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Hiv and broadly neutralizing antibody

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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/29343432/hiv-immunogens-affinity-is-key
#2
Savit Prabhu, Ian A Cockburn, Carola G Vinuesa
Generation of broadly neutralizing antibodies is a key aim of HIV vaccine design, but the precursor B cells are rare. Abbott et al. (2018) report that high affinity and avidity immunogens are required to promote maturation of low frequency B cells in germinal centers.
January 16, 2018: Immunity
https://www.readbyqxmd.com/read/29329113/therapeutic-hiv-1-vaccine-time-for-immunomodulation-and-combinatorial-strategies
#3
Nabila Seddiki, Yves Lévy
PURPOSE OF REVIEW: The purpose is to recall some of the key immunological elements that are at the crossroad and need to be combined for developing a potent therapeutic HIV-1 vaccine. RECENT FINDINGS: Therapeutic vaccines and cytokines have been commonly used to enhance and/or recall preexisting HIV-1 specific cell-mediated immune responses aiming to suppress virus replication. While the vaccine is important to stimulate HIV-1 specific T-cell responses, the cytokine may support the expansion of the stimulated virus-specific T cells...
January 10, 2018: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/29321310/therapeutic-efficacy-of-vectored-pgt121-gene-delivery-in-hiv-1-infected-humanized-mice
#4
Alexander Badamchi-Zadeh, Lawrence J Tartaglia, Peter Abbink, Christine A Bricault, Po-Ting Liu, Michael Boyd, Marinela Kirilova, Noe B Mercado, Ovini S Nanayakkara, Vladimir D Vrbanac, Andrew M Tager, Rafael A Larocca, Michael S Seaman, Dan H Barouch
Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies. However, administration of purified bNAbs poses challenges in resource poor settings, where the HIV-1 disease burden is greatest. In vivo vector-based production of bNAbs represents an alternative strategy. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1 specific bNAb PGT121 in wildtype and immunocompromised C57Bl/6 mice as well as in HIV-1-infected bone marrow-liver-thymus (BLT) humanized mice...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29315059/multi-envelope-hiv-1-vaccine-development-two-targeted-immune-pathways-one-desired-protective-outcome
#5
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/29311326/fitness-landscape-of-the-human-immunodeficiency-virus-envelope-protein-that-is-targeted-by-antibodies
#6
Raymond H Y Louie, Kevin J Kaczorowski, John P Barton, Arup K Chakraborty, Matthew R McKay
HIV is a highly mutable virus, and over 30 years after its discovery, a vaccine or cure is still not available. The isolation of broadly neutralizing antibodies (bnAbs) from HIV-infected patients has led to renewed hope for a prophylactic vaccine capable of combating the scourge of HIV. A major challenge is the design of immunogens and vaccination protocols that can elicit bnAbs that target regions of the virus's spike proteins where the likelihood of mutational escape is low due to the high fitness cost of mutations...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29282882/recent-progress-in-immune-based-interventions-to-prevent-hiv-1-transmission-to-children
#7
Yegor Voronin, Ilesh Jani, Barney S Graham, Coleen K Cunningham, Lynne M Mofenson, Philippa M Musoke, Sallie R Permar, Gabriella Scarlatti
Globally, 150,000 new paediatric human immunodeficiency virus type 1 (HIV-1) infections occurred in 2015. There remain complex challenges to the global elimination of paediatric HIV-1 infection. Thus, for the global community to achieve elimination of new paediatric HIV-1 infections, innovative approaches need to be explored. Immune-based approaches to prevention of mother-to-child transmission (MTCT) may help fill some of the remaining gaps and provide new opportunities to achieve an AIDS-free generation. Immune-based interventions to prevent MTCT of HIV-1 may include paediatric HIV vaccines and passive immunization approaches...
December 2017: Journal of the International AIDS Society
https://www.readbyqxmd.com/read/29281818/vaccine-induction-of-heterologous-tier-2-hiv-1-neutralizing-antibodies-in-animal-models
#8
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/29277486/development-of-a-high-throughput-bead-based-assay-system-to-measure-hiv-1-specific-immune-signatures-in-clinical-samples
#9
Thomas Liechti, Claus Kadelka, Hanna Ebner, Nikolas Friedrich, Roger D Kouyos, Huldrych F Günthard, Alexandra Trkola
The monitoring and assessment of a broadly neutralizing antibody (bnAb) based HIV-1 vaccine require detailed measurements of HIV-1 binding antibody responses to support the detection of correlates of protection. Here we describe the development of a flexible, high-throughput microsphere based multiplex assay system that allows monitoring complex binding antibody signatures. Studying a panel of 13 HIV-1 antigens in a parallel assessment of different IgG subclasses (IgG1, IgG2 and IgG3) we demonstrate the potential of our strategy...
December 22, 2017: Journal of Immunological Methods
https://www.readbyqxmd.com/read/29274699/hiv-1-superinfection-can-occur-in-the-presence-of-broadly-neutralizing-antibodies
#10
Jennifer Serwanga, Deogratius Ssemwanga, Michael Muganga, Ritah Nakiboneka, Susan Nakubulwa, Sylvia Kiwuwa-Muyingo, Lynn Morris, Andrew D Redd, Thomas C Quinn, Pontiano Kaleebu
BACKGROUND: Superinfection of individuals already infected with HIV-1 suggests that pre-existing immune responses may not adequately protect against re-infection. We assessed high-risk female sex workers initially infected with HIV-1 clades A, D or A/D recombinants, to determine if HIV-1 broadly neutralizing antibodies were lacking prior to superinfection. METHODS: Six superinfected female sex workers previously stratified by HIV-1 high-risk behavior, infecting virus clade and volunteer CD4 counts were evaluated at baseline (n = 5) and at 350 days post-superinfection (n = 6); one superinfected volunteer lacked pre-superinfection plasma...
December 20, 2017: Vaccine
https://www.readbyqxmd.com/read/29250072/alterations-in-b-cell-compartment-correlate-with-poor-neutralization-response-and-disease-progression-in-hiv-1-infected-children
#11
Heena Aggarwal, Lubina Khan, Omkar Chaudhary, Sanjeev Kumar, Muzamil Ashraf Makhdoomi, Ravinder Singh, Kanika Sharma, Nitesh Mishra, Rakesh Lodha, Maddur Srinivas, Bimal Kumar Das, Sushil Kumar Kabra, Kalpana Luthra
Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10-20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29239895/development-of-broad-neutralization-activity-in-shiv-infected-rhesus-macaques-after-long-term-infection
#12
Nan Gao, Wei Wang, Chu Wang, Tiejun Gu, Rui Guo, Bin Yu, Wei Kong, Chuan Qin, Elena E Giorgi, Zhiwei Chen, Samantha Townsley, Shiu-Lok Hu, Xianghui Yu, Feng Gao
OBJECTIVE: Non-human primates (NHPs) are the only animal model that can be used to evaluate protection efficacy of HIV-1 Env vaccines. However, whether broadly neutralizing antibodies (bnAbs) can be elicited in NHPs infected with simian/human immunodeficiency virus (SHIV) has not been fully understood. The objective of this study is to investigate whether broad neutralization activities were developed in SHIV-infected macaques after long-term infection as in humans. DESIGN: Neutralization breadth and specificities in plasmas from SHIV-infected macaques could be determined by analyzing a panel of tier 2 viruses and their mutants...
December 12, 2017: AIDS
https://www.readbyqxmd.com/read/29237847/a-trimeric-hiv-1-envelope-gp120-immunogen-induces-potent-and-broad-anti-v1v2-loop-antibodies-against-hiv-1-in-rabbits-and-rhesus-macaques
#13
Andrew T Jones, Venkateswarlu Chamcha, Sannula Kesavardhana, Xiaoying Shen, David Beaumont, Raksha Das, Linda S Wyatt, Celia C LaBranche, Sherry Stanfield-Oakley, Guido Ferrari, David C Montefiori, Bernard Moss, Georgia D Tomaras, Raghavan Varadarajan, Rama Rao Amara
Trimeric HIV-1 envelope (Env) immunogens are attractive due to their ability to display quaternary epitopes targeted by broadly neutralizing antibodies while obscuring unfavorable epitopes. Results from the RV144 trial highlighted the importance of vaccine induced HIV-1 Env V1V2 directed antibodies, with key regions of the V2 loop as targets for vaccine-mediated protection. We recently reported that a trimeric JRFL-gp120 immunogen, generated by inserting a N-terminal trimerization domain in the V1 loop region of a cyclically permuted gp120 (cycP-gp120), induces neutralizing activity against multiple tier-2 HIV-1 isolates in guinea pigs in a DNA prime/protein boost approach...
December 13, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29237833/neutralizing-activity-of-broadly-neutralizing-anti-hiv-1-antibodies-against-clade-b-clinical-isolates-produced-in-peripheral-blood-mononuclear-cells
#14
Yehuda Z Cohen, Julio C C Lorenzi, Michael S Seaman, Lilian Nogueira, Till Schoofs, Lisa Krassnig, Allison Butler, Katrina Millard, Tomas Fitzsimons, Xiaoju Daniell, Juan P Dizon, Irina Shimeliovich, David C Montefiori, Marina Caskey, Michel C Nussenzweig
Recently discovered broadly neutralizing anti-HIV-1 antibodies (bNAbs) demonstrate extensive breadth and potency against diverse HIV-1 strains, and represent a promising approach for the treatment and prevention of HIV-1 infection. The breadth and potency of these antibodies have primarily been evaluated using panels of HIV-1 Env-pseudotyped viruses produced in 293T cells expressing molecularly cloned Envs. Here we report on the ability of 5 bNAbs currently in clinical development to neutralize circulating primary HIV-1 isolates derived from peripheral blood mononuclear cells (PBMC), and compare the results to the pseudovirus panels used to characterize the bNAbs...
December 13, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29237828/identification-of-novel-structural-determinants-in-mw965-env-that-regulate-the-neutralization-phenotype-and-conformational-masking-potential-of-primary-hiv-1-isolates
#15
Zakiya M Qualls, Alok Choudhary, William Honnen, Raja Prattipati, James E Robinson, Abraham Pinter
The subtype C HIV-1 isolate MW965.26 is a highly neutralization-sensitive tier-1a primary isolate that is widely used in vaccine studies, but the basis for the sensitive neutralization phenotype of this isolate is not known. Substituting the MW965.26 V1/V2 domain into a neutralization-sensitive SF162 Env clone resulted in high resistance to standard anti-V3 monoclonal antibodies, demonstrating that this region possessed strong masking activity in a standard Env backbone and indicating that determinants elsewhere in MW965...
December 13, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29234320/increasing-the-clinical-potential-and-applications-of-anti-hiv-antibodies
#16
REVIEW
Casey K Hua, Margaret E Ackerman
Preclinical and early human clinical studies of broadly neutralizing antibodies (bNAbs) to prevent and treat HIV infection support the clinical utility and potential of bNAbs for prevention, postexposure prophylaxis, and treatment of acute and chronic infection. Observed and potential limitations of bNAbs from these recent studies include the selection of resistant viral populations, immunogenicity resulting in the development of antidrug (Ab) responses, and the potentially toxic elimination of reservoir cells in regeneration-limited tissues...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29226015/conserved-hiv-epitopes-for-an-effective-hiv-vaccine
#17
Bikash Sahay, Cuong Q Nguyen, Janet K Yamamoto
Despite major advances in antiretroviral therapy against HIV-1, an effective HIV vaccine is urgently required to reduce the number of new cases of HIV infections in the world. Vaccines are the ultimate tool in the medical arsenal to control and prevent the spread of infectious diseases such as HIV/AIDS. Several failed phase-IIb to -III clinical vaccine trials against HIV-1 in the past generated a plethora of information that could be used for better designing of an effective HIV vaccine in the future. Most of the tested vaccine candidates produced strong humoral responses against the HIV proteins; however, failed to protect due to: 1) the low levels and the narrow breadth of the HIV-1 neutralizing antibodies and the HIV-specific antibody-dependent Fc-mediated effector activities, 2) the low levels and the poor quality of the anti-HIV T-cell responses, and 3) the excessive responses to immunodominant non-protective HIV epitopes, which in some cases blocked the protective immunity and/or enhanced HIV infection...
August 2017: Journal of Clinical & Cellular Immunology
https://www.readbyqxmd.com/read/29226013/novel-therapeutic-approach-for-inhibition-of-hiv-1-using-cell-penetrating-peptide-and-bacterial-toxins
#18
Steven Samuels, Zainab Alwan, Marceline Egnin, Jessie Jaynes, Terry D Connell, Gregory C Bernard, Toufic Nashar
Despite advancements in our understanding of HIV-1 pathogenesis, critical virus components for immunity, vaccines trials, and drugs development, challenges remain in the fight against HIV-1. Of great importance is the inhibitory function of microbicidal cell penetrating peptides and bacterial toxins that interfere with production and neutralize infection of HIV-1 particles. We demonstrate that the neutralizing activity of a cationic 18 amino acids peptide, is similar to a broadly neutralizing human antibody, and inhibits production of two HIV-1 strains in human cell lines...
October 2017: Journal of AIDS & Clinical Research
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
#19
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/29218117/basis-and-statistical-design-of-the-passive-hiv-1-antibody-mediated-prevention-amp-test-of-concept-efficacy-trials
#20
Peter B Gilbert, Michal Juraska, Allan C deCamp, Shelly Karuna, Srilatha Edupuganti, Nyaradzo Mgodi, Deborah J Donnell, Carter Bentley, Nirupama Sista, Philip Andrew, Abby Isaacs, Yunda Huang, Lily Zhang, Edmund Capparelli, Nidhi Kochar, Jing Wang, Susan H Eshleman, Kenneth H Mayer, Craig A Magaret, John Hural, James G Kublin, Glenda Gray, David C Montefiori, Margarita M Gomez, David N Burns, Julie McElrath, Julie Ledgerwood, Barney S Graham, John R Mascola, Myron Cohen, Lawrence Corey
Background: Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. Methods: The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa...
January 2017: Statistical Communications in Infectious Diseases
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