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https://www.readbyqxmd.com/read/29046160/construction-and-production-of-hiv-vlp-harboring-mper-v3-for-potential-vaccine-study
#1
Fatemeh Tohidi, Seyed Mehdi Sadat, Azam Bolhassani, Ramin Yaghobi
Vaccine against HIV-1 is not currently available. In present, Virus like particles (VLPs) as effective strategy was used in several vaccine developing. Two conserved sequences; V3 loop of gp120 and the membrane-proximal external region (MPER) of gp41 are dominant sites for vaccine studies. In this study, we used fusion gene of MPER and V3 to product recombinant VLPs and introduced a novel retroviral VLPs harboring high copy of MPER-V3 for HIV-1 vaccine design. The pEGFP-N1 plasmid harboring MPER-V3 sequence with Vpr linker was constructed...
October 17, 2017: Current HIV Research
https://www.readbyqxmd.com/read/28970835/immunologic-insights-on-the-membrane-proximal-external-region-a-major-human-immunodeficiency-virus-type-1-vaccine-target
#2
REVIEW
Luis M Molinos-Albert, Bonaventura Clotet, Julià Blanco, Jorge Carrillo
Broadly neutralizing antibodies (bNAbs) targeting conserved regions within the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein (Env) can be generated by the human immune system and their elicitation by vaccination will be a key point to protect against the wide range of viral diversity. The membrane proximal external region (MPER) is a highly conserved region within the Env gp41 subunit, plays a major role in membrane fusion and is targeted by naturally induced bNAbs. Therefore, the MPER is considered as an attractive vaccine target...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28931639/trispecific-broadly-neutralizing-hiv-antibodies-mediate-potent-shiv-protection-in-macaques
#3
Ling Xu, Amarendra Pegu, Ercole Rao, Nicole Doria-Rose, Jochen Beninga, Krisha McKee, Dana M Lord, Ronnie R Wei, Gejing Deng, Mark Louder, Stephen D Schmidt, Zachary Mankoff, Lan Wu, Mangaiarkarasi Asokan, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Jochen Kruip, Rebecca Sendak, Young Do Kwon, Tongqing Zhou, Xuejun Chen, Robert T Bailer, Keyun Wang, Misook Choe, Lawrence J Tartaglia, Dan H Barouch, Sijy O'Dell, John-Paul Todd, Dennis R Burton, Mario Roederer, Mark Connors, Richard A Koup, Peter D Kwong, Zhi-Yong Yang, John R Mascola, Gary J Nabel
The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs...
October 6, 2017: Science
https://www.readbyqxmd.com/read/28874543/structure-of-the-ebola-virus-envelope-protein-mper-tm-domain-and-its-interaction-with-the-fusion-loop-explains-their-fusion-activity
#4
Jinwoo Lee, David A Nyenhuis, Elizabeth A Nelson, David S Cafiso, Judith M White, Lukas K Tamm
Ebolavirus (EBOV), an enveloped filamentous RNA virus causing severe hemorrhagic fever, enters cells by macropinocytosis and membrane fusion in a late endosomal compartment. Fusion is mediated by the EBOV envelope glycoprotein GP, which consists of subunits GP1 and GP2. GP1 binds to cellular receptors, including Niemann-Pick C1 (NPC1) protein, and GP2 is responsible for low pH-induced membrane fusion. Proteolytic cleavage and NPC1 binding at endosomal pH lead to conformational rearrangements of GP2 that include exposing the hydrophobic fusion loop (FL) for insertion into the cellular target membrane and forming a six-helix bundle structure...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28783671/potent-and-broad-hiv-neutralizing-antibodies-in-memory-b-cells-and-plasma
#5
LaTonya D Williams, Gilad Ofek, Sebastian Schätzle, Jonathan R McDaniel, Xiaozhi Lu, Nathan I Nicely, Liming Wu, Caleb S Lougheed, Todd Bradley, Mark K Louder, Krisha McKee, Robert T Bailer, Sijy O'Dell, Ivelin S Georgiev, Michael S Seaman, Robert J Parks, Dawn J Marshall, Kara Anasti, Guang Yang, Xiaoyan Nie, Nancy L Tumba, Kevin Wiehe, Kshitij Wagh, Bette Korber, Thomas B Kepler, S Munir Alam, Lynn Morris, Gift Kamanga, Myron S Cohen, Mattia Bonsignori, Shi-Mao Xia, David C Montefiori, Garnett Kelsoe, Feng Gao, John R Mascola, M Anthony Moody, Kevin O Saunders, Hua-Xin Liao, Georgia D Tomaras, George Georgiou, Barton F Haynes
Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1-specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1-infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage...
January 27, 2017: Science Immunology
https://www.readbyqxmd.com/read/28521215/adaptation-of-hiv-1-to-cells-with-low-expression-of-the-ccr5-coreceptor
#6
Nicole Espy, Beatriz Pacheco, Joseph Sodroski
The binding of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer ((gp120/gp41)3) to the receptors CD4 and CCR5 triggers virus entry into host cells. To identify Env regions that respond to CCR5 binding, HIV-1 was serially passaged on a CD4-positive canine cell line expressing progressively lower levels of CCR5. HIV-1 replication was observed in cells expressing ~1300 CCR5 molecules/cell. Env changes that conferred this low-CCR5 replication phenotype were located outside of the known CCR5-binding region of the gp120 Env subunit and did not apparently increase CCR5 binding affinity...
August 2017: Virology
https://www.readbyqxmd.com/read/28436427/broad-and-potent-cross-clade-neutralizing-antibodies-with-multiple-specificities-in-the-plasma-of-hiv-1-subtype-c-infected-individuals
#7
Narayanaiah Cheedarla, K Lucia Precilla, Hemalatha Babu, K K Vidya Vijayan, Manickam Ashokkumar, Padmapriyadarsini Chandrasekaran, Nandagopal Kailasam, Jagadish Chandrabose Sundaramurthi, Soumya Swaminathan, Viswanath Buddolla, S Kalyanaraman Vaniambadi, V D Ramanathan, Luke Elizabeth Hanna
Broadly Cross clade Neutralizing (BCN) antibodies are recognized as potential therapeutic tools and leads for the design of a vaccine that can protect human beings against various clades of Human Immunodeficiency Virus (HIV). In the present study, we screened plasma of 88 HIV-1 infected ART naïve individuals for their neutralization potential using a standard panel of 18 pseudoviruses belonging to different subtypes and different levels of neutralization. We identified 12 samples with good breadth of neutralization (neutralized >90% of the viruses)...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28422789/antigp41-membrane-proximal-external-region-antibodies-and-the-art-of-using-the-membrane-for-neutralization
#8
REVIEW
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...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28392143/development-of-a-dna-vaccine-expressing-a-secreted-hiv-1-gp41-ectodomain-that-includes-the-membrane-proximal-external-region
#9
Luca Melnychuk, Lara Ajamian, Patrick Jean-Pierre, Jiaming Liang, Romina Gheorghe, Mark A Wainberg, Gerasimos J Zaharatos
A limited number of sites on the HIV-1 Envelope protein are vulnerable to broadly neutralizing antibodies (bnAbs). One of these sites, the membrane proximal external region (MPER), is located at the C-terminus of the gp41 ectodomain (gp41ecto). This highly conserved sequence is bound by several well-characterized bnAbs. Efforts to produce a gp41 immunogen are in part hampered by the MPER's hydrophobicity and propensity to induce aggregation. We sought to produce a DNA vaccine expressing a gp41ecto that is both secreted from mammalian cells and maintains binding by bnAbs to the MPER...
May 9, 2017: Vaccine
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
#10
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 complementarity-determining region three of the heavy chain (CDRH3) of 4E10, an anti-MPER bNAb, is an open question that fascinates researchers in the field...
April 21, 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
#11
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/28246356/differential-antibody-responses-to-conserved-hiv-1-neutralizing-epitopes-in-the-context-of-multivalent-scaffolds-and-native-like-gp140-trimers
#12
Charles D Morris, Parisa Azadnia, Natalia de Val, Nemil Vora, Andrew Honda, Erick Giang, Karen Saye-Francisco, Yushao Cheng, Xiaohe Lin, Colin J Mann, Jeffrey Tang, Devin Sok, Dennis R Burton, Mansun Law, Andrew B Ward, Linling He, Jiang Zhu
Broadly neutralizing antibodies (bNAbs) have provided valuable insights into the humoral immune response to HIV-1. While rationally designed epitope scaffolds and well-folded gp140 trimers have been proposed as vaccine antigens, a comparative understanding of their antibody responses has not yet been established. In this study, we probed antibody responses to the N332 supersite and the membrane-proximal external region (MPER) in the context of heterologous protein scaffolds and native-like gp140 trimers. Ferritin nanoparticles and fragment crystallizable (Fc) regions were utilized as multivalent carriers to display scaffold antigens with grafted N332 and MPER epitopes, respectively...
February 28, 2017: MBio
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
#13
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...
May 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
#14
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/28207485/antigp41-membrane-proximal-external-region-antibodies-and-the-art-of-using-the-membrane-for-neutralization
#15
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/28131091/lipophilicity-is-a-key-factor-to-increase-the-antiviral-activity-of-hiv-neutralizing-antibodies
#16
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/28076415/structure-and-recognition-of-a-novel-hiv-1-gp120-gp41-interface-antibody-that-caused-mper-exposure-through-viral-escape
#17
Constantinos Kurt Wibmer, Jason Gorman, Gabriel Ozorowski, Jinal N Bhiman, Daniel J Sheward, Debra H Elliott, Julie Rouelle, Ashley Smira, M Gordon Joyce, Nonkululeko Ndabambi, Aliaksandr Druz, Mangai Asokan, Dennis R Burton, Mark Connors, Salim S Abdool Karim, John R Mascola, James E Robinson, Andrew B Ward, Carolyn Williamson, Peter D Kwong, Lynn Morris, Penny L Moore
A comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41...
January 2017: PLoS Pathogens
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
#18
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
#19
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-neutralizing-antibodies-display-potential-for-prevention-of-hiv-1-infection-of-mucosal-tissue-superior-to-that-of-nonneutralizing-antibodies
#20
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 neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition...
January 1, 2017: Journal of Virology
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