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https://www.readbyqxmd.com/read/28539451/reducing-v3-antigenicity-and-immunogenicity-on-soluble-native-like-hiv-1-env-sosip-trimers
#1
Rajesh P Ringe, Gabriel Ozorowski, Kimmo Rantalainen, Weston B Struwe, Katie Matthews, Jonathan L Torres, Anila Yasmeen, Christopher A Cottrell, Thomas J Ketas, Celia C LaBranche, David C Montefiori, Albert Cupo, Max Crispin, Ian A Wilson, Andrew B Ward, Rogier W Sanders, P J Klasse, John P Moore
Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs), but can also expose binding sites for some types of non-neutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such "off-target" immune responses...
May 24, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28539448/virological-control-by-the-cd4-binding-site-antibody-n6-in-shiv-infected-rhesus-monkeys
#2
Boris Julg, Amarendra Pegu, Peter Abbink, Jinyan Liu, Amanda Brinkman, Katherine Molloy, Shanell Mojta, Abishek Chandrashekar, Katherine Callow, Keyun Wang, Xuejun Chen, Stephen D Schmidt, Jinghe Huang, Richard A Koup, Michael S Seaman, Brandon F Keele, John R Mascola, Mark Connors, Dan H Barouch
Passive immunotherapies against HIV-1 will most likely require broadly neutralizing antibodies (bnAb) with maximum breadth and potency to assure therapeutic efficacy. Recently, the novel CD4 binding site antibody N6 demonstrated extraordinary neutralization breadth and potency against large panels of cross clade pseudoviruses. We evaluated the in-vivo antiviral activity of N6-LS, alone or in combination with the established V3-glycan antibody PGT121, in chronically SHIV-SF162P3 infected macaques. A single dose of N6-LS suppressed plasma viral loads in 4 out of 5 animals at day 7 (mean 1...
May 24, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28539445/structure-of-simian-immunodeficiency-virus-envelope-spikes-bound-with-cd4-and-monoclonal-antibody-36d5
#3
Guiqing Hu, Jun Liu, Kenneth H Roux, Kenneth A Taylor
The HIV-1/SIV envelope spike (Env) mediates the viral entry into host cells. The V3 loop of the gp120 component of the Env trimer contributes to the co-receptor binding site and is a target for neutralizing antibodies. We have used cryoelectron tomography to visualize the binding of CD4 and the V3 loop monoclonal antibody 36D5 to gp120 of the SIV Env. Our results show that 36D5 binds gp120 at the base of the V3 loop and suggest the antibody exerts its neutralization effect by blocking the co-receptor binding site...
May 24, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28514687/particulate-array-of-well-ordered-hiv-clade-c-env-trimers-elicits-neutralizing-antibodies-that-display-a-unique-v2-cap-approach
#4
Paola Martinez-Murillo, Karen Tran, Javier Guenaga, Gustaf Lindgren, Monika Àdori, Yu Feng, Ganesh E Phad, Néstor Vázquez Bernat, Shridhar Bale, Jidnyasa Ingale, Viktoriya Dubrovskaya, Sijy O'Dell, Lotta Pramanik, Mats Spångberg, Martin Corcoran, Karin Loré, John R Mascola, Richard T Wyatt, Gunilla B Karlsson Hedestam
The development of soluble envelope glycoprotein (Env) mimetics displaying ordered trimeric symmetry has ushered in a new era in HIV-1 vaccination. The recently reported native, flexibly linked (NFL) design allows the generation of native-like trimers from clinical isolates at high yields and homogeneity. As the majority of infections world-wide are of the clade C subtype, we examined responses in non-human primates to well-ordered subtype C 16055 trimers administered in soluble or high-density liposomal formats...
May 16, 2017: Immunity
https://www.readbyqxmd.com/read/28514686/glycine-substitution-at-helix-to-coil-transitions-facilitates-the-structural-determination-of-a-stabilized-subtype-c-hiv-envelope-glycoprotein
#5
Javier Guenaga, Fernando Garces, Natalia de Val, Robyn L Stanfield, Viktoriya Dubrovskaya, Brett Higgins, Barbara Carrette, Andrew B Ward, Ian A Wilson, Richard T Wyatt
Advances in HIV-1 envelope glycoprotein (Env) design generate native-like trimers and high-resolution clade A, B, and G structures and elicit neutralizing antibodies. However, a high-resolution clade C structure is critical, as this subtype accounts for the majority of HIV infections worldwide, but well-ordered clade C Env trimers are more challenging to produce due to their instability. Based on targeted glycine substitutions in the Env fusion machinery, we defined a general approach that disfavors helical transitions leading to post-fusion conformations, thereby favoring the pre-fusion state...
May 16, 2017: Immunity
https://www.readbyqxmd.com/read/28514685/virus-like-particles-identify-an-hiv-v1v2-apex-binding-neutralizing-antibody-that-lacks-a-protruding-loop
#6
Evan M Cale, Jason Gorman, Nathan A Radakovich, Ema T Crooks, Keiko Osawa, Tommy Tong, Jiaqi Li, Raju Nagarajan, Gabriel Ozorowski, David R Ambrozak, Mangai Asokan, Robert T Bailer, Anthony K Bennici, Xuejun Chen, Nicole A Doria-Rose, Aliaksandr Druz, Yu Feng, M Gordon Joyce, Mark K Louder, Sijy O'Dell, Courtney Oliver, Marie Pancera, Mark Connors, Thomas J Hope, Thomas B Kepler, Richard T Wyatt, Andrew B Ward, Ivelin S Georgiev, Peter D Kwong, John R Mascola, James M Binley
Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38...
May 16, 2017: Immunity
https://www.readbyqxmd.com/read/28514679/size-doesn-t-matter-shorter-antibody-loops-can-infiltrate-hiv-s-env-apex-defenses
#7
Jinal N Bhiman, Penny L Moore
An HIV vaccine that elicits broadly neutralizing antibodies, which often have unusual structural features, has not yet been developed. In Immunity this month, Cale et al., 2017 describe how a new mode of binding allows a conventional antibody to infiltrate HIV's armor.
May 16, 2017: Immunity
https://www.readbyqxmd.com/read/28514282/recent-progress-in-anti-hiv-broadly-neutralizing-antibody-research
#8
Stacey C Tobin
No abstract text is available yet for this article.
May 16, 2017: AIDS
https://www.readbyqxmd.com/read/28500746/higher-viral-load-and-genetic-diversity-of-hiv-1-in-the-seminal-compartments-than-in-the-blood-of-seven-chinese-homosexual-men-with-early-hiv-1-infection
#9
Yan-Mei Jiao, Guang-Lei Chen, Wei-Jun Zhu, Hui-Huang Huang, Jun-Liang Fu, Wei-Wei Chen, Ming Shi, Tong Zhang, Hao Wu, Fu-Sheng Wang
To date, there have been no reports characterizing the Human Immunodeficiency Virus-1 (HIV-1) in the semen of Chinese men having sex with men (MSM) with early infection of HIV-1.We examined genetic diversity and viral load of HIV-1 in the seminal compartments and blood of Chinese MSM with early HIV-1 infection in this study. Viral load and genetic diversity of HIV-1 in paired samples of semen and blood were analyzed in seven homosexual patients who were with early HIV-1 infection. Levels of HIV-1 RNA and DNA were tested by real-time PCR assays...
May 13, 2017: Microbiology and Immunology
https://www.readbyqxmd.com/read/28494151/design-of-hiv-co-receptor-derived-peptides-that-inhibit-viral-entry-at-submicromolar-concentrations
#10
Kostyantyn D Bobyk, Sivakoteswara R Mandadapu, Katheryn Lohith, Christina Guzzo, Abhishek Bhargava, Paolo Lusso, Carole A Bewley
HIV/AIDS continues to pose an enormous burden on global health. Current HIV therapeutics include inhibitors that target the enzymes HIV protease, reverse transcriptase and integrase, along with viral entry inhibitors that block the initial steps of HIV infection by preventing membrane fusion or virus-coreceptor interactions. With regard to the latter, peptides derived from the HIV coreceptor CCR5 were previously shown to modestly inhibit entry of CCR5-tropic HIV strains, with a peptide containing residues 178-191 of the second extracellular loop (peptide 2C) showing the strongest inhibition...
May 11, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28490588/induction-of-a-tier-1-like-phenotype-in-diverse-tier-2-isolates-by-agents-that-guide-hiv-1-env-to-perturbation-sensitive-non-native-states
#11
Jacklyn Johnson, Yinjie Zhai, Hamid Salimi, Nicole Espy, Noah Eichelberger, Orlando DeLeon, Yunxia O'Malley, Joel Courter, Amos B Smith, Navid Madani, Joseph Sodroski, Hillel Haim
The envelope glycoproteins (Envs) on the surface of HIV-1 particles are targeted by host antibodies. Primary HIV-1 isolates demonstrate different global sensitivities to antibody neutralization; Tier-1 isolates are sensitive whereas Tier-2 isolates are more resistant. Single-site mutations in Env can convert Tier-2 into Tier-1-like viruses. We hypothesized that such global change in neutralization sensitivity results from weakening of intra-molecular interactions that maintain Env integrity. Three strategies commonly applied to perturb protein structure were tested for their effect on global neutralization sensitivity; exposure to low temperature, Env-activating ligands and a chaotropic agent...
May 10, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28483193/expression-of-complete-siv-p27-gag-and-hiv-gp120-engineered-outer-domains-targeted-by-broadly-neutralizing-antibodies-in-live-rubella-vectors
#12
Konstantin Virnik, Edmund Nesti, Cody Dail, Max Hockenbury, Yisheng Ni, Barbara K Felber, William R Schief, Ira Berkower
Infection with HIV or SIV often elicits a potent immune response to viral antigens. This includes T cells and antibodies specific for Gag and Env antigens. In contrast, when given as a vaccine, the same antigens have been weak immunogens, unable to elicit antibodies with comparable titer, durability, or neutralizing activity. We have used the live attenuated rubella vaccine strain RA27/3 as a viral vector to express HIV and SIV antigens. By mimicking an HIV infection, these vectors could elicit stronger and more durable immunity to HIV antigens...
May 31, 2017: Vaccine
https://www.readbyqxmd.com/read/28480334/hpv-serostatus-pre-and-post-vaccination-in-a-randomized-phase-ii-preparedness-trial-among-young-western-cape-south-african-women-the-evri-trial
#13
Staci L Sudenga, B Nelson Torres, Matthys H Botha, Michele Zeier, Martha E Abrahamsen, Richard H Glashoff, Susan Engelbrecht, Maarten F Schim Van der Loeff, Louvina E Van der Laan, Siegfried Kipping, Douglas Taylor, Anna R Giuliano
BACKGROUND: HPV antibodies are a marker of past exposure to the virus. Our objective was to assess HPV serostatus pre- and post-vaccination among HIV-negative women. METHODS: Women aged 16-24 years old were randomized in a placebo controlled trial utilizing the 4-valent HPV (4vHPV) vaccine (NCT01489527, clinicaltrials.gov). Participants (n=389) received the 4vHPV vaccine or placebo following a three dose schedule. Sera were collected at Day 1 and Month 7 for assessment of HPV 6, 11, 16, and 18 neutralizing antibody levels using a multiplex competitive Luminex immunoassay (Merck) based on detecting the L1 capsid antigen for each HPV type...
June 2017: Papillomavirus Research
https://www.readbyqxmd.com/read/28472201/predicting-hiv-1-transmission-and-antibody-neutralization-efficacy-in-vivo-from-stoichiometric-parameters
#14
Oliver F Brandenberg, Carsten Magnus, Peter Rusert, Huldrych F Günthard, Roland R Regoes, Alexandra Trkola
The potential of broadly neutralizing antibodies targeting the HIV-1 envelope trimer to prevent HIV-1 transmission has opened new avenues for therapies and vaccines. However, their implementation remains challenging and would profit from a deepened mechanistic understanding of HIV-antibody interactions and the mucosal transmission process. In this study we experimentally determined stoichiometric parameters of the HIV-1 trimer-antibody interaction, confirming that binding of one antibody is sufficient for trimer neutralization...
May 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28469517/a-little-help-from-the-follicles-understanding-the-germinal-center-response-to-human-immunodeficiency-virus-1-infection-and-prophylactic-vaccines
#15
REVIEW
Ebony N Gary, Michele A Kutzler
Human immunodeficiency virus 1 (HIV-1) is the causative agent of AIDS. There are currently more than 35 million people living with HIV infection worldwide, and more than 2 million new infections occur each year. The global pandemic caused by HIV-1 is the subject of numerous research projects, with the development of a prophylactic vaccine and a therapeutic cure being the ultimate goals. The classic paradigms of vaccinology have proven incapable of producing a viable vaccine due to the complexity of the virus' replication cycle, its genetic diversity, and a lack of understanding of the immune correlates of protection...
2017: Clinical Medicine Insights. Pathology
https://www.readbyqxmd.com/read/28466900/synthetic-multivalent-v3-glycopeptides-display-enhanced-recognition-by-glycan-dependent-hiv-1-broadly-neutralizing-antibodies
#16
Hui Cai, Jared Orwenyo, Javier Guenaga, John Giddens, Christian Toonstra, Richard T Wyatt, Lai-Xi Wang
We describe here the synthesis of novel multivalent HIV V3 domain glycopeptides and their binding to broadly neutralizing antibodies PGT128 and 10-1074. Our binding data reveal a distinct mode of antigen recognition by the two antibodies and further suggest that multivalent glycopeptides could mimic the neutralizing epitopes more efficiently than the monomeric glycopeptide.
May 14, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28463876/systemic-and-topical-use-of-monoclonal-antibodies-to-prevent-the-sexual-transmission-of-hiv
#17
Deborah J Anderson, Joseph A Politch, Larry Zeitlin, Andy Hiatt, Kadryn Kadasia, Kenneth H Mayer, Ruth M Ruprecht, Francois Villinger, Kevin J Whaley
Passive immunization, the transfer of antibodies to a nonimmune individual to provide immunological protection, has been used for over 100 years to prevent and treat human infectious diseases. The introduction of techniques to produce human monoclonal antibodies (mAbs) has revolutionized the field, and a large number of human mAbs have been licensed for the treatment of cancer, autoimmune and inflammatory diseases. With the recent discovery and production of highly potent broadly neutralizing and other multifunctional antibodies to HIV, mAbs are now being considered for HIV therapy and prophylaxis...
May 1, 2017: AIDS
https://www.readbyqxmd.com/read/28458036/a-heterologous-prime-boosting-strategy-with-replicating-vaccinia-virus-vectors-and-plant-produced-hiv-1-gag-dgp41-virus-like-particles
#18
Lydia R Meador, Sarah A Kessans, Jacquelyn Kilbourne, Karen V Kibler, Giuseppe Pantaleo, Mariano Esteban Roderiguez, Joseph N Blattman, Bertram L Jacobs, Tsafrir S Mor
Showing modest efficacy, the RV144 HIV-1 vaccine clinical trial utilized a non-replicating canarypox viral vector and a soluble gp120 protein boost. Here we built upon the RV144 strategy by developing a novel combination of a replicating, but highly-attenuated Vaccinia virus vector, NYVAC-KC, and plant-produced HIV-1 virus-like particles (VLPs). Both components contained the full-length Gag and a membrane anchored truncated gp41 presenting the membrane proximal external region with its conserved broadly neutralizing epitopes in the pre-fusion conformation...
April 27, 2017: Virology
https://www.readbyqxmd.com/read/28446665/dense-array-of-spikes-on-hiv-1-virion-particles
#19
Armando Stano, Daniel P Leaman, Arthur S Kim, Lei Zhang, Ludovic Autin, Jidnyasa Ingale, Syna K Gift, Jared Truong, Richard T Wyatt, Arthur J Olson, Michael B Zwick
HIV-1 is rare among viruses for having a low number of envelope glycoprotein (Env) spikes per virion, i.e. ∼7-14. This exceptional feature has been associated with avoidance of humoral immunity, i.e. B cell activation and antibody neutralization. Virus-like particles (VLPs) with increased density of Env are being pursued for vaccine development; however these typically require protein engineering that alters Env structure. Here, we used instead a strategy that targets the producer cell. We employed fluorescence activated cell sorting (FACS) to sort for cells that are recognized by trimer crossreactive broadly neutralizing antibody (bnAb) and not by non-neutralizing antibodies...
April 26, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28446609/glycosylation-of-the-core-of-the-hiv-1-envelope-subunit-protein-gp120-is-not-required-for-native-trimer-formation-or-viral-infectivity
#20
Ujjwal Rathore, Piyali Saha, Sannula Kesavardhana, Aditya Arun Kumar, Rohini Datta, Sivasankar Devanarayanan, Raksha Das, John R Mascola, Raghavan Varadarajan
The gp120 subunit of HIV-1 envelope (Env) protein is heavily glycosylated at approximately 25 glycosylation sites, of which ~7-8 are located in the V1/V2 and V3 variable loops and the others in the remaining core gp120 region. Glycans partially shield Env from recognition by the host immune system and also are believed to be indispensable for proper folding of gp120 and for viral infectivity. Previous attempts to alter glycosylation sites in Env typically involved mutating the glycosylated asparagine residues to structurally similar glutamines or to alanines...
April 26, 2017: Journal of Biological Chemistry
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