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https://www.readbyqxmd.com/read/28521215/adaptation-of-hiv-1-to-cells-with-low-expression-of-the-ccr5-coreceptor
#1
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...
May 15, 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
#2
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
#3
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
#4
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
#5
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 in culture-based infection models impedes investigation of the underlying factors contributing either to 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 4,000 functional and non-functional recombination breakpoints from either the FRP system or dual infection cultures...
May 1, 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
#6
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...
April 27, 2017: Virology
https://www.readbyqxmd.com/read/28448574/fusion-expression-of-occludin-extracellular-loops-and-an-%C3%AE-helical-bundle-a-new-research-model-for-tight-junction
#7
Xiaojing Chi, Xia Zhao, Wei Wang, Yuqiang Niu, Min Cheng, Xiuying Liu, Sheng Cui, Wei Yang
Tight junctions (TJs) are the outermost structures of intercellular junctions and are highly specialized membrane domains involved in many important cellular processes. However, most TJ proteins are four-time transmembrane proteins and are difficult to express in their correct soluble form, which limits their functional study and therapeutic application. Human occludin (OCLN) is a major component of TJs and an essential co-receptor for hepatitis C virus (HCV) cell entry. To explore expression strategy for recombinant TJ proteins possessing integrated and functional extracellular loops, OCLN was here used as a model molecule, and several prokaryotic fusion constructs were designed by docking OCLN extracellular loops (ECLs) to HIV-1 gp41 NHR and CHR six-helical bundle (6HV1); then their biophysical features and anti-HCV activity were evaluated...
2017: PloS One
https://www.readbyqxmd.com/read/28422789/antigp41-membrane-proximal-external-region-antibodies-and-the-art-of-using-the-membrane-for-neutralization
#8
Nichole Cerutti, Juan Luis Loredo-Varela, Christophe Caillat, Winfried Weissenhorn
PURPOSE OF REVIEW: We summarize the latest research on the progress to understand the neutralizing epitopes present within the membrane proximal external region (MPER) of the HIV-1 fusion protein subunit gp41. RECENT FINDINGS: The HIV-1 fusion protein subunit gp41 contains a highly conserved sequence that is essential for membrane fusion and targeted by broadly neutralizing antibodies such as 2F5, 4E10, Z13e1, and 10E8. These antibodies recognize a linear gp41 epitope with high affinity, but require additional hydrophobic sequences present in their heavy chain CDR3 for neutralization...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28402882/gating-charge-calculations-by-computational-electrophysiology-simulations
#9
Jan-Philipp Machtens, Rodolfo Briones, Claudia Alleva, Bert L de Groot, Christoph Fahlke
Electrical cell signaling requires adjustment of ion channel, receptor, or transporter function in response to changes in membrane potential. For the majority of such membrane proteins, the molecular details of voltage sensing remain insufficiently understood. Here, we present a molecular dynamics simulation-based method to determine the underlying charge movement across the membrane-the gating charge-by measuring electrical capacitor properties of membrane-embedded proteins. We illustrate the approach by calculating the charge transfer upon membrane insertion of the HIV gp41 fusion peptide, and validate the method on two prototypical voltage-dependent proteins, the Kv1...
April 11, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28396421/antigenicity-defined-conformations-of-an-extremely-neutralization-resistant-hiv-1-envelope-spike
#10
Yongfei Cai, Selen Karaca-Griffin, Jia Chen, Sai Tian, Nicholas Fredette, Christine E Linton, Sophia Rits-Volloch, Jianming Lu, Kshitij Wagh, James Theiler, Bette Korber, Michael S Seaman, Stephen C Harrison, Andrea Carfi, Bing Chen
The extraordinary genetic diversity of the HIV-1 envelope spike [Env; trimeric (gp160)3, cleaved to (gp120/gp41)3] poses challenges for vaccine development. Envs of different clinical isolates exhibit different sensitivities to antibody-mediated neutralization. Envs of difficult-to-neutralize viruses are thought to be more stable and conformationally homogeneous trimers than those of easy-to-neutralize viruses, thereby providing more effective concealment of conserved, functionally critical sites. In this study we have characterized the antigenic properties of an Env derived from one of the most neutralization-resistant HIV-1 isolates, CH120...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28392143/development-of-a-dna-vaccine-expressing-a-secreted-hiv-1-gp41-ectodomain-that-includes-the-membrane-proximal-external-region
#11
Luca Melnychuk, Lara Ajamian, Patrick Jean-Pierre, Jiaming Liang, Romina Gheorghe, Mark A Wainberg, Gerasimos J Zaharatos
A limited number of sites on the HIV-1 Envelope protein are vulnerable to broadly neutralizing antibodies (bnAbs). One of these sites, the membrane proximal external region (MPER), is located at the C-terminus of the gp41 ectodomain (gp41ecto). This highly conserved sequence is bound by several well-characterized bnAbs. Efforts to produce a gp41 immunogen are in part hampered by the MPER's hydrophobicity and propensity to induce aggregation. We sought to produce a DNA vaccine expressing a gp41ecto that is both secreted from mammalian cells and maintains binding by bnAbs to the MPER...
May 9, 2017: Vaccine
https://www.readbyqxmd.com/read/28390972/targeting-cell-surface-hiv-1-env-protein-to-suppress-infectious-virus-formation
#12
Arangassery Rosemary Bastian, Charles G Ang, Kantharaju Kamanna, Farida Shaheen, Yu-Hung Huang, Karyn McFadden, Caitlin Duffy, Lauren D Bailey, Ramalingam Venkat Kalyana Sundaram, Irwin Chaiken
HIV-1 Env protein is essential for host cell entry, and targeting Env remains an important antiretroviral strategy. We previously found that a peptide triazole thiol KR13 and its gold nanoparticle conjugate AuNP-KR13 directly and irreversibly inactivate the virus by targeting the Env protein, leading to virus gp120 shedding, membrane disruption and p24 capsid protein release. Here, we examined the consequences of targeting cell-surface Env with the virus inactivators. We found that both agents led to formation of non-infectious virus from transiently transfected HEK293T cells...
April 6, 2017: Virus Research
https://www.readbyqxmd.com/read/28386076/quantitative-humoral-profiling-of-the-hiv-1-proteome-in-elite-controllers-and-patients-with-very-long-term-efficient-antiretroviral-therapy
#13
Wang Zhang, Mohammed M Morshed, Kajsa Noyan, Aman Russom, Anders Sönnerborg, Ujjwal Neogi
A major challenge in evaluating the success of HIV eradication approaches is the need for accurate measurement of persistent HIV during effective antiretroviral therapy (ART). Previous studies have reported that the anti-HIV antibody assay "luciferase immuno-precipitation systems (LIPS)" can distinguish HIV-infected individuals harboring different sizes of the viral reservoirs. We performed antibody profiling of HIV-1 proteomes using LIPS in viremic progressors (n = 38), elite controllers (ECs; n = 19) and patients with fully suppressive long-term antiretroviral therapy (ART) (n = 19) (mean 17 years)...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28381572/improving-the-expression-and-purification-of-soluble-recombinant-native-like-hiv-1-envelope-glycoprotein-trimers-by-targeted-sequence-changes
#14
Rajesh P Ringe, Gabriel Ozorowski, Anila Yasmeen, Albert Cupo, Victor M Cruz Portillo, Pavel Pugach, Michael Golabek, Kimmo Rantalainen, Lauren G Holden, Christopher A Cottrell, Ian A Wilson, Rogier W Sanders, Andrew B Ward, P J Klasse, John P Moore
Soluble, recombinant native-like envelope glycoprotein (Env) trimers of various human immunodeficiency virus type 1 (HIV-1) genotypes are being developed for structural studies and as vaccine candidates aimed at the induction of broadly neutralizing antibodies (bNAbs). The prototypic design is designated SOSIP.664, but many HIV-1 env genes do not yield fully native-like trimers efficiently. One such env gene is CZA97.012 from a neutralization-resistant (Tier-2) clade C virus. As appropriately purified, native-like CZA97...
April 5, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28375134/report-antibacterial-activity-of-a-peptide-derived-from-hiv-1-mn-strain-gp41-envelope-glycoprotein-against-methicillin-resistant-staphylococcus-aureus
#15
Sin-Yeang Teow, Syed Atif Ali
Peptides derived from HIV-1 transmembrane proteins have been extensively studied for antimicrobial activities, and they are known as antimicrobial peptides (AMPs). These AMPs have also been reported to potently combat the drug-resistant microbes. In this study, we demonstrated that peptide #6383 originated from HIV-1 MN strain membrane-spanning domain of gp41 was active (2-log reductions) at 100βg/mL (56.5βM) against methicillin-resistant Staphylococcus aureus (MRSA) in 10% and 50% human plasma-supplemented phosphate buffered saline (PBS)...
November 2016: Pakistan Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28356533/a-lipopeptide-hiv-1-2-fusion-inhibitor-with-highly-potent-in-vitro-ex-vivo-and-in-vivo-antiviral-activity
#16
Huihui Chong, Jing Xue, Shengwen Xiong, Zhe Cong, Xiaohui Ding, Yuanmei Zhu, Zixuan Liu, Ting Chen, Yifan Feng, Lei He, Yan Guo, Qiang Wei, Yusen Zhou, Chuan Qin, Yuxian He
Peptides derived from the C-terminal heptad repeat (CHR) region of the HIV-1 fusogenic protein gp41 are potent viral entry inhibitors, and currently enfuvirtide (T-20) is the only one for clinical use; however, emerging drug-resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, HIV-2 sequence, intra-helical salt-bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad and long-lasting antiviral activity...
March 29, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28340570/the-therapeutic-hiv-env-c5-gp41-vaccine-candidate-vacc-c5-induces-specific-t-cell-regulation-in-a-phase-i-ii-clinical-study
#17
Kristin Brekke, Maja Sommerfelt, Mats Ökvist, Anne Margarita Dyrhol-Riise, Dag Kvale
BACKGROUND: Levels of non-neutralising antibodies (AB) to the C5 domain of HIV Env gp120 are inversely related to progression of HIV infection. In this phase I/II clinical study we investigated safety of Vacc-C5, a peptide-based therapeutic vaccine candidate corresponding to C5/gp41(732-744) as well as the effects on pre-existing AB levels to C5/gp41(732-744), immune activation and T cell responses including exploratory assessments of Vacc-C5-induced T cell regulation. Our hypothesis was that exposure of the C5 peptide motif may have detrimental effects due to several of its HLA-like features and that enhancement of non-neutralising anti-C5 AB by vaccination could reduce C5 exposure and thereby chronic immune activation...
March 24, 2017: BMC Infectious Diseases
https://www.readbyqxmd.com/read/28300601/functional-contacts-between-mper-and-the-anti-hiv-1-broadly-neutralizing-antibody-4e10-extend-into-the-core-of-the-membrane
#18
Edurne Rujas, Sara Insausti, Miguel García-Porras, Rubén Sánchez-Eugenia, Kouhei Tsumoto, José L Nieva, Jose M M Caaveiro
The exceptional breadth of broadly neutralizing antibodies (bNAbs) against the membrane-proximal external region (MPER) of the transmembrane protein gp41 makes this class of antibodies an ideal model to design HIV vaccines. From a practical point of view, however, the preparation of vaccines eliciting bNAbs is still a major roadblock that limits their clinical application. Fresh mechanistic insights are necessary to develop more effective strategies. In particular, the function of the unusually long complementarity-determining region three of the heavy chain (CDRH3) of 4E10, an anti-MPER bNAb, is an open question that fascinates researchers in the field...
April 21, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28282446/antigenic-and-immunosuppressive-properties-of-a-trimeric-recombinant-transmembrane-envelope-protein-gp41-of-hiv-1
#19
Michael Mühle, Melissa Lehmann, Kerstin Hoffmann, Daniel Stern, Tobias Kroniger, Werner Luttmann, Joachim Denner
The transmembrane envelope (TM) protein gp41 of the human immunodeficiency virus-1 (HIV-1) plays an important role during virus infection inducing the fusion of the viral and cellular membranes. In addition, there are indications that the TM protein plays a role in the immunopathogenesis leading to the acquired immunodeficiency syndrome (AIDS). Inactivated virus particles and recombinant gp41 have been reported to inhibit lymphocyte proliferation, as well as to alter cytokine release and gene expression. The same was shown for a peptide corresponding to a highly conserved domain of all retroviral TM proteins, the immunosuppressive domain...
2017: PloS One
https://www.readbyqxmd.com/read/28250125/conformational-states-of-a-soluble-uncleaved-hiv-1-envelope-trimer
#20
Yuhang Liu, Junhua Pan, Yongfei Cai, Nikolaus Grigorieff, Stephen C Harrison, Bing Chen
The HIV-1 envelope spike [Env; trimeric (gp160)3 cleaved to (gp120/gp41)3] induces membrane fusion, leading to viral entry. It is also the viral component targeted by neutralizing antibodies. Vaccine development requires production, in quantities suitable for clinical studies, of a recombinant form that resembles functional Env. HIV-1 gp140 trimers-the uncleaved ectodomains of (gp160)3-from a few selected viral isolates adopt a compact conformation with many antigenic properties of native Env spikes. One is currently being evaluated in a clinical trial...
May 15, 2017: Journal of Virology
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