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https://www.readbyqxmd.com/read/29343576/increased-epitope-complexity-correlated-with-antibody-affinity-maturation-and-a-novel-binding-mode-revealed-by-structures-of-rabbit-antibodies-against-the-third-variable-loop-v3-of-hiv-1-gp120
#1
Ruimin Pan, Yali Qin, Marisa Banasik, William Lees, Adrian J Shepherd, Michael W Cho, Xiang-Peng Kong
The V3 loop of HIV-1 gp120 is an immunodominant region targeted by neutralizing antibodies (nAbs). Despite limited breadth, better characterization of the structural details of the interactions between these nAbs and their target epitopes would enhance our understanding of the mechanism of neutralization and facilitate designing better immunogens to induce nAbs with greater breadth. Recently, we isolated two anti-V3 neutralizing monoclonal antibodies (mAbs), 10A3 and 10A37, from a rabbit immunized with gp120 of the M group consensus sequence...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29315059/multi-envelope-hiv-1-vaccine-development-two-targeted-immune-pathways-one-desired-protective-outcome
#2
Julia L Hurwitz, Mattia Bonsignori
In 2016, there were more than 30 million individuals living with HIV-1, ∼1.8 million new HIV-1 infections, and ∼1 million HIV-1-related deaths according to UNAIDS ( unaids.org ). Hence, a preventive HIV-1 vaccine remains a global priority. The variant envelopes of HIV-1 present a significant obstacle to vaccine development and the vaccine field has realized that immunization with a single HIV-1 envelope protein will not be sufficient to generate broadly neutralizing antibodies. Here we describe two nonmutually exclusive, targeted pathways with which a multi-envelope HIV-1 vaccine may generate protective immune responses against variant HIV-1...
January 9, 2018: Viral Immunology
https://www.readbyqxmd.com/read/29281818/vaccine-induction-of-heterologous-tier-2-hiv-1-neutralizing-antibodies-in-animal-models
#3
Kevin O Saunders, Laurent K Verkoczy, Chuancang Jiang, Jinsong Zhang, Robert Parks, Haiyan Chen, Max Housman, Hilary Bouton-Verville, Xiaoying Shen, Ashley M Trama, Richard Scearce, Laura Sutherland, Sampa Santra, Amanda Newman, Amanda Eaton, Kai Xu, Ivelin S Georgiev, M Gordon Joyce, Georgia D Tomaras, Mattia Bonsignori, Steven G Reed, Andres Salazar, John R Mascola, M Anthony Moody, Derek W Cain, Mireille Centlivre, Sandra Zurawski, Gerard Zurawski, Harold P Erickson, Peter D Kwong, S Munir Alam, Yves Levy, David C Montefiori, Barton F Haynes
The events required for the induction of broad neutralizing antibodies (bnAbs) following HIV-1 envelope (Env) vaccination are unknown, and their induction in animal models as proof of concept would be critical. Here, we describe the induction of plasma antibodies capable of neutralizing heterologous primary (tier 2) HIV-1 strains in one macaque and two rabbits. Env immunogens were designed to induce CD4 binding site (CD4bs) bnAbs, but surprisingly, the macaque developed V1V2-glycan bnAbs. Env immunization of CD4bs bnAb heavy chain rearrangement (VHDJH) knockin mice similarly induced V1V2-glycan neutralizing antibodies (nAbs), wherein the human CD4bs VH chains were replaced with mouse rearrangements bearing diversity region (D)-D fusions, creating antibodies with long, tyrosine-rich HCDR3s...
December 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/29222332/stabilization-of-the-gp120-v3-loop-through-hydrophobic-interactions-reduces-the-immunodominant-v3-directed-non-neutralizing-response-to-hiv-1-envelope-trimers
#4
Steven W de Taeye, Alba Torrents de la Peña, Andrea Vecchione, Enzo Scutigliani, Kwinten Sliepen, Judith A Burger, Patricia van der Woude, Anna Schorcht, Edith E Schermer, Marit J van Gils, Celia C LaBranche, David C Montefiori, Ian A Wilson, John P Moore, Andrew B Ward, Rogier W Sanders
To provide protective immunity against circulating primary HIV-1 strains, a vaccine most likely has to induce broadly neutralizing antibodies (bNAbs) to the HIV-1 envelope (Env) glycoprotein spike. Recombinant Env trimers such as the prototype BG505 SOSIP.664 that closely mimic the native Env spike can induce autologous neutralizing antibodies (NAbs) against relatively resistant (tier-2) primary viruses. Ideally, Env immunogens should present bNAb epitopes, but limit the presentation of immunodominant non-NAb epitopes that might induce off-target and potentially interfering responses...
December 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29209323/non-neutralizing-antibodies-directed-against-hiv-and-their-functions
#5
REVIEW
Luzia M Mayr, Bin Su, Christiane Moog
B cells produce a plethora of anti-HIV antibodies (Abs) but only few of them exhibit neutralizing activity. This was long considered a profound limitation for the enforcement of humoral immune responses against HIV-1 infection, especially since these neutralizing Abs (nAbs) are extremely difficult to induce. However, increasing evidence shows that additional non-neutralizing Abs play a significant role in decreasing the viral load, leading to partial and sometimes even total protection. Mechanisms suspected to participate in protection are numerous...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29162799/structure-based-design-of-native-like-hiv-1-envelope-trimers-to-silence-non-neutralizing-epitopes-and-eliminate-cd4-binding
#6
Daniel W Kulp, Jon M Steichen, Matthias Pauthner, Xiaozhen Hu, Torben Schiffner, Alessia Liguori, Christopher A Cottrell, Colin Havenar-Daughton, Gabriel Ozorowski, Erik Georgeson, Oleksandr Kalyuzhniy, Jordan R Willis, Michael Kubitz, Yumiko Adachi, Samantha M Reiss, Mia Shin, Natalia de Val, Andrew B Ward, Shane Crotty, Dennis R Burton, William R Schief
Elicitation of broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal. Native-like trimers mimicking virion-associated spikes present nearly all bnAb epitopes and are therefore promising vaccine antigens. However, first generation native-like trimers expose epitopes for non-neutralizing antibodies (non-nAbs), which may hinder bnAb induction. We here employ computational and structure-guided design to develop improved native-like trimers that reduce exposure of non-nAb epitopes in the V3-loop and trimer base, minimize both CD4 reactivity and CD4-induced non-nAb epitope exposure, and increase thermal stability while maintaining bnAb antigenicity...
November 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/29150603/bacterially-derived-synthetic-mimetics-of-mammalian-oligomannose-prime-antibody-responses-that-neutralize-hiv-infectivity
#7
Ralph Pantophlet, Nino Trattnig, Sasha Murrell, Naiomi Lu, Dennis Chau, Caitlin Rempel, Ian A Wilson, Paul Kosma
Oligomannose-type glycans are among the major targets on the gp120 component of the HIV envelope protein (Env) for broadly neutralizing antibodies (bnAbs). However, attempts to elicit oligomannose-specific nAbs by immunizing with natural or synthetic oligomannose have so far not been successful, possibly due to B cell tolerance checkpoints. Here we design and synthesize oligomannose mimetics, based on the unique chemical structure of a recently identified bacterial lipooligosaccharide, to appear foreign to the immune system...
November 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29142124/truncating-the-gp41-cytoplasmic-tail-of-siv-decreases-sensitivity-to-neutralizing-antibodies-without-increasing-envelope-content-of-virions
#8
Ellen White, Fan Wu, Elena Chertova, Julian Bess, James D Roser, Jeffrey D Lifson, Vanessa M Hirsch
An incomplete understanding of native HIV and SIV envelope glycoprotein (Env) impedes the development of structural models of Env and vaccine design. This shortcoming is due in part to the low number of Env trimers on virus particles. For SIV, this low expression can be counteracted by truncating the cytoplasmic tail (CT) of Env. CT truncation has been shown to increase Env incorporation into the virion and is commonly used in vaccine and imaging studies, but its effects on viral antigenicity have not been fully elucidated...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29066544/maternal-but-not-infant-anti-hiv-1-neutralizing-antibody-response-associates-with-enhanced-transmission-and-infant-morbidity
#9
Melissa Ghulam-Smith, Alex Olson, Laura F White, Charles S Chasela, Sascha R Ellington, Athena P Kourtis, Denise J Jamieson, Gerald Tegha, Charles M van der Horst, Manish Sagar
A significant number of infants acquire HIV-1 through their infected mother's breast milk, primarily due to limited access to antiretrovirals. Passive immunization with neutralizing antibodies (nAbs) may prevent this transmission. Previous studies, however, have generated conflicting results about the ability of nAbs to halt mother-to-child transmission (MTCT) and their impact on infant outcomes. This study compared plasma neutralizing activity in exposed infants and the infected mothers (n = 63) against heterologous HIV-1 variants and the quasispecies present in the mother...
October 24, 2017: MBio
https://www.readbyqxmd.com/read/29020058/hiv-transmitted-founder-vaccines-elicit-autologous-tier-2-neutralizing-antibodies-for-the-cd4-binding-site
#10
Nathanael P McCurley, Arban Domi, Rahul Basu, Kevin O Saunders, Celia C LaBranche, David C Montefiori, Barton F Haynes, Harriet L Robinson
Here we report the construction, antigenicity and initial immunogenicity testing of DNA and modified vaccinia Ankara (MVA) vaccines expressing virus-like particles (VLPs) displaying sequential clade C Envelopes (Envs) that co-evolved with the elicitation of broadly neutralizing antibodies (bnAbs) to the CD4 binding site (CD4bs) in HIV-infected individual CH0505. The VLP-displayed Envs showed reactivity for conformational epitopes displayed on the receptor-binding form of Env. Two inoculations of the DNA-T/F vaccine, followed by 3 inoculations of the MVA-T/F vaccine and a final inoculation of the MVA-T/F plus a gp120-T/F protein vaccine elicited nAb to the T/F virus in 2 of 4 rhesus macaques (ID50 of ~175 and ~30)...
2017: PloS One
https://www.readbyqxmd.com/read/28928750/the-role-of-maternal-hiv-envelope-specific-antibodies-and-mother-to-child-transmission-risk
#11
REVIEW
Ayooluwa O Douglas, David R Martinez, Sallie R Permar
Despite the wide availability of antiretroviral therapy (ART) prophylaxis during pregnancy, >150,000 infants become infected through mother-to-child transmission (MTCT) of HIV worldwide. It is likely that additional intervention strategies, such as a maternal HIV vaccine, will be required to eliminate pediatric HIV infections. A deeper understanding of the fine specificity and function of maternal HIV envelope (Env)-specific responses that provide partial protection against MTCT will be critical to inform the design of immunologic strategies to curb the pediatric HIV epidemic...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28918477/in-vitro-inhibition-of-hiv-1-replication-in-autologous-cd4-t-cells-indicates-viral-containment-by-multifactorial-mechanisms
#12
Ting Tu, Jianbo Zhan, Danlei Mou, Wei Li, Bin Su, Tong Zhang, Tao Li, Ning Li, Hao Wu, Cong Jin, Huabiao Chen
HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibodies (NAbs) are present during chronic infection, but the relative contributions of these effector mechanisms to viral containment remain unclear. Here, using an in vitro model involving autologous CD4(+) T cells, primary HIV-1 isolates, HIV-1-specific CTLs, and neutralizing monoclonal antibodies, we show that b12, a potent and broadly neutralizing monoclonal antibody to HIV-1, was able to block viral infection when preincubated with virus prior to infection, but was much less effective than CTLs at limiting virus replication when added to infected cell cultures...
September 15, 2017: Virologica Sinica
https://www.readbyqxmd.com/read/28841647/probing-the-compartmentalization-of-hiv-1-in-the-central-nervous-system-through-its-neutralization-properties
#13
Karl Stefic, Antoine Chaillon, Mélanie Bouvin-Pley, Alain Moreau, Martine Braibant, Frédéric Bastides, Guillaume Gras, Louis Bernard, Francis Barin
Compartmentalization of HIV-1 has been observed in the cerebrospinal fluid (CSF) of patients at different clinical stages. Considering the low permeability of the blood-brain barrier, we wondered if a reduced selective pressure by neutralizing antibodies (NAb) in the central nervous system (CNS) could favor the evolution of NAb-sensitive viruses in this compartment. Single genome amplification (SGA) was used to sequence full-length HIV-1 envelope variants (453 sequences) from paired CSF and blood plasma samples in 9 subjects infected by HIV variants of various clades and suffering from diverse neurologic disorders...
2017: PloS One
https://www.readbyqxmd.com/read/28835491/hiv-1-cross-reactive-primary-virus-neutralizing-antibody-response-elicited-by-immunization-in-nonhuman-primates
#14
Yimeng Wang, Sijy O'Dell, Hannah L Turner, Chi-I Chiang, Lin Lei, Javier Guenaga, Richard Wilson, Paola Martinez-Murillo, Nicole Doria-Rose, Andrew B Ward, John R Mascola, Richard T Wyatt, Gunilla B Karlsson Hedestam, Yuxing Li
Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross-reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28834745/improving-the-immunogenicity-of-native-like-hiv-1-envelope-trimers-by-hyperstabilization
#15
Alba Torrents de la Peña, Jean-Philippe Julien, Steven W de Taeye, Fernando Garces, Miklos Guttman, Gabriel Ozorowski, Laura K Pritchard, Anna-Janina Behrens, Eden P Go, Judith A Burger, Edith E Schermer, Kwinten Sliepen, Thomas J Ketas, Pavel Pugach, Anila Yasmeen, Christopher A Cottrell, Jonathan L Torres, Charlotte D Vavourakis, Marit J van Gils, Celia LaBranche, David C Montefiori, Heather Desaire, Max Crispin, Per Johan Klasse, Kelly K Lee, John P Moore, Andrew B Ward, Ian A Wilson, Rogier W Sanders
The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation...
August 22, 2017: Cell Reports
https://www.readbyqxmd.com/read/28792942/hiv-1-neutralizing-antibody-induced-by-simian-adenovirus-and-poxvirus-mva-vectored-bg505-native-like-envelope-trimers
#16
Silvia Capucci, Edmund G Wee, Torben Schiffner, Celia C LaBranche, Nicola Borthwick, Albert Cupo, Jonathan Dodd, Hansi Dean, Quentin Sattentau, David Montefiori, Per J Klasse, Rogier W Sanders, John P Moore, Tomáš Hanke
Rabbits and monkeys immunized with HIV type 1 (HIV-1) native-like BG505 SOSIP.664 (BG505s) glycoprotein trimers are known to induce antibodies that can neutralize the autologous tier-2 virus. Here, we assessed the induction of HIV-1 trimer binding and neutralizing antibody (nAb) titres when BG505s trimers were also delivered by non-replicating simian (chimpanzee) adenovirus and non-replicating poxvirus modified vaccinia virus Ankara (MVA) vaccine vectors. First, we showed that approximately two-thirds and one-third of the trimers secreted from the ChAdOx1...
2017: PloS One
https://www.readbyqxmd.com/read/28696188/evolution-of-cross-neutralizing-antibodies-and-mapping-epitope-specificity-in-plasma-of-chronic-hiv-1-infected-antiretroviral-therapy-na%C3%A3-ve-children-from-india
#17
Muzamil A Makhdoomi, Lubina Khan, Sanjeev Kumar, Heena Aggarwal, Ravinder Singh, Rakesh Lodha, Mohit Singla, Bimal K Das, Sushil K Kabra, Kalpana Luthra
Delineating the factors leading to the development of broadly neutralizing antibodies (bnAbs) during natural HIV-1 infection and dissecting their epitope specificities generates useful information for vaccine design. This is the first longitudinal study to assess the plasma-neutralizing antibody response and neutralizing determinants in HIV-1-infected children from India. We enrolled 26 and followed up 20 antiretroviral therapy (ART)-naïve, asymptomatic, chronic HIV-1-infected children. Five (19.2 %) baseline and 10 (50 %) follow-up plasma samples neutralized ≥50 % of subtypes A, B and C tier 2 viruses at an ID50 titre ≥150...
July 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28636956/elicitation-of-robust-tier-2-neutralizing-antibody-responses-in-nonhuman-primates-by-hiv-envelope-trimer-immunization-using-optimized-approaches
#18
Matthias Pauthner, Colin Havenar-Daughton, Devin Sok, Joseph P Nkolola, Raiza Bastidas, Archana V Boopathy, Diane G Carnathan, Abishek Chandrashekar, Kimberly M Cirelli, Christopher A Cottrell, Alexey M Eroshkin, Javier Guenaga, Kirti Kaushik, Daniel W Kulp, Jinyan Liu, Laura E McCoy, Aaron L Oom, Gabriel Ozorowski, Kai W Post, Shailendra K Sharma, Jon M Steichen, Steven W de Taeye, Talar Tokatlian, Alba Torrents de la Peña, Salvatore T Butera, Celia C LaBranche, David C Montefiori, Guido Silvestri, Ian A Wilson, Darrell J Irvine, Rogier W Sanders, William R Schief, Andrew B Ward, Richard T Wyatt, Dan H Barouch, Shane Crotty, Dennis R Burton
The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer...
June 20, 2017: Immunity
https://www.readbyqxmd.com/read/28615205/intrasubtype-b-hiv-1-superinfection-correlates-with-delayed-neutralizing-antibody-response
#19
Gabriel A Wagner, Elise Landais, Gemma Caballero, Pham Phung, Sergei L Kosakovsky Pond, Pascal Poignard, Douglas D Richman, Susan J Little, Davey M Smith
Understanding whether the neutralizing antibody (NAb) response impacts HIV-1 superinfection and how superinfection subsequently modulates the NAb response can help clarify correlates of protection from HIV exposures and better delineate pathways of NAb development. We examined associations between the development of NAb and the occurrence of superinfection in a well-characterized, antiretroviral therapy (ART)-naive, primary infection cohort of men who have sex with men. Deep sequencing was applied to blood plasma samples from the cohort to detect cases of superinfection...
September 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28599793/a-cross-reacting-material-crm197-conjugate-vaccine-induces-diphtheria-toxin-neutralizing-antibody-response-in-children-and-adolescents-infected-or-not-with-hiv
#20
Giselle P Silva, Rafaela S Santos, Wânia F Pereira-Manfro, Bianca Ferreira, Daniella M Barreto, Ana Cristina C Frota, Cristina B Hofer, Lucimar G Milagres
Anti-diphtheria antibody levels decrease with aging, and frequent booster vaccinations are required to maintain herd immunity. We analyzed the diphtheria toxin neutralizing antibody (DT-Nab) response induced by a conjugate vaccine (meningococcal C polysaccharide-CRM197) in HIV-vertically infected (HI) children and adolescents and healthy controls (HC) with matched age. We report the association of DT-Nab with the bactericidal antibodies to serogroup C meningococcus (MenC). Before vaccination, 21 HI patients (50%) had no protection against diphtheria (≤0...
June 6, 2017: Vaccine
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