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Broadly neutralizing antibody

Awadalkareem Adam, Tom Schüttoff, Sven Reiche, Christian Jassoy
OBJECTIVES: To determine the seroprevalence of dengue in central and eastern Sudan and the breadth of neutralizing antibody responses. METHODS: Blood was drawn from 483 patients with fever who visited outpatient clinics in Port Sudan, Red Sea state, in three towns in Kassala state and in El Obeid, North Kordofan in December 2012 and January 2013. Sera were tested for dengue virus IgG and IgM by ELISA (Panbio) and sera without serologic evidence of acute infection (IgM negative) were used for the analysis of the seroprevalence...
June 15, 2018: Tropical Medicine & International Health: TM & IH
Juliana Flemming, Lisa Wiesen, Alon Herschhorn
The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) mediate virus entry and are the target of neutralizing antibodies. Binding of the metastable HIV-1 Env trimer to the CD4 receptor triggers structural rearrangements that mediate Env conformational transitions from a closed conformation to a more open state through an intermediate step. Recent studies have revealed new insights on the dynamics, regulation and molecular mechanisms of Env transitions along the entry pathway. Here we provide an overview of the current knowledge on Env conformational dynamics and the relationship between Env conformational states and neutralization selectivity of the broadly neutralizing antibodies (bNAbs) that develop in 10-20% of infected individuals and may provide guidance for the development of an effective HIV-1 vaccine...
June 15, 2018: AIDS Research and Human Retroviruses
Mei-Le Keck, Florian Wrensch, Brian G Pierce, Thomas F Baumert, Steven K H Foung
Hepatitis C virus (HCV) continues to spread worldwide with an annual increase of 1.75 million new infections. The number of HCV cases in the U.S. is now greater than the number of HIV cases and is increasing in young adults because of the opioid epidemic sweeping the country. HCV-related liver disease is the leading indication of liver transplantation. An effective vaccine is of paramount importance to control and prevent HCV infection. While this vaccine will need to induce both cellular and humoral immunity, this review is focused on the required antibody responses...
2018: Frontiers in Immunology
Peng Zhang, Jason Gorman, Hui Geng, Qingbo Liu, Yin Lin, Yaroslav Tsybovsky, Eden P Go, Barna Dey, Tsion Andine, Alice Kwon, Mit Patel, Deepali Gururani, Ferzan Uddin, Christina Guzzo, Raffaello Cimbro, Huiyi Miao, Krisha McKee, Gwo-Yu Chuang, Loïc Martin, Francesca Sironi, Mauro S Malnati, Heather Desaire, Edward A Berger, John R Mascola, Michael A Dolan, Peter D Kwong, Paolo Lusso
The HIV-1 envelope (Env) spike is a trimer of gp120/gp41 heterodimers that mediates viral entry. Binding to CD4 on the host cell membrane is the first essential step for infection but disrupts the native antigenic state of Env, posing a key obstacle to vaccine development. We locked the HIV-1 Env trimer in a pre-fusion configuration, resulting in impaired CD4 binding and enhanced binding to broadly neutralizing antibodies. This design was achieved via structure-guided introduction of neo-disulfide bonds bridging the gp120 inner and outer domains and was successfully applied to soluble trimers and native gp160 from different HIV-1 clades...
June 13, 2018: Cell Host & Microbe
James B Munro
No immunogen has been found that elicits a broadly neutralizing antibody (bNAb) response sufficient for development into an HIV vaccine. In this issue of Cell Host and Microbe, Zhang et al. (2018) rationally design an HIV envelope glycoprotein variant that provides new hope that such an immunogen may be attainable.
June 13, 2018: Cell Host & Microbe
Raffael Nachbagauer, David Shore, Hua Yang, Scott K Johnson, Jon D Gabbard, S Mark Tompkins, Jens Wrammert, Patrick C Wilson, James Stevens, Rafi Ahmed, Florian Krammer, Ali H Ellebedy
Broadly cross-reactive antibodies that recognize conserved epitopes within the influenza virus hemagglutinin (HA) stalk domain are of particular interest for their potential use as therapeutic and prophylactic agents against multiple influenza virus subtypes including zoonotic virus strains. Here, we characterized four human HA stalk-reactive monoclonal antibodies (mAbs) for their binding breadth and affinity, in vitro neutralization capacity, and in vivo protective potential against an highly pathogenic avian influenza virus...
June 13, 2018: Journal of Virology
Kimmo Rantalainen, Zachary T Berndsen, Sasha Murrell, Liwei Cao, Oluwarotimi Omorodion, Jonathan L Torres, Mengyu Wu, Jeffrey Umotoy, Jeffrey Copps, Pascal Poignard, Elise Landais, James C Paulson, Ian A Wilson, Andrew B Ward
Broadly neutralizing antibodies (bnAbs) targeting the HIV envelope glycoprotein (Env) typically take years to develop. Longitudinal analyses of both neutralizing antibody lineages and viruses at serial time points during infection provide a basis for understanding the co-evolutionary contest between HIV and the humoral immune system. Here, we describe the structural characterization of an apex-targeting antibody lineage and autologous clade A viral Env from a donor in the Protocol C cohort. Comparison of Ab-Env complexes at early and late time points reveals that, within the antibody lineage, the CDRH3 loop rigidifies, the bnAb angle of approach steepens, and surface charges are mutated to accommodate glycan changes...
June 12, 2018: Cell Reports
Jennifer I Lai, Deeptak Verma, Chris Bailey-Kellogg, Margaret E Ackerman
Structure-based approaches to antigen design utilize insights from antibody (Ab):antigen interactions and a refined understanding of protective Ab responses to engineer novel antigens presenting epitopes with conformations relevant to eliciting or discovering protective humoral responses. For human immunodeficiency virus-1 (HIV-1), one model of protection is provided by broadly neutralizing Abs (bnAbs) against epitopes present in the closed prefusion trimeric conformation of HIV-1 envelope glycoprotein, such as the variable loops 1-2 (V1V2) apex...
June 12, 2018: Protein Engineering, Design & Selection: PEDS
Johnathan D Guest, Brian G Pierce
Hepatitis C virus (HCV) is a major global health concern, and though therapeutic options have improved, no vaccine is available despite decades of research. As HCV can rapidly mutate to evade the immune response, an effective HCV vaccine must rely on identification and characterization of sites critical for broad immune protection and viral neutralization. This knowledge depends on structural and mechanistic insights of the E1 and E2 envelope glycoproteins, which assemble as a heterodimer on the surface of the virion, engage coreceptors during host cell entry, and are the primary targets of antibodies...
2018: Frontiers in Immunology
Byungsu Kwon, Myungwoon Lee, Alan J Waring, Mei Hong
The HIV-1 glycoprotein, gp41, mediates fusion of the virus lipid envelope with the target cell membrane during virus entry into cells. Despite extensive studies of this protein, inconsistent and contradictory structural information abounds in the literature about the C-terminal membrane-interacting region of gp41. This C-terminal region contains the membrane-proximal external region (MPER), which harbors the epitopes for four broadly neutralizing antibodies, and the transmembrane domain (TMD), which anchors the protein to the virus lipid envelope...
June 11, 2018: Journal of the American Chemical Society
Shridhar Bale, Alexandra Martiné, Richard Wilson, Anna-Janina Behrens, Valérie Le Fourn, Natalia de Val, Shailendra K Sharma, Karen Tran, Jonathan L Torres, Pierre-Alain Girod, Andrew B Ward, Max Crispin, Richard T Wyatt
Native flexibly linked (NFL) HIV-1 envelope glycoprotein (Env) trimers are cleavage-independent and display a native-like, well-folded conformation that preferentially displays broadly neutralizing determinants. The NFL platform simplifies large-scale production of Env by eliminating the need to co-transfect the precursor-cleaving protease, furin that is required by the cleavage-dependent SOSIP trimers. Here, we report the development of a CHO-M cell line that expressed BG505 NFL trimers at a high level of homogeneity and yields of ~1...
2018: Frontiers in Immunology
Ying Wen, Katharine J Bar, Jonathan Z Li
PURPOSE OF REVIEW: Clinical trials with an antiretroviral therapy (ART) interruption remains indispensable for assessing strategies for ART-free HIV remission. This review highlights the lessons learned from ART interruption studies so far, including the risks to the participants and implications for HIV remission. RECENT FINDINGS: Historically, analytic HIV treatment interruption (ATI) studies were commonly designed with a prolonged duration of ART interruption and with viral load set point as the primary outcome...
June 6, 2018: Current Opinion in HIV and AIDS
Hadi M Yassine, Patrick M McTamney, Jeffery C Boyington, Tracy J Ruckwardt, Michelle C Crank, Maria K Smatti, Julie E Ledgerwood, Barney S Graham
A better understanding of the seroprevalence and specificity of influenza HA stem-directed broadly neutralizing antibodies (bNAbs) in the human population could significantly inform influenza vaccine design efforts. Here, we utilized probes comprising headless, HA stabilized stem (SS) to determine the prevalence, binding and neutralization breadth of antibodies directed to HA stem-epitope in a cross-sectional analysis of the general population. Five group-1 HA SS probes, representing five subtypes, were chosen for this analyses...
June 5, 2018: Scientific Reports
Kai Xu, Priyamvada Acharya, Rui Kong, Cheng Cheng, Gwo-Yu Chuang, Kevin Liu, Mark K Louder, Sijy O'Dell, Reda Rawi, Mallika Sastry, Chen-Hsiang Shen, Baoshan Zhang, Tongqing Zhou, Mangaiarkarasi Asokan, Robert T Bailer, Michael Chambers, Xuejun Chen, Chang W Choi, Venkata P Dandey, Nicole A Doria-Rose, Aliaksandr Druz, Edward T Eng, S Katie Farney, Kathryn E Foulds, Hui Geng, Ivelin S Georgiev, Jason Gorman, Kurt R Hill, Alexander J Jafari, Young D Kwon, Yen-Ting Lai, Thomas Lemmin, Krisha McKee, Tiffany Y Ohr, Li Ou, Dongjun Peng, Ariana P Rowshan, Zizhang Sheng, John-Paul Todd, Yaroslav Tsybovsky, Elise G Viox, Yiran Wang, Hui Wei, Yongping Yang, Amy F Zhou, Rui Chen, Lu Yang, Diana G Scorpio, Adrian B McDermott, Lawrence Shapiro, Bridget Carragher, Clinton S Potter, John R Mascola, Peter D Kwong
A central goal of HIV-1 vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains...
June 4, 2018: Nature Medicine
Tariq Ahmad Najar, Uddipan Kar, Jessica A Flynn, Raghavan Varadarajan
The surface glycoprotein hemagglutinin (HA) of influenza virus is the primary target for design of an effective universal influenza vaccine as it is capable of eliciting broadly cross-reactive antibodies against different HA subtypes. Several monoclonal antibodies targeting the stem region of HA that are able to neutralize various subtypes of influenza virus have been isolated in the recent past. Designing a stable, HA stem immunogen that attains a native-like conformation and can elicit such antibodies has been a challenge...
June 4, 2018: Biochemistry
Kevin Wiehe, Todd Bradley, R Ryan Meyerhoff, Connor Hart, Wilton B Williams, David Easterhoff, William J Faison, Thomas B Kepler, Kevin O Saunders, S Munir Alam, Mattia Bonsignori, Barton F Haynes
HIV-1 broadly neutralizing antibodies (bnAbs) require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations for optimal neutralization potency. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. One bottleneck for induction of bnAbs is the evolution of viral envelopes (Envs) that can select bnAb B cell receptors (BCR) with improbable mutations. Here we define the probability of bnAb mutations and demonstrate the functional significance of key improbable mutations in three bnAb B cell lineages...
May 25, 2018: Cell Host & Microbe
Julie Prigent, Annaëlle Jarossay, Cyril Planchais, Caroline Eden, Jérémy Dufloo, Ayrin Kök, Valérie Lorin, Oxana Vratskikh, Thérèse Couderc, Timothée Bruel, Olivier Schwartz, Michael S Seaman, Oliver Ohlenschläger, Jordan D Dimitrov, Hugo Mouquet
Human high-affinity antibodies to pathogens often recognize unrelated ligands. The molecular origin and the role of this polyreactivity are largely unknown. Here, we report that HIV-1 broadly neutralizing antibodies (bNAbs) are frequently polyreactive, cross-reacting with non-HIV-1 molecules, including self-antigens. Mutating bNAb genes to increase HIV-1 binding and neutralization also results in de novo polyreactivity. Unliganded paratopes of polyreactive bNAbs with improved HIV-1 neutralization exhibit a conformational flexibility, which contributes to enhanced affinity of bNAbs to various HIV-1 envelope glycoproteins and non-HIV antigens...
May 29, 2018: Cell Reports
Hui Cai, Roushu Zhang, Jared Orwenyo, John Giddens, Qiang Yang, Celia C LaBranche, David C Montefiori, Lai-Xi Wang
HIV-1 envelope glycoproteins gp120 and gp41 are presented on the virus surface as a trimer of heterodimer and are the targets of broadly neutralizing antibodies (bNAbs). We describe here the synthesis and preliminary immunological evaluation of a three-component trivalent HIV-1 V3 glycopeptide immunogen aiming to raise glycopeptide epitope-specific antibodies. Click chemistry confers efficient synthesis of the lipopeptide-glycopeptide conjugate that carries three copies of HIV-1 JR-FL gp120 V3 glycopeptide with a high-mannose glycan at the N332 glycosylation site...
May 23, 2018: ACS Central Science
Jiachen Huang, Qiangde Duan, Weiping Zhang
Enterotoxigenic Escherichia coli (ETEC) producing heat-labile toxin (LT) and/or heat-stable toxin (STa) are a top cause of children's diarrhea and travelers' diarrhea. Holotoxin-structured GM1 -binding LT is a strong immunogen and an effective adjuvant, and can serve a carrier or a platform for multivalent vaccine development. However, the significance of peptide domains or epitopes of LT particularly enzymatic LTA subunit in association with LT enterotoxicity and immunogenicity has not been characterized. In this study, we identified B-cell epitopes in silico from LTA subunit and examined epitopes for immunogenicity and association with LT enterotoxicity...
May 25, 2018: Applied and Environmental Microbiology
Claus Kadelka, Thomas Liechti, Hanna Ebner, Merle Schanz, Peter Rusert, Nikolas Friedrich, Emanuel Stiegeler, Dominique L Braun, Michael Huber, Alexandra U Scherrer, Jacqueline Weber, Therese Uhr, Herbert Kuster, Benjamin Misselwitz, Matthias Cavassini, Enos Bernasconi, Matthias Hoffmann, Alexandra Calmy, Manuel Battegay, Andri Rauch, Sabine Yerly, Vincent Aubert, Thomas Klimkait, Jürg Böni, Roger D Kouyos, Huldrych F Günthard, Alexandra Trkola
Understanding pathways that promote HIV-1 broadly neutralizing antibody (bnAb) induction is crucial to advance bnAb-based vaccines. We recently demarcated host, viral, and disease parameters associated with bnAb development in a large HIV-1 cohort screen. By establishing comprehensive antibody signatures based on IgG1, IgG2, and IgG3 activity to 13 HIV-1 antigens in 4,281 individuals in the same cohort, we now show that the same four parameters that are significantly linked with neutralization breadth, namely viral load, infection length, viral diversity, and ethnicity, also strongly influence HIV-1-binding antibody responses...
May 24, 2018: Journal of Experimental Medicine
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