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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/28713388/exploiting-natural-cross-reactivity-between-human-immunodeficiency-virus-hiv-1-p17-protein-and-anti-gp41-2f5-antibody-to-induce-hiv-1-neutralizing-responses-in-vivo
#2
Bernard Verrier, Stéphane Paul, Céline Terrat, Liza Bastide, Agathe Ensinas, Capucine Phelip, Blandine Chanut, Laura Bulens-Grassigny, Fabienne Jospin, Christophe Guillon
Anti-p17 antibodies are able to neutralize human immunodeficiency virus (HIV) entry in a mouse model. In this study, we identified a region of sequence similarity between the epitopes of anti-p17 neutralizing antibodies and anti-gp41 neutralizing 2F5 antibody and verified cross-reactivity between p17 and 2F5 in vitro. The p17 sequence was modified to increase sequence identity between the p17 and 2F5 epitopes, which resulted in enhanced cross-reactivity in vitro. Immunogenicity of wild-type and modified p17 was characterized in a rabbit model...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28712768/neutralizing-antibodies-against-a-specific-human-immunodeficiency-virus-gp41-epitope-are-associated-with-long-term-non-progressor-status
#3
Olivier Lucar, Bin Su, Valérie Potard, Assia Samri, Brigitte Autran, Christiane Moog, Patrice Debré, Vincent Vieillard
Antibodies (Abs) play a central role in human immunodeficiency virus (HIV) protection due to their multiple functional inhibitory activities. W614A-3S Abs recognize a specific form of a highly conserved motif of the gp41 envelope protein and can elicit viral neutralization to protect CD4(+) T cells. Here, we describe in detail the neutralizing profile of W614A-3S Abs in untreated long-term non-progressor (LTNP) HIV-infected patients. W614A-3S Abs were detected in 23.5% (16/68) of untreated LTNP patients compared with <5% (5/104) of HIV-1 progressor patients...
July 11, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28700571/open-and-closed-structures-reveal-allostery-and-pliability-in-the-hiv-1-envelope-spike
#4
Gabriel Ozorowski, Jesper Pallesen, Natalia de Val, Dmitry Lyumkis, Christopher A Cottrell, Jonathan L Torres, Jeffrey Copps, Robyn L Stanfield, Albert Cupo, Pavel Pugach, John P Moore, Ian A Wilson, Andrew B Ward
For many enveloped viruses, binding to a receptor(s) on a host cell acts as the first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication. The envelope glycoprotein (Env) trimer on the surface of HIV is responsible for receptor binding and fusion. Although Env can tolerate a high degree of mutation in five variable regions (V1-V5), and also at N-linked glycosylation sites that contribute roughly half the mass of Env, the functional sites for recognition of receptor CD4 and co-receptor CXCR4/CCR5 are conserved and essential for viral fitness...
July 12, 2017: Nature
https://www.readbyqxmd.com/read/28696158/immunization-with-hiv-1-envelope-t20-encoding-dna-vaccines-elicits-cross-clade-neutralizing-antibody-responses
#5
S Stenler, K E Lundin, L Hansen, S Petkov, N Mozafari, M Isaguliants, P Blomberg, C I E Smith, D M Goldenberg, C-H Chang, K Ljungberg, J Hinkula, B Wahren
BACKGROUND: Genetic immunization is expected to induce the expression of antigens in a native form. The encoded peptide epitopes are presented on endogenous MHC molecules, mimicking antigen presentation during a viral infection. We have explored the potential of enfuvirtide (T20), a short HIV peptide with antiviral properties, to enhance immune response to HIV antigens. To generate an expression vector, the T20 sequence was cloned into a conventional plasmid, the novel minicircle construct, and a replicon plasmid...
July 11, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28686629/the-characteristics-of-screening-and-confirmatory-test-results-for-hiv-in-xi-an-china
#6
Linchuan Wang, Kai-Hua Zhou, He-Ping Zhao, Ji-Han Wang, Hai-Chao Zheng, Yan Yu, Wei Chen
OBJECTIVES: Individuals with recent or acute HIV infection are more infectious than those with established infection. Our objective was to analyze the characteristics of detection among HIV infections in Xi'an. METHODS: A 4th-generation kit (Architect HIV Ag/Ab Combo) and three 3rd-generationEIA kits (WanTai, XinChuang and Livzon) were used for HIV screening. Overall, 665 individuals were identified as positive and were tested by western blotting (WB). The characteristics of the screening and confirmatory tests were analyzed, including the band patterns, the early detection performance and the false-positive rates...
2017: PloS One
https://www.readbyqxmd.com/read/28671952/differences-in-serum-iga-responses-to-hiv-1-gp41-in-elite-controllers-compared-to-viral-suppressors-on-highly-active-antiretroviral-therapy
#7
Rafiq Nabi, Zina Moldoveanu, Qing Wei, Elizabeth T Golub, Helen G Durkin, Ruth M Greenblatt, Betsy C Herold, Marek J Nowicki, Seble Kassaye, Michael W Cho, Abraham Pinter, Alan L Landay, Jiri Mestecky, Pamela A Kozlowski
Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC) and viremic noncontrollers (HN) on highly active antiretroviral therapy (HAART). Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays...
2017: PloS One
https://www.readbyqxmd.com/read/28667249/conformational-heterogeneity-of-the-hiv-envelope-glycan-shield
#8
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/28659478/enfuvirtide-t20-based-lipopeptide-is-a-potent-hiv-1-cell-fusion-inhibitor-implication-for-viral-entry-and-inhibition
#9
Xiaohui Ding, Xiujuan Zhang, Huihui Chong, Yuanmei Zhu, Huamian Wei, Xiyuan Wu, Jinsheng He, Xinquan Wang, Yuxian He
The peptide drug Enfuvirtide (T20) is the only viral fusion inhibitor used in combination therapy of HIV-1 infection, but it has a relatively low antiviral activity and easily induces drug-resistance. Emerging studies demonstrate that lipopeptide-based fusion inhibitors have greatly improved antiviral potency and in vivo stability, such as LP-11 and LP-19 that mainly target the gp41 pocket site. In this study, we focused on developing a T20-based lipopeptide inhibitor that lacks pocket-binding sequence and targets a different site...
June 28, 2017: Journal of Virology
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/28590477/evaluation-of-ligand-based-nmr-screening-methods-to-characterize-small-molecule-binding-to-hiv-1-glycoprotein-41
#11
Shidong Chu, Guangyan Zhou, Miriam Gochin
Small molecule inhibitors of glycoprotein-41 (gp41) are able to prevent HIV infection by binding to a hydrophobic pocket (HP) contained within the gp41 ectodomain, and preventing progression of fusion. There is little structural information on gp41-ligand complexes, owing to hydrophobicity of the ligands, occlusion of the HP in folded gp41 ectodomain, and failure to form crystals of complexes. Here we used an engineered gp41 ectodomain protein containing an exposed HP and a small molecule designed to bind with weak affinity to the HP...
June 28, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28579616/enhancement-of-endocytic-uptake-of-hiv-1-virions-into-cd4-negative-epithelial-cells-by-hiv-1-gp41-via-its-interaction-with-pob1
#12
Yue Tan, Junyi Wang, Shan Su, Qian Wang, Shibo Jiang, Lu Lu, Ying-Hua Chen
No abstract text is available yet for this article.
June 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28561588/protein-domain-mimics-as-modulators-of-protein-protein-interactions
#13
Nicholas Sawyer, Andrew M Watkins, Paramjit S Arora
Protein-protein interactions (PPIs) are ubiquitous in biological systems and often misregulated in disease. As such, specific PPI modulators are desirable to unravel complex PPI pathways and expand the number of druggable targets available for therapeutic intervention. However, the large size and relative flatness of PPI interfaces make them challenging molecular targets. This Account describes our systematic approach using secondary and tertiary protein domain mimics (PDMs) to specifically modulate PPIs. Our strategy focuses on mimicry of regular secondary and tertiary structure elements from one of the PPI partners to inspire rational PDM design...
May 31, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28545817/pre-screening-of-crude-peptides-in-a-serological-bead-based-suspension-array
#14
Tinka Jelsma, Fimme J van der Wal, Helmi Fijten, Nicolas Dailly, Evert van Dijk, Willie L Loeffen
Most serological assays detect antibody responses in biological samples through affinity of serum antibodies for antigens provided in the assay. Certain antigens, however, may be difficult to produce and/or may contain unwanted epitopes. In these cases, a practical alternative may be the use of peptides as representatives for specific epitopes. Peptides can be obtained after purification in large quantities for a modest price, but screening of a large set of peptides during development may be relatively expensive...
May 22, 2017: Journal of Virological Methods
https://www.readbyqxmd.com/read/28521215/adaptation-of-hiv-1-to-cells-with-low-expression-of-the-ccr5-coreceptor
#15
Nicole Espy, Beatriz Pacheco, Joseph Sodroski
The binding of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer ((gp120/gp41)3) to the receptors CD4 and CCR5 triggers virus entry into host cells. To identify Env regions that respond to CCR5 binding, HIV-1 was serially passaged on a CD4-positive canine cell line expressing progressively lower levels of CCR5. HIV-1 replication was observed in cells expressing ~1300 CCR5 molecules/cell. Env changes that conferred this low-CCR5 replication phenotype were located outside of the known CCR5-binding region of the gp120 Env subunit and did not apparently increase CCR5 binding affinity...
August 2017: Virology
https://www.readbyqxmd.com/read/28514686/glycine-substitution-at-helix-to-coil-transitions-facilitates-the-structural-determination-of-a-stabilized-subtype-c-hiv-envelope-glycoprotein
#16
Javier Guenaga, Fernando Garces, Natalia de Val, Robyn L Stanfield, Viktoriya Dubrovskaya, Brett Higgins, Barbara Carrette, Andrew B Ward, Ian A Wilson, Richard T Wyatt
Advances in HIV-1 envelope glycoprotein (Env) design generate native-like trimers and high-resolution clade A, B, and G structures and elicit neutralizing antibodies. However, a high-resolution clade C structure is critical, as this subtype accounts for the majority of HIV infections worldwide, but well-ordered clade C Env trimers are more challenging to produce due to their instability. Based on targeted glycine substitutions in the Env fusion machinery, we defined a general approach that disfavors helical transitions leading to post-fusion conformations, thereby favoring the pre-fusion state...
May 16, 2017: Immunity
https://www.readbyqxmd.com/read/28503119/targeting-hiv-1-envelope-proteins-using-a-fragment-discovery-all-atom-computational-algorithm
#17
Michael H Peters
INTRODUCTION: HIV viral envelope proteins are targets for small inhibitor molecules aimed at disrupting the cellular entry process. Potential peptide-class inhibitor molecules (rDNA drugs) have been previously identified, with mixed results, through biomimicry and phage display experimental methods. Here we describe a new approach based on computational fragment discovery. The method has the potential to not only optimize peptide binding affinity but also to rapidly produce alternative inhibitors against mutated strains...
April 2017: Current Enzyme Inhibition
https://www.readbyqxmd.com/read/28484468/the-membrane-proximal-region-of-c-c-chemokine-receptor-type-5-participates-in-the-infection-of-hiv-1
#18
Yue Tan, Pei Tong, Junyi Wang, Lei Zhao, Jing Li, Yang Yu, Ying-Hua Chen, Ji Wang
The initial infection and transmission of HIV-1 requires C-C chemokine receptor type 5 (CCR5). Here, we report that the membrane-proximal region (MPR, aa 22-38) of CCR5 participates in the infection of HIV-1. First, MPR-specific antibodies elicited in mice dose-dependently inhibited the infection of CCR5-tropic HIV-1. Second, substituting MPR with the same region from other co-receptors significantly impaired HIV-1 infection, while the key residues identified by alanine scanning mutagenesis formed an exposed leucine zipper-like structure...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28472629/an-in-vitro-model-to-mimic-selection-of-replication-competent-hiv-1-intersubtype-recombination-in-dual-or-superinfected-patients
#19
Bernard S Bagaya, Meijuan Tian, Gabrielle C Nickel, José F Vega, Yuejin Li, Ping He, Katja Klein, Jamie F S Mann, Wei Jiang, Eric J Arts, Yong Gao
The low frequency of HIV-1 recombinants within entire viral populations in both individual patients and culture-based infection models impedes investigation of the underlying factors contributing to either the occurrence of recombinants or the survival of recombinants once they are formed. So far, most of the related studies have no consideration of recombinants' functionality. Here, we established a functional recombinant production (FRP) system to produce pure and functional HIV-1 intersubtype Env recombinants and utilized 454 pyrosequencing to investigate the distribution of over 4000 functional and non-functional recombination breakpoints from either the FRP system or dual infection cultures...
July 7, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28458036/a-heterologous-prime-boosting-strategy-with-replicating-vaccinia-virus-vectors-and-plant-produced-hiv-1-gag-dgp41-virus-like-particles
#20
Lydia R Meador, Sarah A Kessans, Jacquelyn Kilbourne, Karen V Kibler, Giuseppe Pantaleo, Mariano Esteban Roderiguez, Joseph N Blattman, Bertram L Jacobs, Tsafrir S Mor
Showing modest efficacy, the RV144 HIV-1 vaccine clinical trial utilized a non-replicating canarypox viral vector and a soluble gp120 protein boost. Here we built upon the RV144 strategy by developing a novel combination of a replicating, but highly-attenuated Vaccinia virus vector, NYVAC-KC, and plant-produced HIV-1 virus-like particles (VLPs). Both components contained the full-length Gag and a membrane anchored truncated gp41 presenting the membrane proximal external region with its conserved broadly neutralizing epitopes in the pre-fusion conformation...
July 2017: Virology
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