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https://www.readbyqxmd.com/read/29785023/hiv-vaccine-candidate-activation-of-hypoxia-and-the-inflammasome-in-cd14-monocytes-is-associated-with-a-decreased-risk-of-siv-mac251-acquisition
#1
Monica Vaccari, Slim Fourati, Shari N Gordon, Dallas R Brown, Massimilano Bissa, Luca Schifanella, Isabela Silva de Castro, Melvin N Doster, Veronica Galli, Maria Omsland, Dai Fujikawa, Giacomo Gorini, Namal P M Liyanage, Hung V Trinh, Katherine M McKinnon, Kathryn E Foulds, Brandon F Keele, Mario Roederer, Richard A Koup, Xiaoying Shen, Georgia D Tomaras, Marcus P Wong, Karissa J Munoz, Johannes S Gach, Donald N Forthal, David C Montefiori, David J Venzon, Barbara K Felber, Margherita Rosati, George N Pavlakis, Mangala Rao, Rafick-Pierre Sekaly, Genoveffa Franchini
Qualitative differences in the innate and adaptive responses elicited by different HIV vaccine candidates have not been thoroughly investigated. We tested the ability of the Aventis Pasteur live recombinant canarypox vector (ALVAC)-SIV, DNA-SIV and Ad26-SIV vaccine prime modalities together with two ALVAC-SIV + gp120 protein boosts to reduce the risk of SIVmac251 acquisition in rhesus macaques. We found that the DNA and ALVAC prime regimens were effective, but the Ad26 prime was not. The activation of hypoxia and the inflammasome in CD14+ CD16- monocytes, gut-homing CCR5-negative CD4+ T helper 2 (TH 2) cells and antibodies to variable region 2 correlated with a decreased risk of SIVmac251 acquisition...
May 21, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29775175/hiv-induced-matrix-metalloproteinase-9-activation-through-mitogen-activated-protein-kinase-signalling-promotes-hsv-1-cell-to-cell-spread-in-oral-epithelial-cells
#2
Irna Sufiawati, Sharof M Tugizov
We have shown that cell-free HIV-1 and viral proteins tat and gp120 activate mitogen-activated protein kinases (MAPKs) in tonsil epithelial cells, disrupting their tight and adherens junctions. This causes liberation of the HSV-1 receptor nectin-1 from assembled adherens junctions, leading to promotion of HSV-1 infection and spread. In the present study, we show that HIV-associated activation of MAPK leads to upregulation of transcription factor NF-κB and matrix metalloproteinase-9 (MMP-9). This induces the disruption of tight and adherens junctions, increasing HSV-1 cell-to-cell spread...
May 18, 2018: Journal of General Virology
https://www.readbyqxmd.com/read/29773895/crispr-cas9-system-targeting-regulatory-genes-of-hiv-1-inhibits-viral-replication-in-infected-t-cell-cultures
#3
Youdiil Ophinni, Mari Inoue, Tomohiro Kotaki, Masanori Kameoka
The CRISPR/Cas9 system provides a novel and promising tool for editing the HIV-1 proviral genome. We designed RNA-guided CRISPR/Cas9 targeting the HIV-1 regulatory genes tat and rev with guide RNAs (gRNA) selected from each gene based on CRISPR specificity and sequence conservation across six major HIV-1 subtypes. Each gRNA was cloned into lentiCRISPRv2 before co-transfection to create a lentiviral vector and transduction into target cells. CRISPR/Cas9 transduction into 293 T and HeLa cells stably expressing Tat and Rev proteins successfully abolished the expression of each protein relative to that in non-transduced and gRNA-absent vector-transduced cells...
May 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29772712/inhibition-of-human-immunodeficiency-virus-type-1-entry-by-a-keggin-polyoxometalate
#4
Xiaoli Wang, Jiao Wang, Wenmei Zhang, Boye Li, Ying Zhu, Qin Hu, Yishu Yang, Xiaoguang Zhang, Hong Yan, Yi Zeng
Here, we report the anti-human immunodeficiency virus (HIV) potency and underlying mechanisms of a Keggin polyoxometalate (PT-1, K₆HPTi₂W10 O40 ). Our findings showed that PT-1 exhibited highly potent effects against a diverse group of HIV type 1 (HIV-1) strains and displayed low cytotoxicity and genotoxicity. The time-addition assay revealed that PT-1 acted at an early stage of infection, and these findings were supported by the observation that PT-1 had more potency against Env-pseudotyped virus than vesicular stomatitis virus glycoprotein (VSVG) pseudotyped virus...
May 16, 2018: Viruses
https://www.readbyqxmd.com/read/29772652/gp120-v5-is-targeted-by-the-first-wave-of-sequential-neutralizing-antibodies-in-shiv-sf162p3n-infected-rhesus-macaques
#5
Manxue Jia, Hong Lu, Xiang-Peng Kong, Cecilia Cheng-Mayer, Xueling Wu
Simian-human immunodeficiency virus (SHIV) infection provides a relevant animal model to study HIV-1 neutralization breadth. With previously identified SHIVSF162P3N infected rhesus macaques that did or did not develop neutralization breadth, we characterized the transmitted/founder viruses and initial autologous/homologous neutralizing antibodies in these animals. The plasma viral load and blood CD4 count did not distinguish macaques with and without breadth, and only one tested homologous envelope clone revealed a trend for macaques with breadth to favor an early homologous response...
May 16, 2018: Viruses
https://www.readbyqxmd.com/read/29772059/the-orphan-g-protein-coupled-receptor-75-signaling-is-activated-by-the-chemokine-ccl5
#6
Simona Dedoni, Lee A Campbell, Brandon K Harvey, Valeria Avdoshina, Italo Mocchetti
The chemokine CCL5 prevents neuronal cell death mediated both by amyloid β, as well as the human immunodeficiency virus (HIV) viral proteins gp120 and Tat. Because CCL5 binds to CCR5, CCR3 and/or CCR1 receptors, it is unclear which of these receptors plays a role in neuroprotection. Indeed, CCL5 also has neuroprotective activity in cells lacking these receptors. CCL5 may bind to a G protein-coupled receptor 75 (GPR75), which encodes for a 540 amino-acid orphan receptor of the Gqα family. In this study, we have used SH-SY5Y human neuroblastoma cells to characterize whether CCL5 could activate a Gq signaling through GPR75...
May 17, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29767965/bifunctional-chimera-that-coordinately-targets-human-immunodeficiency-virus-1-hiv-1-envelope-gp120-and-host-cell-ccr5-co-receptor-at-the-virus-cell-interface
#7
Adel A Rashad, Li-Rui Song, Andrew P Holmes, Kriti Acharya, Shiyu Zhang, Zhi-Long Wang, Ebony Gary, Xin Xie, Vanessa Pirrone, Michele A Kutzler, Ya-Qiu Long, Irwin Chaiken
To address the urgent need for new agents to reduce the global occurrence and spread of AIDS, we investigated the underlying hypothesis that antagonists of HIV-1 Envelope (Env) gp120 and host cell co-receptor (CoR) proteins can be covalently joined into bifunctional synergistic combinations that will improve antiviral. A synthetic protocol was established to covalently combine a CCR5 small molecule antagonist and a gp120 peptide triazole antagonist to form the bifunctional chimera. Importantly, the chimeric inhibitor preserved the specific targeting properties of the two separate chimera components, and at the same time exhibited low to sub-nanomolar potencies, in inhibiting cell infection by different pseudoviruses, that were substantially greater than those of a non-covalent mixture of individual components...
May 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29746590/structural-and-immunologic-correlates-of-chemically-stabilized-hiv-1-envelope-glycoproteins
#8
Torben Schiffner, Jesper Pallesen, Rebecca A Russell, Jonathan Dodd, Natalia de Val, Celia C LaBranche, David Montefiori, Georgia D Tomaras, Xiaoying Shen, Scarlett L Harris, Amin E Moghaddam, Oleksandr Kalyuzhniy, Rogier W Sanders, Laura E McCoy, John P Moore, Andrew B Ward, Quentin J Sattentau
Inducing broad spectrum neutralizing antibodies against challenging pathogens such as HIV-1 is a major vaccine design goal, but may be hindered by conformational instability within viral envelope glycoproteins (Env). Chemical cross-linking is widely used for vaccine antigen stabilization, but how this process affects structure, antigenicity and immunogenicity is poorly understood and its use remains entirely empirical. We have solved the first cryo-EM structure of a cross-linked vaccine antigen. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a CD4 binding site-specific broadly neutralizing antibody (bNAb) Fab fragment reveals how cross-linking affects key properties of the trimer...
May 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29743357/the-antiviral-activity-of-the-cellular-glycoprotein-lgals3bp-90k-is-species-specific
#9
Veronika Lodermeyer, George Ssebyatika, Vânia Passos, Aparna Ponnurangam, Angelina Malassa, Ellen Ewald, Christina M Stürzel, Frank Kirchhoff, Margalida Rotger, Christine S Falk, Amalio Telenti, Thomas Krey, Christine Goffinet
Cellular antiviral proteins interfere with distinct steps of replication cycles of viruses. The galectin 3 binding protein (LGALS3BP, also known as 90K) was previously shown to lower the infectivity of nascent HIV-1 virions when expressed in virus-producing cells. This antiviral effect was accompanied by impaired gp160Env processing and reduced viral incorporation of mature Env glycoproteins. Here, we examined the ability of 90K orthologs from primate species to reduce particle infectivity of distinct lentiviruses...
May 9, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29738673/top-down-chemoenzymatic-approach-to-synthesizing-diverse-high-mannose-n-glycans-and-related-neoglycoproteins-for-carbohydrate-microarray-analysis
#10
Christian Toonstra, Lisa Wu, Chao Li, Denong Wang, Lai-Xi Wang
High mannose type N-glycans are an important component of neutralizing epitopes on HIV-1 envelope glycoprotein gp120. They also serve as signals for protein folding, trafficking, and degradation in protein quality control. A number of lectins and antibodies recognize high-mannose type N-glycans, and glycan array technology has provided an avenue to probing these oligomannose-specific proteins. We describe in this paper a top-down chemoenzymatic approach to synthesizing a library of high-mannose N-glycans and related neoglycoproteins for glycan microarray analysis...
May 8, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29738662/characterization-of-a-sulfated-anti-hiv-antibody-using-an-expanded-genetic-code
#11
Xiang Li, Justin Hitomi, Chang C Liu
Tyrosine sulfation is a crucial post-translational modification for certain anti-HIV antibodies that neutralize HIV. One of the most neutralizing sulfated anti-HIV antibodies, E51, contains a region in its VH CDR3 loop with five tyrosine (Tyr) residues, which are hypothesized to be partially or fully sulfated to bind to HIV's gp120 coat protein. However, the gp120-binding contribution of each sulfate or more complex sulfation patterns is unclearunknown. In addition, natural sulfation of Tyr-rich loops usually yields a mixture of multiply sulfated products, complicating attempts to dissect the function of individual E51 sulfoforms with unique sulfation patterns...
May 8, 2018: Biochemistry
https://www.readbyqxmd.com/read/29731169/identification-of-near-pan-neutralizing-antibodies-against-hiv-1-by-deconvolution-of-plasma-humoral-responses
#12
Mohammad Mohseni Sajadi, Amir Dashti, Zahra Rikhtegaran Tehrani, William D Tolbert, Michael S Seaman, Xin Ouyang, Neelakshi Gohain, Marzena Pazgier, Dongkyoon Kim, Guy Cavet, Jean Yared, Robert R Redfield, George K Lewis, Anthony L DeVico
Anti-HIV-1 envelope broadly neutralizing monoclonal antibodies (bNAbs) isolated from memory B cells may not fully represent HIV-1-neutralizing profiles measured in plasma. Accordingly, we characterized near-pan-neutralizing antibodies extracted directly from the plasma of two "elite neutralizers." Circulating anti-gp120 polyclonal antibodies were deconvoluted using proteomics to guide lineage analysis of bone marrow plasma cells. In both subjects, a single lineage of anti-CD4-binding site (CD4bs) antibodies explained the plasma-neutralizing activity...
April 28, 2018: Cell
https://www.readbyqxmd.com/read/29729526/characterization-of-twin-cysteine-motif-in-the-v2-loop-region-of-gp120-in-primate-lentiviruses
#13
Dane Bowder, Jesse Thompson, Kate Durst, Haley Hollingsead, Duoyi Hu, Wenzhong Wei, Shi-Hua Xiang
The twin-cysteine motif (TCM) in the V2 loop region of gp120, identified in our previous report on the simian immunodeficiency virus mac239 (SIVmac239), is a conserved evolutionary element in all primate lentiviruses except for HIV-1 which has lost the TCM during cross-species transmission. In this study, we have further explored the TCM in other SIV and HIV-2 strains. Our data shows that strains from different evolutionary lineages have different phenotypes when the twin-cysteines are removed. In the SIVsm/HIV-2 lineage, removal of the twin-cysteines decreases envelope trimer stability, but in the SIVagm lineage, a blockage of gp160 processing is observed...
May 2, 2018: Virology
https://www.readbyqxmd.com/read/29729322/methamphetamine-augment-hiv-1-tat-mediated-memory-deficits-by-altering-the-expression-of-synaptic-proteins-and-neurotrophic-factors
#14
Anantha Ram Nookala, Daniel C Schwartz, Nitish S Chaudhari, Alexy Glazyrin, Edward B Stephens, Nancy E J Berman, Anil Kumar
Methamphetamine (METH) abuse is common among individuals infected with HIV-1 and has been shown to affect HIV replication and pathogenesis. These HIV-1 infected individuals also exhibit greater neuronal injury and higher cognitive decline. HIV-1 proteins, specifically gp120 and HIV-1 Tat, have been earlier shown to affect neurocognition. HIV-1 Tat, a viral protein released early during HIV-1 replication, contributes to HIV-associated neurotoxicity through various mechanisms including production of pro-inflammatory cytokines, reactive oxygen species and dysregulation of neuroplasticity...
May 2, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29729309/hiv-glycoprotein-gp120-enhances-mesenchymal-stem-cell-migration-by-upregulating-cxcr4-expression
#15
Lei Li, Ryan Z L Lim, Lawrence S U Lee, Nicholas S Y Chew
BACKGROUND: HIV infection and/or the direct pathogenic effects of circulating HIV proteins impairs the physiological function of mesenchymal stem cells (MSCs), and contribute to the pathogenesis of age-related clinical comorbidities in people living with HIV. The SDF-1/CXCR4 pathway is vital for modulating MSC proliferation, migration and differentiation. HIV glycoprotein gp120 inhibits SDF-1 induced chemotaxis by downregulating the expression and function of CXCR4 in monocytes, B and T cells...
May 2, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29726564/sulfonate-ended-carbosilane-dendrimers-with-a-flexible-scaffold-cause-inactivation-of-hiv-1-virions-and-gp120-shedding
#16
Daniel Sepúlveda-Crespo, Francisco J de la Mata, Rafael Gómez, Mª A Muñoz-Fernández
Infection with human immunodeficiency virus type 1 (HIV-1) continues to be a global public health issue, especially in low-resource countries. Sexual transmission is responsible for the majority of HIV-1 infections worldwide. Women are more susceptible to HIV-1 acquisition than men and represent nearly 50% of the HIV-infected population. Topical vaginal microbicides that act at the earlier stages of infection offer a prevention strategy to reduce the acquisition of HIV-1. Dendrimers are nano-sized, radially symmetric molecules with a well-defined and monodisperse structure consisting of tree-like arms or branches...
May 4, 2018: Nanoscale
https://www.readbyqxmd.com/read/29720517/antiviral-activity-of-hiv-gp120-targeting-bispecific-t-cell-engager-bite%C3%A2-antibody-constructs
#17
Johannes Brozy, Erika Schlaepfer, Christina K S Mueller, Mary-Aude Rochat, Silvana K Rampini, Renier Myburgh, Tobias Raum, Peter Kufer, Patrick A Baeuerle, Markus Muenz, Roberto F Speck
Today's gold standard in HIV therapy is the combined antiretroviral therapy (cART). It requires strict adherence by patients and life-long medication, which can lower the viral load below detection limits and prevent HIV-associated immunodeficiency, but cannot cure patients. The bispecific T cell engaging (BiTE®) antibody technology has demonstrated long-term relapse-free outcomes in patients with relapsed and refractory acute lymphocytic leukemia. We here generated BiTE® antibody constructs that target the HIV-1 envelope protein gp120 (HIV gp120) using either the scFv B12 or VRC01, the first two extracellular domains (1+2) of human CD4 alone or joined to the single chain variable fragment (scFv) of the antibody 17b fused to an anti-human CD3ϵ scFv...
May 2, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29718999/glycoengineering-hiv-1-env-creates-supercharged-and-hybrid-glycans-to-increase-neutralizing-antibody-potency-breadth-and-saturation
#18
Ema T Crooks, Samantha L Grimley, Michelle Cully, Keiko Osawa, Gillian Dekkers, Kevin Saunders, Sebastian Rӓmisch, Sergey Menis, William R Schief, Nicole Doria-Rose, Barton Haynes, Ben Murrell, Evan Mitchel Cale, Amarendra Pegu, John R Mascola, Gestur Vidarsson, James M Binley
The extensive glycosylation of HIV-1 envelope (Env) glycoprotein leaves few glycan-free holes large enough to admit broadly neutralizing antibodies (bnAb). Consequently, most bnAbs must inevitably make some glycan contacts and avoid clashes with others. To investigate how Env glycan maturation regulates HIV sensitivity to bnAbs, we modified HIV-1 pseudovirus (PV) using various glycoengineering (GE) tools. Promoting the maturation of α-2,6 sialic acid (SA) glycan termini increased PV sensitivity to two bnAbs that target the V2 apex and one to the interface between Env surface gp120 and transmembrane gp41 subunits, typically by up to 30-fold...
May 2, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29702672/characterization-of-hiv-1-gp120-antibody-specificities-induced-in-anogenital-secretions-of-rv144-vaccine-recipients-after-late-boost-immunizations
#19
Siriwat Akapirat, Chitraporn Karnasuta, Sandhya Vasan, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sirinan Madnote, Hathairat Savadsuk, Surawach Rittiroongrad, Jiraporn Puangkaew, Sanjay Phogat, James Tartaglia, Faruk Sinangil, Mark S de Souza, Jean-Louis Excler, Jerome H Kim, Merlin L Robb, Nelson L Michael, Viseth Ngauy, Robert J O'Connell, Nicos Karasavvas
Sexual transmission is the principal driver of the human immunodeficiency virus (HIV) pandemic. Understanding HIV vaccine-induced immune responses at mucosal surfaces can generate hypotheses regarding mechanisms of protection, and may influence vaccine development. The RV144 (ClinicalTrials.gov NCT00223080) efficacy trial showed protection against HIV infections but mucosal samples were not collected, therefore, the contribution of mucosal antibodies to preventing HIV-1 acquisition is unknown. Here, we report the generation, magnitude and persistence of antibody responses to recombinant gp120 envelope and antigens including variable one and two loop scaffold antigens (gp70V1V2) previously shown to correlate with risk in RV144...
2018: PloS One
https://www.readbyqxmd.com/read/29698406/generation-and-characterization-of-a-bivalent-protein-boost-for-future-clinical-trials-hiv-1-subtypes-cr01_ae-and-b-gp120-antigens-with-a-potent-adjuvant
#20
Yingxia Wen, Hung V Trinh, Christine E Linton, Chiara Tani, Nathalie Norais, DeeAnn Martinez-Guzman, Priyanka Ramesh, Yide Sun, Frank Situ, Selen Karaca-Griffin, Christopher Hamlin, Sayali Onkar, Sai Tian, Susan Hilt, Padma Malyala, Rushit Lodaya, Ning Li, Gillis Otten, Giuseppe Palladino, Kristian Friedrich, Yukti Aggarwal, Celia LaBranche, Ryan Duffy, Xiaoying Shen, Georgia D Tomaras, David C Montefiori, William Fulp, Raphael Gottardo, Brian Burke, Jeffrey B Ulmer, Susan Zolla-Pazner, Hua-Xin Liao, Barton F Haynes, Nelson L Michael, Jerome H Kim, Mangala Rao, Robert J O'Connell, Andrea Carfi, Susan W Barnett
The RV144 Phase III clinical trial with ALVAC-HIV prime and AIDSVAX B/E subtypes CRF01_AE (A244) and B (MN) gp120 boost vaccine regime in Thailand provided a foundation for the future development of improved vaccine strategies that may afford protection against the human immunodeficiency virus type 1 (HIV-1). Results from this trial showed that immune responses directed against specific regions V1V2 of the viral envelope (Env) glycoprotein gp120 of HIV-1, were inversely correlated to the risk of HIV-1 infection...
2018: PloS One
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