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HIV neutralizing antibody

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https://www.readbyqxmd.com/read/28816583/mammalian-cell-surface-display-for-monoclonal-antibody-based-facs-selection-of-viral-envelope-proteins
#1
Tim-Henrik Bruun, Veronika Grassmann, Benjamin Zimmer, Benedikt Asbach, David Peterhoff, Alexander Kliche, Ralf Wagner
The elicitation of broadly and efficiently neutralizing antibodies in humans by active immunization is still a major obstacle in the development of vaccines against pathogens such as the human immunodeficiency virus (HIV), influenza virus, hepatitis C virus or cytomegalovirus. Here, we describe a mammalian cell surface display and monoclonal antibody (mAb)-mediated panning technology that allows affinity-based selection of envelope (Env) variants from libraries. To this end, we established an experimental setup featuring: 1) single and site specific integration of Env to link genotype and phenotype, 2) inducible Env expression to avoid cytotoxicity effects, 3) translational coupling of Env and enhanced green fluorescent protein expression to normalize for Env protein levels, and 4) display on HEK cells to ensure native folding and mammalian glycosylation...
August 17, 2017: MAbs
https://www.readbyqxmd.com/read/28814388/the-impact-of-poxvirus-vector-priming-protein-co-administration-and-vaccine-intervals-on-hiv-gp120-vaccine-elicited-antibody-magnitude-and-function-in-infant-macaques
#2
Bonnie Phillips, Genevieve G Fouda, Josh Eudailey, Justin Pollara, Alan D Curtis, Erika Kunz, Maria Dennis, Xiaoying Shen, Camden Bay, Michael Hudgens, David Pickup, S Munir Alam, Amir Ardeshir, Pamela A Kozlowski, Koen K A Van Rompay, Guido Ferrari, M Anthony Moody, Sallie Permar, Kristina De Paris
Despite success in reducing vertical HIV transmission by maternal antiretroviral therapy, several obstacles limit its efficacy during breastfeeding, and breast-milk transmission is now the dominant mode of mother-to-child transmission (MTCT) of HIV in infants. Thus, a pediatric vaccine is needed to eradicate oral HIV infections in newborns and infants. Utilizing the infant rhesus macaque model, we compared 3 different vaccine regimens: (i) HIV Env protein only; (ii) a poxvirus vector (MVA)-HIV Env prime/HIV Env protein boost, and (iii) co-administration of HIV Env protein and MVA-HIV Env at all time points...
August 16, 2017: Clinical and Vaccine Immunology: CVI
https://www.readbyqxmd.com/read/28809479/natural-seminal-amyloids-as-targets-for-development-of-synthetic-inhibitors-of-hiv-transmission
#3
Daniel A Sheik, Stephen Dewhurst, Jerry Yang
Amyloids refer to a class of protein or peptide aggregates that are heterogeneous in size, morphology, and composition, and are implicated to play a central role in many neurodegenerative and systemic diseases. The strong correlation between biological activity and extent of aggregation of amyloidogenic proteins and peptides has led to an explosion of research efforts to target these materials with synthetic molecules or engineered antibodies to try to attenuate their function in disease pathology. Although many of these efforts to attenuate amyloid function have shown great promise in laboratory settings, the vast majority of work has been focused on targeting amyloids associated with neurologic diseases, which has been met with significant additional challenges that preclude clinical evaluation...
August 15, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28799906/of-mice-macaques-and-men-broadly-neutralizing-antibody-immunotherapy-for-hiv-1
#4
REVIEW
Yoshiaki Nishimura, Malcolm A Martin
The neutralizing antibodies targeting the HIV-1 envelope protein have been a major focus for HIV therapy. Early studies with anti-HIV-1 neutralizing monoclonal antibodies (mAbs) administered to infected individuals showed some promise, as they resulted in transient reductions in plasma viremia in some recipients. However, resistant viral variants rapidly emerged. A major development during the past 6 to 7 years has been the isolation and characterization of highly potent and broadly neutralizing mAbs (bNAbs) from infected individuals known as "elite neutralizers...
August 9, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28794282/partial-efficacy-of-a-broadly-neutralizing-antibody-against-cell-associated-shiv-infection
#5
Matthew S Parsons, Sarah B Lloyd, Wen Shi Lee, Anne B Kristensen, Thakshila Amarasena, Rob J Center, Brandon F Keele, Jeffrey D Lifson, Celia C LaBranche, David Montefiori, Bruce D Wines, P Mark Hogarth, Kristine M Swiderek, Vanessa Venturi, Miles P Davenport, Stephen J Kent
Broadly neutralizing antibodies (BnAbs) protect macaques from cell-free simian/human immunodeficiency virus (SHIV) challenge, but their efficacy against cell-associated SHIV is unclear. Virus in cell-associated format is highly infectious, present in transmission-competent bodily fluids, and potentially capable of evading antibody-mediated neutralization. The PGT121 BnAb, which recognizes an epitope consisting of the V3 loop and envelope glycans, mediates antibody-dependent cellular cytotoxicity and neutralization of cell-to-cell HIV-1 transmission...
August 9, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28794022/potent-in-vivo-nk-cell-mediated-elimination-of-hiv-1-infected-cells-mobilized-by-a-gp120-bispecific-and-hexavalent-broadly-neutralizing-fusion-protein
#6
Ariola Bardhi, Yanling Wu, Weizao Chen, Zhongyu Zhu, Jian Hua Zheng, Hing Wong, Emily Jeng, Jennifer Jones, Christina Ochsenbauer, John C Kappes, Dimiter S Dimitrov, Tianlei Ying, Harris Goldstein
Antibodies bound to HIV-1 envelope protein expressed by infected cells mobilize antibody dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to functional HIV-1 cure...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28792942/hiv-1-neutralizing-antibody-induced-by-simian-adenovirus-and-poxvirus-mva-vectored-bg505-native-like-envelope-trimers
#7
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/28783671/potent-and-broad-hiv-neutralizing-antibodies-in-memory-b-cells-and-plasma
#8
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/28768869/protective-efficacy-of-broadly-neutralizing-antibodies-with-incomplete-neutralization-activity-against-shiv-in-rhesus-monkeys
#9
Boris Julg, Devin Sok, Stephen D Schmidt, Peter Abbink, Ruchi M Newman, Thomas Broge, Caitlyn Linde, Joseph Nkolola, Khoa Le, David Su, Julia Torabi, Melissa Pack, Amarendra Pegu, Todd M Allen, John R Mascola, Dennis R Burton, Dan H Barouch
HIV broadly neutralizing antibodies (bnAbs) have been shown to occasionally display unusual virus neutralization profiles with non-sigmoidal slopes and plateaus at <100% neutralization against a variety of viruses. The significance of incomplete neutralization for the ability of bnAbs to mediate protective effects in vivo however is undetermined. In the current study, we selected two bnAbs, PGT121 and 3BNC117, as they incompletely neutralize the clade C SHIV stock (SHIV-327c) at 85% and 70%, respectively, and performed a protection study in rhesus macaques...
August 2, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28762497/t-cell-dependent-antigen-adjuvanted-with-dotap-cpg-b-but-not-dotap-cpg-a-induces-robust-germinal-center-responses-and-high-affinity-antibodies-in-mice
#10
Munir Akkaya, Billur Akkaya, Patrick W Sheehan, Pietro Miozzo, Mirna Pena, Chen-Feng Qi, Javier Manzella-Lapeira, Silvia Bolland, Susan K Pierce
The development of vaccines for infectious diseases for which we currently have none, including HIV, will likely require the use of adjuvants that strongly promote germinal center responses and somatic hypermutation to produce broadly neutralizing antibodies. Here we compared the outcome of immunization with the T-cell dependent antigen, NP-conjugated to chicken gamma globulin (NP-CGG) adjuvanted with the toll-like receptor 9 (TLR9) ligands, CpG-A or CpG-B, alone or conjugated with the cationic lipid carrier, DOTAP...
August 1, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28758637/dna-prime-protein-boost-vaccination-elicits-robust-humoral-response-in-rhesus-macaques-using-oligomeric-simian-immunodeficiency-virus-envelope-and-advax-delta-inulin-adjuvant
#11
Veena Menon, Victor I Ayala, Sneha P Rangaswamy, Irene Kalisz, Stephen Whitney, Lindsey Galmin, Asma Ashraf, Celia LaBranche, David Montefiori, Nikolai Petrovsky, Vaniambadi S Kalyanaraman, Ranajit Pal
The partial success of the RV144 trial underscores the importance of envelope-specific antibody responses for an effective HIV-1 vaccine. Oligomeric HIV-1 envelope proteins delivered with a potent adjuvant are expected to elicit strong antibody responses with broad neutralization specificity. To test this hypothesis, two SIV envelope proteins were formulated with delta inulin-based adjuvant (Advax) and used to immunize nonhuman primates. Oligomeric gp140-gp145 from SIVmac251 and SIVsmE660 was purified to homogeneity...
July 31, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28757252/non-neutralizing-antibodies-alter-the-course-of-hiv-1-infection-in%C3%A2-vivo
#12
Joshua A Horwitz, Yotam Bar-On, Ching-Lan Lu, Daniela Fera, Ainsley A K Lockhart, Julio C C Lorenzi, Lilian Nogueira, Jovana Golijanin, Johannes F Scheid, Michael S Seaman, Anna Gazumyan, Susan Zolla-Pazner, Michel C Nussenzweig
Non-neutralizing antibodies (nnAbs) to HIV-1 show little measurable activity in prevention or therapy in animal models yet were the only correlate of protection in the RV144 vaccine trial. To investigate the role of nnAbs on HIV-1 infection in vivo, we devised a replication-competent HIV-1 reporter virus that expresses a heterologous HA-tag on the surface of infected cells and virions. Anti-HA antibodies bind to, but do not neutralize, the reporter virus in vitro. However, anti-HA protects against infection in humanized mice and strongly selects for nnAb-resistant viruses in an entirely Fc-dependent manner...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28752105/an-entry-competent-intermediate-state-of-the-hiv-1-envelope-glycoproteins
#13
Alon Herschhorn, Joseph Sodroski
The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) mediate viral entry and are the sole target of neutralizing antibodies. Recent studies show that the metastable HIV-1 Env trimer can transit among three conformational states: State 1, State 3, and State 2, corresponding to the "closed", "open" and intermediate conformations, respectively. During virus entry, binding to the CD4 receptor drives Env from state 1 to state 3. In the unliganded Env, transitions from the closed (State 1) conformation are restrained by intramolecular interactions among different Env residues, which regulate HIV-1 Env conformation...
2017: Receptors & Clinical Investigation
https://www.readbyqxmd.com/read/28747530/sequence-intrinsic-somatic-mutation-mechanisms-contribute-to-affinity-maturation-of-vrc01-class-hiv-1-broadly-neutralizing-antibodies
#14
Joyce K Hwang, Chong Wang, Zhou Du, Robin M Meyers, Thomas B Kepler, Donna Neuberg, Peter D Kwong, John R Mascola, M Gordon Joyce, Mattia Bonsignori, Barton F Haynes, Leng-Siew Yeap, Frederick W Alt
Variable regions of Ig chains provide the antigen recognition portion of B-cell receptors and derivative antibodies. Ig heavy-chain variable region exons are assembled developmentally from V, D, J gene segments. Each variable region contains three antigen-contacting complementarity-determining regions (CDRs), with CDR1 and CDR2 encoded by the V segment and CDR3 encoded by the V(D)J junction region. Antigen-stimulated germinal center (GC) B cells undergo somatic hypermutation (SHM) of V(D)J exons followed by selection for SHMs that increase antigen-binding affinity...
July 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28747500/panels-of-hiv-1-subtype-c-env-reference-strains-for-standardized-neutralization-assessments
#15
Peter Hraber, Cecilia Rademeyer, Carolyn Williamson, Michael S Seaman, Raphael Gottardo, Haili Tang, Kelli Greene, Hongmei Gao, Celia LaBranche, John R Mascola, Lynn Morris, David C Montefiori, Bette Korber
In the search for effective immunologic interventions to prevent and treat HIV-1 infection, standardized reference reagents are a cost-effective way to maintain robustness and reproducibility among immunological assays. To support planned and ongoing studies where clade C predominates, here we describe three virus panels, chosen from 200 well-characterized clade C envelope (Env)-pseudotyped viruses from early infection. All 200 Envs were expressed as single-round of replication pseudoviruses, and tested to quantify neutralization titers by 16 broadly neutralizing antibodies (bnAbs) and sera from 30 subjects with chronic clade C infections...
July 26, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28747495/hiv-and-siv-maintain-high-levels-of-infectivity-in-the-complete-absence-of-mucin-type-o-glycosylation
#16
James M Termini, Elizabeth S Church, Zachary A Silver, Stuart M Haslam, Anne Dell, Ronald C Desrosiers
A highly conserved threonine near the C-terminus of gp120 of HIV and SIV was investigated for its contributions to envelope protein function and virion infectivity. When this highly conserved Thr residue was substituted with anything other than serine (the other amino acid that can accept O-glycosylation), the resulting virus was non-infectious. We found that this Thr was critical for the association of gp120 with the virion and that amino acid substitution increased the amount of dissociated gp120 in the cell culture supernatant...
July 26, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28743743/characterization-of-a-stable-hiv-1-b-c-recombinant-soluble-and-trimeric-envelope-glycoprotein-env-highly-resistant-to-cd4-induced-conformational-changes
#17
Rajesh Kumar, Gabriel Ozorowski, Vivek Kumar, Lauren G Holden, Tripti Shrivastava, Shilpa Patil, Suprit Deshpande, Andrew B Ward, Jayanta Bhattacharya
The HIV-1 envelope (Env) is a glycoprotein which is a trimer of heterodimer containing gp120 and gp41 subunits, mediates virus entry and is a major target of broadly neutralizing antibodies (bnAbs) developed during infection in some individuals. The engagement of the HIV-1 gp120 glycoprotein to the host CD4 protein triggers conformational changes in gp120 that allows its binding to coreceptors, and is necessary for virus entry to establish infection. Native-like HIV-1 Env immunogens representing distinct clades have been proposed to improve immunogenicity of bnAbs...
July 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28740221/escape-from-humoral-immunity-is-associated-with-treatment-failure-in-hiv-1-infected-patients-receiving-long-term-antiretroviral-therapy
#18
Yabo Ouyang, Qianqian Yin, Wei Li, Zhenpeng Li, Desheng Kong, Yanling Wu, Kunxue Hong, Hui Xing, Yiming Shao, Shibo Jiang, Tianlei Ying, Liying Ma
Interindividual heterogeneity in the disease progression of HIV-1-infected patients receiving long-term antiretroviral therapy suggests that some host-related factors may have limited treatment efficacy. To understand the nature of factors contributing to treatment failure, we performed a retrospective cohort study of 45 chronically HIV-1-infected individuals sharing a similar demographics and route of infection, compared the differences between virologically suppressed (VS) and treatment failure (TF) patients with respect to clinical, immunological and virological characteristics...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28739603/novel-in-vitro-booster-vaccination-to-rapidly-generate-antigen-specific-human-monoclonal-antibodies
#19
Irene Sanjuan Nandin, Carol Fong, Cecilia Deantonio, Juan A Torreno-Pina, Simone Pecetta, Paula Maldonado, Francesca Gasparrini, Jose Ordovas-Montanes, Samuel W Kazer, Svend Kjaer, Daryl W Borley, Usha Nair, Julia A Coleman, Daniel Lingwood, Alex K Shalek, Eric Meffre, Pascal Poignard, Dennis R Burton, Facundo D Batista
Vaccines remain the most effective tool to prevent infectious diseases. Here, we introduce an in vitro booster vaccination approach that relies on antigen-dependent activation of human memory B cells in culture. This stimulation induces antigen-specific B cell proliferation, differentiation of B cells into plasma cells, and robust antibody secretion after a few days of culture. We validated this strategy using cells from healthy donors to retrieve human antibodies against tetanus toxoid and influenza hemagglutinin (HA) from H1N1 and newly emergent subtypes such as H5N1 and H7N9...
July 24, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28738289/germinal-center-enhancement-by-extended-antigen-availability
#20
REVIEW
Kimberly M Cirelli, Shane Crotty
Vaccine elicitation of protective antibody responses has proved difficult for a number of important human pathogens, including HIV-1. The amount of somatic hypermutation associated with the development of broadly neutralizing antibodies against HIV has not been achieved using conventional immunization strategies. An underexplored aspect of vaccine design is modulation of antigen kinetics. Immunization strategies with extended antigen availability have recently been shown to enhance humoral responses. In this review, we explore the mechanisms through which sustained antigen availability can enhance germinal center responses and the potency of antibody responses...
July 21, 2017: Current Opinion in Immunology
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