway from a single time point...
2016: PloS One
https://www.readbyqxmd.com/read/27265468/structure-of-transmembrane-subunits-gp47-of-the-foamy-virus-envelope-glycoproteins
#12
M Wang, H Zhang, Q-M Liu, Y Sun, Z Li, W-H Liu, X-H He, J Song, Y-X Wang
The successful foamy viruses (FVs) infection includes at least two essential events, attachment to the cell surface and fusion of the viral envelope with the cell membrane. For the FVs, membrane fusion between virus and cell is mediated by envelope glycoprotein (Env) transmembrane (TM) subunit gp47. Compared with other retroviruses, FV TM subunit shares a similar but not identical structural characteristic. This paper focuses on in sillico analyses of all 15 available FV TM subunits gp47 based on their amino acid sequences...
June 2016: Acta Virologica
https://www.readbyqxmd.com/read/27179640/on-the-microscopic-and-mesoscopic-perturbations-of-lipid-bilayers-upon-interaction-with-the-mper-domain-of-the-hiv-glycoprotein-gp41
#13
Rosario Oliva, Alessandro Emendato, Giuseppe Vitiello, Augusta De Santis, Manuela Grimaldi, Anna Maria D'Ursi, Elena Busi, Pompea Del Vecchio, Luigi Petraccone, Gerardino D'Errico
The effect of the 665-683 fragment of the HIV fusion glycoprotein 41, corresponding to the MPER domain of the protein and named gp41MPER, on the microscopic structure and mesoscopic arrangement of palmitoyl oleoyl phosphatidylcholine (POPC) and POPC/sphingomyelin (SM)/cholesterol (CHOL) lipid bilayers is analyzed. The microscopic structuring of the bilayers has been studied by Electron Spin Resonance (ESR) spectroscopy, using glycerophosphocholines spin-labelled in different positions along the acyl chain. Transitions of the bilayer liquid crystalline state have been also monitored by Differential Scanning Calorimetry (DSC)...
August 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27147747/in-vivo-analysis-of-infectivity-fusogenicity-and-incorporation-of-a-mutagenic-viral-glycoprotein-library-reveals-determinants-for-virus-incorporation
#14
Daniel J Salamango, Khalid K Alam, Donald H Burke, Marc C Johnson
UNLABELLED: Enveloped viruses utilize transmembrane surface glycoproteins to gain entry into target cells. Glycoproteins from diverse viral families can be incorporated into nonnative viral particles in a process termed pseudotyping; however, the molecular mechanisms governing acquisition of these glycoproteins are poorly understood. For murine leukemia virus envelope (MLV Env) glycoprotein, incorporation into foreign viral particles has been shown to be an active process, but it does not appear to be caused by direct interactions among viral proteins...
July 15, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27053554/optimization-of-the-solubility-of-hiv-1-neutralizing-antibody-10e8-through-somatic-variation-and-structure-based-design
#15
Young D Kwon, Ivelin S Georgiev, Gilad Ofek, Baoshan Zhang, Mangaiarkarasi Asokan, Robert T Bailer, Amy Bao, William Caruso, Xuejun Chen, Misook Choe, Aliaksandr Druz, Sung-Youl Ko, Mark K Louder, Krisha McKee, Sijy O'Dell, Amarendra Pegu, Rebecca S Rudicell, Wei Shi, Keyun Wang, Yongping Yang, Mandy Alger, Michael F Bender, Kevin Carlton, Jonathan W Cooper, Julie Blinn, Joshua Eudailey, Krissey Lloyd, Robert Parks, S Munir Alam, Barton F Haynes, Neal N Padte, Jian Yu, David D Ho, Jinghe Huang, Mark Connors, Richard M Schwartz, John R Mascola, Peter D Kwong
UNLABELLED: Extraordinary antibodies capable of near pan-neutralization of HIV-1 have been identified. One of the broadest is antibody 10E8, which recognizes the membrane-proximal external region (MPER) of the HIV-1 envelope and neutralizes >95% of circulating HIV-1 strains. If delivered passively, 10E8 might serve to prevent or treat HIV-1 infection. Antibody 10E8, however, is markedly less soluble than other antibodies. Here, we describe the use of both structural biology and somatic variation to develop optimized versions of 10E8 with increased solubility...
July 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27028935/optimal-combinations-of-broadly-neutralizing-antibodies-for-prevention-and-treatment-of-hiv-1-clade-c-infection
#16
Kshitij Wagh, Tanmoy Bhattacharya, Carolyn Williamson, Alex Robles, Madeleine Bayne, Jetta Garrity, Michael Rist, Cecilia Rademeyer, Hyejin Yoon, Alan Lapedes, Hongmei Gao, Kelli Greene, Mark K Louder, Rui Kong, Salim Abdool Karim, Dennis R Burton, Dan H Barouch, Michel C Nussenzweig, John R Mascola, Lynn Morris, David C Montefiori, Bette Korber, Michael S Seaman
The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses...
March 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/26986483/immunological-characterization-of-plant-based-hiv-1-gag-dgp41-virus-like-particles
#17
Sarah A Kessans, Mark D Linhart, Lydia R Meador, Jacquelyn Kilbourne, Brenda G Hogue, Petra Fromme, Nobuyuki Matoba, Tsafrir S Mor
It is widely anticipated that a prophylactic vaccine may be needed to control the HIV/AIDS epidemic worldwide. Despite over two decades of research, a vaccine against HIV-1 remains elusive, although a recent clinical trial has shown promising results. Recent studies have focused on highly conserved domains within HIV-1 such as the membrane proximal external region (MPER) of the envelope glycoprotein, gp41. MPER has been shown to play critical roles in mucosal transmission of HIV-1, though this peptide is poorly immunogenic on its own...
2016: PloS One
https://www.readbyqxmd.com/read/26941313/cryo-em-structure-of-a-native-fully-glycosylated-cleaved-hiv-1-envelope-trimer
#18
Jeong Hyun Lee, Gabriel Ozorowski, Andrew B Ward
The envelope glycoprotein trimer (Env) on the surface of HIV-1 recognizes CD4(+) T cells and mediates viral entry. During this process, Env undergoes substantial conformational rearrangements, making it difficult to study in its native state. Soluble stabilized trimers have provided valuable insights into the Env structure, but they lack the hydrophobic membrane proximal external region (MPER, an important target of broadly neutralizing antibodies), the transmembrane domain, and the cytoplasmic tail. Here we present (i) a cryogenic electron microscopy (cryo-EM) structure of a clade B virus Env, which lacks only the cytoplasmic tail and is stabilized by the broadly neutralizing antibody PGT151, at a resolution of 4...
March 4, 2016: Science
https://www.readbyqxmd.com/read/26875765/a-novel-antimicrobial-peptide-derived-from-membrane-proximal-external-region-of-human-immunodeficiency-virus-type-1
#19
Xiaoqiu He, Huayan Zhang, Yuhua Shi, Xin Gong, Shanshan Guan, He Yin, Lan Yang, Yongjiao Yu, Ziyu Kuai, Dongni Liu, Rui Hua, Song Wang, Yaming Shan
With increasing microbial drug resistance worldwide, antimicrobial peptides (AMPs) are considered promising alternatives to addressing this problem. In this study, a series of synthetic peptides were designed based on the membrane-disrupting properties of the membrane-proximal external region (MPER) of human immunodeficiency virus type 1 (HIV-1) envelope protein. The peptide AP16-A was found to exhibit the most effective antimicrobial activities against both Gram-negative and Gram-positive bacteria. The minimal bactericidal concentration (MBC) of AP16-A ranged from 2 μg/ml to 16 μg/ml...
April 2016: Biochimie
https://www.readbyqxmd.com/read/26803471/modulating-immunogenic-properties-of-hiv-1-gp41-membrane-proximal-external-region-by-destabilizing-six-helix-bundle-structure
#20
Saikat Banerjee, Heliang Shi, Habtom H Habte, Yali Qin, Michael W Cho
The C-terminal alpha-helix of gp41 membrane-proximal external region (MPER; (671)NWFDITNWLWYIK(683)) encompassing 4E10/10E8 epitopes is an attractive target for HIV-1 vaccine development. We previously reported that gp41-HR1-54Q, a trimeric protein comprised of the MPER in the context of a stable six-helix bundle (6HB), induced strong immune responses against the helix, but antibodies were directed primarily against the non-neutralizing face of the helix. To better target 4E10/10E8 epitopes, we generated four putative fusion intermediates by introducing double point mutations or deletions in the heptad repeat region 1 (HR1) that destabilize 6HB in varying degrees...
March 2016: Virology
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