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https://www.readbyqxmd.com/read/28727817/immunogenicity-of-a-novel-clade-b-hiv-1-vaccine-combination-results-of-phase-1-randomized-placebo-controlled-trial-of-an-hiv-1-gm-csf-expressing-dna-prime-with-a-modified-vaccinia-ankara-vaccine-boost-in-healthy-hiv-1-uninfected-adults
#1
Susan P Buchbinder, Nicole A Grunenberg, Brittany J Sanchez, Kelly E Seaton, Guido Ferrari, M Anthony Moody, Nicole Frahm, David C Montefiori, Christine M Hay, Paul A Goepfert, Lindsey R Baden, Harriet L Robinson, Xuesong Yu, Peter B Gilbert, M Juliana McElrath, Yunda Huang, Georgia D Tomaras
BACKGROUND: A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env. METHODS: Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM_M or DgDgMM_M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively...
2017: PloS One
https://www.readbyqxmd.com/read/28701403/monoclonal-antibodies-derived-from-humans-vaccinated-with-the-rv144-hiv-vaccine-containing-the-hvem-binding-domain-of-herpes-simplex-virus-hsv-glycoprotein-d-neutralize-hsv-infection-mediate-adcc-and-protect-mice-from-ocular-challenge-with-hsv-1
#2
Kening Wang, Georgia D Tomaras, Sinthujan Jegaskanda, M Anthony Moody, Hua-Xin Liao, Kyle Goodman, Phillip W Berman, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Jaranit Kaewkungwal, Barton F Haynes, Jeffrey I Cohen
The RV144 HIV vaccine trial included a recombinant HIV glycoprotein 120 (gp120) construct fused to a small portion of herpes simplex virus (HSV-1) glycoprotein D (gD), such that the first 40 amino acids of gp120 were replaced by the signal sequence and the first 27 amino acids of the mature form of gD. This region of gD contains most of the binding site for HVEM, an HSV receptor important for virus infection of epithelial cells and lymphocytes. RV144 induced antibodies to HIV that were partially protective against infection as well as antibodies to HSV...
July 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28701402/increased-durable-b-cell-and-adcc-responses-associated-with-t-helper-responses-to-hiv-1-envelope-in-macaques-vaccinated-with-gp140-occluded-at-the-cd4-receptor-binding-site
#3
Willy M J M Bogers, Susan W Barnett, Herman Oostermeijer, Ivonne G Nieuwenhuis, Niels Beenhakker, Daniella Mortier, Petra Mooij, Gerrit Koopman, Edmund Remarque, Gregoire Martin, Rachel Pei-Jen Lai, Antu K Dey, Yide Sun, Brian Burke, Guido Ferrari, David Montefiori, Loic Martin, David Davis, Indresh Srivastava, Jonathan L Heeney
Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens for more long lived, efficacious HIV-1 vaccine induced B-cell responses. HIV-1 Env gp140 (native or un-cleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells may result in anergic effects on T-cell recruitment and consequently a lack of strong robust and durable B-memory responses. To test this hypothesis we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3kD CD4 miniprotein mimetic serving to block ligation of gp140 on CD4+T-cells while preserving CD4 inducible (CDi) neutralizing and epitopes targeted by antibody dependent cellular cytotoxic (ADCC) effector responses...
July 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28695547/human-immunodeficiency-virus-promotes-mitochondrial-toxicity
#4
REVIEW
Summer J Rozzi, Valeria Avdoshina, Jerel A Fields, Margarita Trejo, Hoai T Ton, Gerard P Ahern, Italo Mocchetti
Combined antiretroviral therapies (cART) have had remarkable success in reducing morbidity and mortality among patients infected with human immunodeficiency virus (HIV). However, mild forms of HIV-associated neurocognitive disorders (HAND), characterized by loss of synapses, remain. cART may maintain an undetectable HIV RNA load but does not eliminate the expression of viral proteins such as trans-activator of transcription (Tat) and the envelope glycoprotein gp120 in the brain. These two viral proteins are known to promote synaptic simplifications by several mechanisms, including alteration of mitochondrial function and dynamics...
July 10, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28678869/v1v2-specific-complement-activating-serum-igg-as-a-correlate-of-reduced-hiv-1-infection-risk-in-rv144
#5
Lautaro G Perez, David R Martinez, Allan C deCamp, Abraham Pinter, Phillip W Berman, Donald Francis, Faruk Sinangil, Carter Lee, Kelli Greene, Hongmei Gao, Sorachai Nitayaphan, Supachai Rerks-Ngarm, Jaranit Kaewkungwal, Punnee Pitisuttithum, James Tartaglia, Robert J O'Connell, Merlin L Robb, Nelson L Michael, Jerome H Kim, Peter Gilbert, David C Montefiori
Non-neutralizing IgG to the V1V2 loop of HIV-1 gp120 correlates with a decreased risk of HIV-1 infection but the mechanism of protection remains unknown. This V1V2 IgG correlate was identified in RV144 Thai trial vaccine recipients, who were primed with a canarypox vector expressing membrane-bound gp120 (vCP1521) and boosted with vCP1521 plus a mixture gp120 proteins from clade B and clade CRF01_AE (B/E gp120). We sought to determine whether the mechanism of vaccine protection might involve antibody-dependent complement activation...
2017: PloS One
https://www.readbyqxmd.com/read/28667249/conformational-heterogeneity-of-the-hiv-envelope-glycan-shield
#6
Mingjun Yang, Jing Huang, Raphael Simon, Lai-Xi Wang, Alexander D MacKerell
To better understand the conformational properties of the glycan shield covering the surface of the HIV gp120/gp41 envelope (Env) trimer, and how the glycan shield impacts the accessibility of the underlying protein surface, we performed enhanced sampling molecular dynamics (MD) simulations of a model glycosylated HIV Env protein and related systems. Our simulation studies revealed a conformationally heterogeneous glycan shield with a network of glycan-glycan interactions more extensive than those observed to date...
June 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28666874/anti-dengue-virus-activity-of-scytovirin-and-evaluation-of-point-mutation-effects-by-molecular-dynamics-and-binding-free-energy-calculations
#7
Andrei Santos Siqueira, Alex Ranieri Jerônimo Lima, Rafael Conceição de Souza, Alberdan Silva Santos, João Lídio da Silva Gonçalves Vianez Júnior, Evonnildo Costa Gonçalves
The absence of a specific treatment against DENV has led to intensive research into developing strategies for curing the infection. One lectin with high antiviral activity is scytovirin, which was isolated from the cyanobacterium Scytonema varium and has proven activity against HIV and Zaire Ebola Virus. To achieve the results presented here, we tested the affinity of full-length scytovirin, SD1 and SD2 separately, and six SD1 mutants for DENV glycoprotein E carbohydrate by Molecular Dynamics (MD) simulations and binding free energy calculations...
June 27, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28658672/identification-of-a-novel-hiv-1-neutralizing-antibody-from-a-crf07_bc-infected-chinese-donor
#8
Youxiang Sun, Yuanyuan Qiao, Yuanmei Zhu, Huihui Chong, Yuxian He
The identification of human monoclonal antibodies (mAbs) able to neutralize a broad spectrum of primary HIV-1 isolates is highly important for understanding the immune response of HIV-1 infection and developing vaccines and therapeutics. In this study, we isolated a novel human mAb termed Y498 from a phage display antibody library constructed with the PBMC samples of a CRF07_BC-infected Chinese donor whose sera exhibited broadly neutralizing activity. Y498 cross-reacted with diverse Env antigens and neutralized 30% of 70 tested HIV-1 isolates...
June 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636951/structure-of-cc-chemokine-receptor-5-with-a-potent-chemokine-antagonist-reveals-mechanisms-of-chemokine-recognition-and-molecular-mimicry-by-hiv
#9
Yi Zheng, Gye Won Han, Ruben Abagyan, Beili Wu, Raymond C Stevens, Vadim Cherezov, Irina Kufareva, Tracy M Handel
CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc...
June 20, 2017: Immunity
https://www.readbyqxmd.com/read/28634358/hiv-1-gp41-targeting-fusion-inhibitory-peptides-enhance-the-gp120-targeting-protein-mediated-inactivation-of-hiv-1-virions
#10
Qianqian Qi, Qian Wang, Weizao Chen, Lanying Du, Dimiter S Dimitrov, Lu Lu, Shibo Jiang
Protein- or peptide-based viral inactivators are being developed as novel antiviral drugs with improved efficacy, pharmacokinetics and toxicity profiles because they actively inactivate cell-free human immunodeficiency virus type 1 (HIV-1) virions before attachment to host cells. By contrast, most clinically used antiviral drugs must penetrate host cells to inhibit viral replication. In this study, we pre-treated HIV-1 particles with a gp120-targeting bispecific multivalent protein, 2Dm2m or 4Dm2m, in the presence or absence of the gp41-targeting HIV-1 fusion inhibitory peptides enfuvirtide (T20), T2635, or sifuvirtide (SFT)...
June 21, 2017: Emerging Microbes & Infections
https://www.readbyqxmd.com/read/28632942/the-glycans-mediated-mechanism-on-the-interactions-of-gp120-with-cd4-and-antibody-insights-from-molecular-dynamics-simulation
#11
Yan Zhang, Yuzhen Niu, Jia Qi Tian, Xuewei Liu, Xiaojun Yao, Huanxiang Liu
N-linked glycans such as 234 and 276 gp120 glycans are vital components of HIV evasion from humoral immunity and important for HIV-1 neutralization of many broadly neutralizing antibodies (bNAbs). However, it is unknown the action mechanism of two glycans. To investigate the roles of the glycans on the interactions of gp120 with CD4 and antibody, molecular dynamics simulations based on gp120-CD4-8ANC195 complex with 234 and 276 gp120 glycans, 234 gp120 glycan, 276 gp120 glycan and without glycan were performed...
June 20, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28630473/impact-of-antigen-density-on-the-binding-mechanism-of-igg-antibodies
#12
Maya Hadzhieva, Anastas D Pashov, Srinivas Kaveri, Sébastien Lacroix-Desmazes, Hugo Mouquet, Jordan D Dimitrov
The density and distribution pattern of epitopes at the surface of pathogens have a profound impact on immune responses. Although multiple lines of evidence highlight the significance of antigen surface density for antibody binding, a quantitative description of its effect on recognition mechanisms is missing. Here, we analyzed binding kinetics and thermodynamics of six HIV-1 neutralizing antibodies as a function of the surface density of envelope glycoprotein gp120. Antibodies that recognize gp120 with low to moderate binding affinity displayed the most pronounced sensitivity to variation in antigen density, with qualitative and substantial quantitative changes in the energetics of the binding process as revealed by non-equilibrium and equilibrium thermodynamic analyses...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28628526/determinants-of-hiv-1-cd4-independent-brain-adaptation
#13
Madina Shakirzyanova, Xiang-Peng Kong, Cecilia Cheng-Mayer
BACKGROUND: HIV-1 is known to adapt to the local environment in its usage of receptors and it can become CD4 independent in the brain where the receptor is scarce. This adaptation is through amino acid variations, but the patterns of such variation are not yet well understood. Given that infection of long-lived CD4-low and CD4-negative cells in anatomic compartments such as the brain expand cell tropism in vivo and may serve as potential viral reservoirs that pose challenge for HIV eradication, understanding the evolution to CD4-independence and envelope conformation associated with infection in the absence of CD4 will not only broaden our insights into HIV pathogenesis, but may guide functional cure strategies as well...
June 15, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/28620613/evidence-of-divergent-amino-acid-usage-in-comparative-analyses-of-r5-and-x4-associated-hiv-1-vpr-sequences
#14
Gregory C Antell, Will Dampier, Benjamas Aiamkitsumrit, Michael R Nonnemacher, Vanessa Pirrone, Wen Zhong, Katherine Kercher, Shendra Passic, Jean Williams, Yucheng Liu, Tony James, Jeffrey M Jacobson, Zsofia Szep, Brian Wigdahl, Fred C Krebs
Vpr is an HIV-1 accessory protein that plays numerous roles during viral replication, and some of which are cell type dependent. To test the hypothesis that HIV-1 tropism extends beyond the envelope into the vpr gene, studies were performed to identify the associations between coreceptor usage and Vpr variation in HIV-1-infected patients. Colinear HIV-1 Env-V3 and Vpr amino acid sequences were obtained from the LANL HIV-1 sequence database and from well-suppressed patients in the Drexel/Temple Medicine CNS AIDS Research and Eradication Study (CARES) Cohort...
2017: International Journal of Genomics
https://www.readbyqxmd.com/read/28615206/plasticity-and-epitope-exposure-of-the-hiv-1-envelope-trimer
#15
Rebecca L R Powell, Maxim Totrov, Vincenza Itri, Xiaomei Liu, Alisa Fox, Susan Zolla-Pazner
We recently showed that mutations in the HIV-1 Envelope (Env) destabilize the V3 loop, rendering neutralization-resistant viruses sensitive to V3-directed monoclonal antibodies (mAbs). Here we investigated the propagation of this effect on other Env epitopes, with special emphasis on V2 loop exposure. Wildtype JR-FL and 19 mutant JR-FL pseudoviruses were tested for neutralization sensitivity to 21 mAbs specific for epitopes in V2, the CD4 binding site (CD4bs), and the CD4-induced (CD4i) region. Certain glycan mutants, mutations in the gp120 hydrophobic core, and mutations in residues involved in intra-protomer interactions exposed epitopes in the V2i region (overlays the α4β7 integrin binding site) and the V3 crown, suggesting a general destabilization of the distal region of the trimer apex...
June 14, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28615205/intrasubtype-b-hiv-1-superinfection-correlates-with-delayed-neutralizing-antibody-response
#16
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...
June 14, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28593989/pentavalent-hiv-1-vaccine-protects-against-simian-human-immunodeficiency-virus-challenge
#17
Todd Bradley, Justin Pollara, Sampa Santra, Nathan Vandergrift, Srivamshi Pittala, Chris Bailey-Kellogg, Xiaoying Shen, Robert Parks, Derrick Goodman, Amanda Eaton, Harikrishnan Balachandran, Linh V Mach, Kevin O Saunders, Joshua A Weiner, Richard Scearce, Laura L Sutherland, Sanjay Phogat, Jim Tartaglia, Steven G Reed, Shiu-Lok Hu, James F Theis, Abraham Pinter, David C Montefiori, Thomas B Kepler, Kristina K Peachman, Mangala Rao, Nelson L Michael, Todd J Suscovich, Galit Alter, Margaret E Ackerman, M Anthony Moody, Hua-Xin Liao, Georgia Tomaras, Guido Ferrari, Bette T Korber, Barton F Haynes
The RV144 Thai trial HIV-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp120 subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy. Here we design an ALVAC/Pentavalent B/E/E/E/E vaccine to increase the diversity of gp120 motifs in the immunogen to elicit a broader antibody response and enhance protection. We find that immunization of rhesus macaques with the pentavalent vaccine results in protection of 55% of pentavalent-vaccine-immunized macaques from simian-human immunodeficiency virus (SHIV) challenge...
June 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28592540/covalent-linkage-of-hiv-1-trimers-to-synthetic-liposomes-elicits-improved-b-cell-and-antibody-responses
#18
Shridhar Bale, Geraldine Goebrecht, Armando Stano, Richard Wilson, Takayuki Ota, Karen Tran, Jidnyasa Ingale, Michael B Zwick, Richard T Wyatt
We have demonstrated that a liposomal array of well-ordered trimers enhances B cell activation, germinal center formation and the elicitation of tier-2 autologous neutralizing antibodies. Previously, we coupled well-ordered cleavage-independent NFL trimer via their C-terminal poly-histidine tails to nickel-lipids integrated into the lipid bilayer. Despite favorable in vivo effects, concern remains over the potentially longer term in vivo instability of non-covalent linkage of the trimers to the liposomes. Accordingly, we tested both cobalt coupling and covalent linkage of the trimers to the liposomes by reengineering the poly-histidine tail to include a free cysteine on each protomer of model BG505 NFL trimers to allow covalent linkage...
June 7, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28584151/discovery-and-characterization-of-a-novel-cd4-binding-adnectin-with-potent-anti-hiv-activity
#19
David Wensel, Yongnian Sun, Zhufang Li, Sharon Zhang, Caryn Picarillo, Thomas McDonagh, David Fabrizio, Mark Cockett, Mark Krystal, Jonathan Davis
A novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated using in vitro selection. This inhibitor binds to human CD4 with high affinity (3.9 nM) and inhibits viral entry at a step post-CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display, then further optimized for improved anti-viral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad spectrum activity...
June 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28560687/hiv-1-gp120-upregulates-brain-derived-neurotrophic-factor-bdnf-expression-in-bv2-cells-via-the-wnt-%C3%AE-catenin-signaling-pathway
#20
Yongdi Wang, Jinxu Liao, Shao-Jun Tang, Jianhong Shu, Wenping Zhang
HIV-1 gp120 plays a critical role in the pathogenesis of HIV-associated pain, but the underlying molecular mechanisms are incompletely understood. This study aims to determine the effect and possible mechanism of HIV-1 gp120 on BDNF expression in BV2 cells (a murine-derived microglial cell line). We observed that gp120 (10 ng/ml) activated BV2 cells in cultures and upregulated proBDNF/mBDNF. Furthermore, gp120-treated BV2 also accumulated Wnt3a and β-catenin, suggesting the activation of the Wnt/β-catenin pathway...
June 2017: Journal of Molecular Neuroscience: MN
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