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https://www.readbyqxmd.com/read/28300601/functional-contacts-between-mper-and-the-anti-hiv-1-broadly-neutralizing-antibody-4e10-extend-into-the-core-of-the-membrane
#1
Edurne Rujas, Sara Insausti, Miguel García-Porras, Rubén Sánchez-Eugenia, Kouhei Tsumoto, José L Nieva, Jose M M Caaveiro
The exceptional breadth of broadly neutralizing antibodies (bNAbs) against the membrane-proximal external region (MPER) of the transmembrane protein gp41 makes this class of antibodies an ideal model to design HIV vaccines. From a practical point of view, however, the preparation of vaccines eliciting bNAbs is still a major roadblock that limits their clinical application. Fresh mechanistic insights are necessary to develop more effective strategies. In particular, the function of the unusually long complementary determining region three of the heavy chain (CDRH3) of 4E10, an anti-MPER bNAb, is an open question that fascinates researchers in the field...
March 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28282446/antigenic-and-immunosuppressive-properties-of-a-trimeric-recombinant-transmembrane-envelope-protein-gp41-of-hiv-1
#2
Michael Mühle, Melissa Lehmann, Kerstin Hoffmann, Daniel Stern, Tobias Kroniger, Werner Luttmann, Joachim Denner
The transmembrane envelope (TM) protein gp41 of the human immunodeficiency virus-1 (HIV-1) plays an important role during virus infection inducing the fusion of the viral and cellular membranes. In addition, there are indications that the TM protein plays a role in the immunopathogenesis leading to the acquired immunodeficiency syndrome (AIDS). Inactivated virus particles and recombinant gp41 have been reported to inhibit lymphocyte proliferation, as well as to alter cytokine release and gene expression. The same was shown for a peptide corresponding to a highly conserved domain of all retroviral TM proteins, the immunosuppressive domain...
2017: PloS One
https://www.readbyqxmd.com/read/28250125/conformational-states-of-a-soluble-uncleaved-hiv-1-envelope-trimer
#3
Yuhang Liu, Junhua Pan, Yongfei Cai, Nikolaus Grigorieff, Stephen C Harrison, Bing Chen
HIV-1 envelope spike [Env; trimeric (gp160)3, cleaved to (gp120/gp41)3] induces membrane fusion, leading to viral entry. It is also the viral component targeted by neutralizing antibodies. Vaccine development requires production, in quantities suitable for clinical studies, of a recombinant form that resembles functional Env. HIV-1 gp140 trimers - the uncleaved ectodomains of (gp160)3 - from a few selected viral isolates adopt a compact conformation with many antigenic properties of native Env spikes. One is currently being evaluated in a clinical trial...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28250119/new-connections-cell-to-cell-hiv-1-transmission-resistance-to-broadly-neutralizing-antibodies-and-an-envelope-sorting-motif
#4
S Abigail Smith, Cynthia A Derdeyn
HIV-1 infection from cell to cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al show that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell to cell infection in a context dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28237764/evaluation-of-a-novel-multi-immunogen-vaccine-strategy-for-targeting-4e10-10e8-neutralizing-epitopes-on-hiv-1-gp41-membrane-proximal-external-region
#5
Saikat Banerjee, Heliang Shi, Marisa Banasik, Hojin Moon, William Lees, Yali Qin, Andrew Harley, Adrian Shepherd, Michael W Cho
The membrane proximal external region (MPER) of HIV-1 gp41 is targeted by broadly neutralizing antibodies (bnAbs) 4E10 and 10E8. In this proof-of-concept study, we evaluated a novel multi-immunogen vaccine strategy referred to as Incremental, Phased Antigenic Stimulation for Rapid Antibody Maturation (IPAS-RAM) to induce 4E10/10E8-like bnAbs. Rabbits were immunized sequentially, but in a phased manner, with three immunogens that are progressively more native (gp41-28×3, gp41-54CT, and rVV-gp160DH12). Although nAbs were not induced, epitope-mapping analyses indicated that IPAS-RAM vaccination was better able to target antibodies towards the 4E10/10E8 epitopes than homologous prime-boost immunization using gp41-28×3 alone...
February 23, 2017: Virology
https://www.readbyqxmd.com/read/28225819/lipid-interactions-and-angle-of-approach-to-the-hiv-1-viral-membrane-of-broadly-neutralizing-antibody-10e8-insights-for-vaccine-and-therapeutic-design
#6
Adriana Irimia, Andreia M Serra, Anita Sarkar, Ronald Jacak, Oleksandr Kalyuzhniy, Devin Sok, Karen L Saye-Francisco, Torben Schiffner, Ryan Tingle, Michael Kubitz, Yumiko Adachi, Robyn L Stanfield, Marc C Deller, Dennis R Burton, William R Schief, Ian A Wilson
Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater neutralizing breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The 10E8 epitope has been identified as the conserved membrane proximal external region (MPER) of gp41 subunit of the envelope (Env) viral glycoprotein and is a major vaccine target. However, the MPER is proximal to the viral membrane and may be laterally inserted into the membrane in the Env prefusion form. Nevertheless, 10E8 has not been reported to have significant lipid-binding reactivity...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28209172/evaluation-of-the-contribution-of-the-transmembrane-region-to-the-ectodomain-conformation-of-the-human-immunodeficiency-virus-hiv-1-envelope-glycoprotein
#7
Hanh T Nguyen, Navid Madani, Haitao Ding, Emerald Elder, Amy Princiotto, Christopher Gu, Patrice Darby, James Alin, Alon Herschhorn, John C Kappes, Youdong Mao, Joseph G Sodroski
BACKGROUND: The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env), a Type 1 transmembrane protein, assembles into a trimeric spike complex that mediates virus entry into host cells. The high potential energy of the metastable, unliganded Env trimer is maintained by multiple non-covalent contacts among the gp120 exterior and gp41 transmembrane Env subunits. Structural studies suggest that the gp41 transmembrane region forms a left-handed coiled coil that contributes to the Env trimer interprotomer contacts...
February 16, 2017: Virology Journal
https://www.readbyqxmd.com/read/28207485/antigp41-membrane-proximal-external-region-antibodies-and-the-art-of-using-the-membrane-for-neutralization
#8
Nichole Cerutti, Juan Luis Loredo-Varela, Christophe Caillat, Winfried Weissenhorn
PURPOSE OF REVIEW: We summarize the latest research on the progress to understand the neutralizing epitopes present within the membrane proximal external region (MPER) of the HIV-1 fusion protein subunit gp41. RECENT FINDINGS: The HIV-1 fusion protein subunit gp41 contains a highly conserved sequence that is essential for membrane fusion and targeted by broadly neutralizing antibodies such as 2F5, 4E10, Z13e1, and 10E8. These antibodies recognize a linear gp41 epitope with high affinity, but require additional hydrophobic sequences present in their heavy chain CDR3 for neutralization...
February 15, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28203239/sublingual-priming-with-a-hiv-gp41-based-subunit-vaccine-elicits-mucosal-antibodies-and-persistent-b-memory-responses-in-non-human-primates
#9
Selma Bekri, Pierre Bourdely, Carmelo Luci, Nathalie Dereuddre-Bosquet, Bin Su, Frédéric Martinon, Véronique M Braud, Irene Luque, Pedro L Mateo, Sara Crespillo, Francisco Conejero-Lara, Christiane Moog, Roger Le Grand, Fabienne Anjuère
Persistent B cell responses in mucosal tissues are crucial to control infection against sexually transmitted pathogens like human immunodeficiency virus 1 (HIV-1). The genital tract is a major site of infection by HIV. Sublingual (SL) immunization in mice was previously shown to generate HIV-specific B cell immunity that disseminates to the genital tract. We report here the immunogenicity in female cynomolgus macaques of a SL vaccine based on a modified gp41 polypeptide coupled to the cholera toxin B subunit designed to expose hidden epitopes and to improve mucosal retention...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28202751/superiority-in-rhesus-macaques-of-targeting-hiv-1-env-gp140-to-cd40-versus-lox-1-in-combination-with-replication-competent-nyvac-kc-for-induction-of-env-specific-antibody-and-t-cell-responses
#10
Gerard Zurawski, Xiaoying Shen, Sandra Zurawski, Georgia D Tomaras, David C Montefiori, Mario Roederer, Guido Ferrari, Christine Lacabaratz, Peter Klucar, Zhiqing Wang, Kathryn E Foulds, Shing-Fen Kao, Xuesong Yu, Alicia Sato, Nicole L Yates, Celia LaBranche, Sherry Stanfield-Oakley, Karen Kibler, Bertram Jacobs, Andres Salazar, Steve Self, Jimmy Fulp, Raphael Gottardo, Lindsey Galmin, Deborah Weiss, Anthony Cristillo, Giuseppe Pantaleo, Yves Levy
We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in Rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly ICLC adjuvant either alone or co-administered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to P =0...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28179429/serinc5-inhibits-hiv-1-fusion-pore-formation-by-promoting-functional-inactivation-of-envelope-glycoproteins
#11
Chetan Sood, Mariana Marin, Ajit Chande, Massimo Pizzato, Gregory B Melikyan
The host proteins, SERINC3 and SERINC5, have been recently shown to incorporate into HIV-1 particles and compromise their ability to fuse with target cells - an effect that is antagonized by the viral Nef protein. Env glycoproteins from different HIV-1 isolates exhibit a broad range of sensitivity to SERINC-mediated restriction, and the mechanism by which SERINCs interfere with HIV-1 fusion remains unclear. Here, we show that incorporation of SERINC5 into virions in the absence of Nef inhibits the formation of small fusion pores between viruses and cells...
February 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28167814/prevalence-of-transmitted-drug-resistance-mutations-and-polymorphisms-in-hiv-1-reverse-transcriptase-protease-and-gp41-sequences-among-recent-seroconverters-in-southern-poland
#12
Joanna Smoleń-Dzirba, Magdalena Rosińska, Piotr Kruszyński, Jolanta Bratosiewicz-Wąsik, Robert Wojtyczka, Janusz Janiec, Bartosz Szetela, Marek Beniowski, Monika Bociąga-Jasik, Elżbieta Jabłonowska, Tomasz J Wąsik, And The Cascade Collaboration In EuroCoord
BACKGROUND Monitoring of drug resistance-related mutations among patients with recent HIV-1 infection offers an opportunity to describe current patterns of transmitted drug resistance (TDR) mutations. MATERIAL AND METHODS Of 298 individuals newly diagnosed from March 2008 to February 2014 in southern Poland, 47 were deemed to have recent HIV-1 infection by the limiting antigen avidity immunoassay. Proviral DNA was amplified and sequenced in the reverse transcriptase, protease, and gp41 coding regions. Mutations were interpreted according to the Stanford Database algorithm and/or the International Antiviral Society USA guidelines...
February 7, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28151945/antigenic-characterization-of-the-human-immunodeficiency-virus-hiv-1-envelope-glycoprotein-precursor-incorporated-into-nanodiscs
#13
Kristen C Witt, Luis Castillo-Menendez, Haitao Ding, Nicole Espy, Shijian Zhang, John C Kappes, Joseph Sodroski
The entry of human immunodeficiency virus (HIV-1) into host cells is mediated by the viral envelope glycoproteins (Envs), which are derived by the proteolytic cleavage of a trimeric gp160 Env precursor. The mature Env trimer is a major target for entry inhibitors and vaccine-induced neutralizing antibodies. Env interstrain variability, conformational flexibility and heavy glycosylation contribute to evasion of the host immune response, and create challenges for structural characterization and vaccine development...
2017: PloS One
https://www.readbyqxmd.com/read/28133805/evolution-of-b-cell-analysis-and-env-trimer-redesign
#14
REVIEW
Gunilla B Karlsson Hedestam, Javier Guenaga, Martin Corcoran, Richard T Wyatt
HIV-1 and its surface envelope glycoproteins (Env), gp120 and gp41, have evolved immune evasion strategies that render the elicitation of effective antibody responses to the functional Env entry unit extremely difficult. HIV-1 establishes chronic infection and stimulates vigorous immune responses in the human host; forcing selection of viral variants that escape cellular and antibody (Ab)-mediated immune pressure, yet possess contemporary fitness. Successful survival of fit variants through the gauntlet of the human immune system make this virus and these glycoproteins a formidable challenge to target by vaccination, requiring a systematic approach to Env mimetic immunogen design and evaluation of elicited responses...
January 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28131091/lipophilicity-is-a-key-factor-to-increase-the-antiviral-activity-of-hiv-neutralizing-antibodies
#15
Marcelo T Augusto, Axel Hollmann, Fulvia Troise, Ana S Veiga, Antonello Pessi, Nuno C Santos
The HIV broadly neutralizing antibody 2F5 targets the transiently exposed epitope in the membrane proximal external region (MPER) of HIV-1 gp41, by a two-step mechanism involving the viral membrane and this viral glycoprotein. It was recently shown that 2F5 conjugation with a cholesterol moiety outside of the antibody paratope substantially increases its antiviral activity. Additionally, the antiviral activity of D5, a human antibody that binds to the N-terminal heptad repeat (NHR) of gp41 and lacks membrane binding, was boosted by the same cholesterol conjugation...
April 1, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28128339/nano-biomimetic-carriers-are-implicated-in-mechanistic-evaluation-of-intracellular-gene-delivery
#16
Mohsen Alipour, Saman Hosseinkhani, Reza Sheikhnejad, Roya Cheraghi
Several tissue specific non-viral carriers have been developed for gene delivery purposes. However, the inability to escape endosomes, undermines the efficacy of these carriers. Researchers inspired by HIV and influenza virus, have randomly used Gp41 and H5WYG fusogenic peptides in several gene delivery systems without any rational preference. Here for the first time, we have genetically engineered two Nano-biomimetic carriers composed of either HWYG (HNH) or Gp41 (GNH) that precisely provide identical conditions for the study and evaluation of these fusogenic peptides...
January 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28122974/monoclonal-antibodies-to-v2-v3-the-cd4-binding-site-and-gp41-hiv-1-mediate-phagocytosis-in-a-dose-dependent-manner
#17
Thomas Musich, Liuzhe Li, Lily Liu, Susan Zolla-Pazner, Marjorie Robert-Guroff, Miroslaw K Gorny
In light of weak or absent neutralizing activity mediated by anti-V2 monoclonal Abs (mAbs), we tested whether they can mediate Ab-dependent cellular phagocytosis (ADCP) which is an important element of anti-HIV-1 immunity. We tested six anti-V2 mAbs and compared them with 21 mAbs specific for V3, the CD4-binding site (CD4bs), and gp41 derived from HIV-1 chronically infected individuals and produced by hybridoma cells. ADCP activity was measured by flow cytometry using uptake by THP-1 monocytic cells of fluorescent beads coated with gp120, gp41, BG505 SOSIP...
January 25, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28122636/breast-milk-and-in-utero-transmission-of-hiv-1-select-for-envelope-variants-with-unique-molecular-signatures
#18
Kyle J Nakamura, Laura Heath, Edwin R Sobrera, Thomas A Wilkinson, Katherine Semrau, Chipepo Kankasa, Nicole H Tobin, Nicholas E Webb, Benhur Lee, Donald M Thea, Louise Kuhn, James I Mullins, Grace M Aldrovandi
BACKGROUND: Mother-to-child transmission of human immunodeficiency virus-type 1 (HIV-1) poses a serious health threat in developing countries, and adequate interventions are as yet unrealized. HIV-1 infection is frequently initiated by a single founder viral variant, but the factors that influence particular variant selection are poorly understood. RESULTS: Our analysis of 647 full-length HIV-1 subtype C and G viral envelope sequences from 22 mother-infant pairs reveals unique genotypic and phenotypic signatures that depend upon transmission route...
January 26, 2017: Retrovirology
https://www.readbyqxmd.com/read/28121713/a-novel-hiv-1-gp41-tripartite-model-for-rational-design-of-hiv-1-fusion-inhibitors-with-improved-antiviral-activity
#19
Shan Su, Qian Wang, Wei Xu, Fei Yu, Chen Hua, Yun Zhu, Shibo Jiang, Lu Lu
OBJECTIVES: During HIV-1 fusion process, the N-terminal heptad repeat (NHR) of the HIV-1 gp41 interacts with the C-terminal heptad repeat (CHR) to form the fusion active 6-helix bundle (6-HB), thus being an effective target for the design of CHR-peptide-based HIV-1 fusion inhibitors. To overcome the limitations of the simplified helix wheel model of 6-HB, we herein developed a novel HIV-1 gp41 NHR-CHR-NHR tripartite model for the rational design of HIV-1 fusion inhibitors with improved antiviral activities...
January 24, 2017: AIDS
https://www.readbyqxmd.com/read/28104377/changes-in-lipid-bilayer-structure-caused-by-the-helix-to-sheet-transition-of-an-hiv-1-gp41-fusion-peptide-derivative
#20
William T Heller, Durgesh K Rai
HIV-1, like other enveloped viruses, undergoes fusion with the cell membrane to infect it. Viral coat proteins are thought to bind the virus to the membrane and actively fuse the viral and cellular membranes together. The actual molecular mechanism of fusion is challenging to visualize, resulting in the use of model systems. Here, the bilayer curvature modifying properties of a synthetic variant of the HIV-1 gp41 fusion peptide with lipid bilayer vesicles composed of a mixture of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylserine (DMPS) were studied...
January 16, 2017: Chemistry and Physics of Lipids
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