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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
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
David Wensel, Yongnian Sun, Jonathan Davis, Zhufang Li, Sharon Zhang, Thomas McDonagh, David Fabrizio, Mark Cockett, Mark Krystal
The N17 region of gp41 in HIV-1 is the most conserved region in gp160. mRNA selection technologies were used to identify an Adnectin that binds to this region and inhibits gp41-induced membrane fusion. Additional selection conditions were used to optimize the Adnectin to greater potency (5.4 ± 2.6 nM) to HIV-1 and improved binding affinity to a N17-containing helical trimer (0.8 ± 0.4 nM). Resistance to this Adnectin mapped to a single Glu to Arg change within the N17 coding region. The optimized Adnectin (6200_A08) exhibited high potency and broad spectrum against 123 envelope proteins and multiple clinical isolate viruses, although certain envelope proteins did exhibit reduced susceptibility against 6200_A08 alone...
May 9, 2018: Journal of Virology
Etai Rotem, Omri Faingold, Meital Charni, Yoel A Klug, Daniel Harari, Liraz Shmuel-Galia, Alon Nudelman, Varda Rotter, Yechiel Shai
The ability of the Lentivirus HIV-1 to inhibit T-cell activation by its gp41 fusion protein is well documented, yet limited data exists regarding other viral fusion proteins. HIV-1 utilizes membrane binding region of gp41 to inhibit T-cell receptor (TCR) complex activation. Here we examined whether this T-cell suppression strategy is unique to the HIV-1 gp41. We focused on T-cell modulation by the gp21 fusion peptide (FP) of the Human T-lymphotropic Virus 1 (HTLV-1), a Deltaretrovirus that like HIV infects CD4+ T-cells...
May 4, 2018: PLoS Pathogens
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
Huan Liu, Xiaojie Su, Lulu Si, Lu Lu, Shibo Jiang
A human immunodeficiency virus type-1 (HIV-1) vaccine which is able to effectively prevent infection would be the most powerful method of extinguishing pandemic of the acquired immunodeficiency syndrome (AIDS). Yet, achieving such vaccine remains great challenges. The membrane-proximal external region (MPER) is a highly conserved region of the envelope glycoprotein (Env) gp41 subunit near the viral envelope surface, and it plays a key role in membrane fusion. It is also the target of some reported broadly neutralizing antibodies (bNAbs)...
April 17, 2018: Protein & Cell
Maxence Duchemin, Marwa Khamassi, Lin Xu, Daniela Tudor, Morgane Bomsel
The protective efficacy of human immunodeficiency virus-1 (HIV-1) antibodies (Abs) remains mostly correlated with their in vitro neutralizing activity engaging their Fab region. However, anti-HIV-1 Abs also mediate a broad array of Fc-mediated effector functions including Ab-dependent cellular cytotoxicity (ADCC), which depend primarily on the Ab isotype. While ADCC is commonly associated with HIV-1 gp120 envelope-specific IgGs, whether IgAs, especially those targeting the HIV-1 gp41 envelope, also mediate ADCC remains elusive...
2018: Frontiers in Immunology
Yimeng Li, Shu Shen, Liangbo Hu, Fei Deng, Just M Vlak, Zhihong Hu, Hualin Wang, Manli Wang
gp41 , one of the baculovirus core genes, encodes the only recognized tegument (O-glyco) protein of the occlusion-derived virion (ODV) phenotype so far. A previous study using a temperature-sensitive Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) mutant showed that GP41 plays a crucial role in budded virion (BV) formation. However, the precise function of GP41 in the baculovirus replication cycle remains unclear. In this study, AcMNPV GP41 was found to accumulate around the ring zone region (RZ) within the infected nucleus and finally assembled into both BV and ODV...
April 11, 2018: Journal of Virology
Thandeka Moyo, June Ereño-Orbea, Rajesh Abraham Jacob, Clara E Pavillet, Samuel Mundia Kariuki, Emily N Tangie, Jean-Philippe Julien, Jeffrey R Dorfman
Understanding the mechanisms used by HIV-1 to evade antibody neutralization may contribute to the design of a high-coverage vaccine. The tier 3 virus 253-11, is poorly neutralized by subtype-matched and subtype C sera, even when compared to other tier 3 viruses, and is also recognized poorly by V3/glycan targeting monoclonal antibodies. We found that sequence polymorphism in the V3 loop and N-linked glycosylation sites only minimally contribute to the high neutralization resistance of 253-11. Interestingly, the 253-11 membrane proximal external region (MPER) is rarely recognized by sera in the context of the wild-type virus, but is commonly recognized in the context of an HIV-2 chimeric virus, suggesting steric or kinetic hindrance of binding to MPER in the native Env...
April 4, 2018: Journal of Virology
Luis R Castillo-Menendez, Kristen Witt, Nicole Espy, Amy Princiotto, Navid Madani, Beatriz Pacheco, Andrés Finzi, Joseph Sodroski
The mature envelope glycoprotein (Env) spike on the surface of human immunodeficiency virus (HIV-1) infected cells and virions is derived by proteolytic cleavage of a trimeric gp160 glycoprotein precursor. In these studies, we compared the conformations of cleaved and uncleaved membrane Envs with truncated cytoplasmic tails to those of stabilized soluble gp140 SOSIP.664 Env trimers. Deletion of the gp41 cytoplasmic tail did not significantly affect the sensitivity of viruses with the HIV-1AD8 Env to inhibition by antibodies or a CD4-mimetic compound...
April 4, 2018: Journal of Virology
Dehua Liu, Hongyun Wang, Mizuki Yamamoto, Jiping Song, Rui Zhang, Qingling Du, Yasushi Kawaguchi, Jun-Ichiro Inoue, Zene Matsuda
BACKGROUND: The native pre-fusion structure of gp120/gp41 complex of human immunodeficiency virus type 1 was recently revealed. In the model, the helices of gp41 (α6, α7, α8, and α9) form a four-helix collar underneath trimeric gp120. Gp41 is a class I fusion protein and mediates membrane fusion by forming a post-fusion structure called the six-helix bundle (6HB). The comparison of the pre- and post-fusion structures revealed the large conformational changes in gp41 during the antiparallel packing of the N- and C-terminal heptad repeats (NHRs and CHRs) in membrane fusion...
April 2, 2018: Retrovirology
Soraya Sangjan, Silawun Ampol, Guo Jia-Jun, Sutchana Tabprasit, Navin Horthongkham, Thippawan Chuenchitra, Pattama Ekpo, Wannee Kantakamalakul
BACKGROUND: There have been a few studies aimed at identifying epitopes of ADCC-inducing antibodies when compared to those of neutralizing antibodies and cytotoxic T lymphocytes against a variety of HIV-1 clades. OBJECTIVE: To map the common ADCC epitopes of HIV-1 CRF01_AE. METHODS: We screened 65 sera of confirmed early HIV-1 CRF01_AE infected individuals for ADCC antibody against gp120 utilizing an EGFP-CEM-NKr flow cytometric assay. Sera with high ADCC antibody were then examined against ADCC epitopes using the complete HIV-1 CRF01_AE gp160- and subtype A Gag-overlapping peptide sets which were divided into 7 pools:E1-E7 and 5 pools:G1-G5, respectively...
March 31, 2018: Asian Pacific Journal of Allergy and Immunology
Han Wang, Jonathan Liu, Kai P Yuet, Andrew J Hill, Paul W Sternberg
Bipartite expression systems, such as the GAL4-UAS system, allow fine manipulation of gene expression and are powerful tools for interrogating gene function. Recently, we established cGAL, a GAL4-based bipartite expression system for transgene control in Caenorhabditis elegans , where a single promoter dictates the expression pattern of a cGAL driver, which then binds target upstream activation sequences to drive expression of a downstream effector gene. Here, we report a split strategy for cGAL using the split intein gp41-1 for intersectional control of transgene expression...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jiegang Huang, Minlian Wang, Chunyuan Huang, Bingyu Liang, Junjun Jiang, Chuanyi Ning, Ning Zang, Hui Chen, Jie Liu, Rongfeng Chen, Yanyan Liao, Li Ye, Hao Liang
Objectives: Identifying recent infections is necessary to monitor HIV/AIDS epidemic; however, it needs to be further developed. Methods and Results: Participants were defined as having recent infection or older infection according to the estimated duration of HIV-1 infection and further assigned into training set and validation set according to their entering time points. Western blot (WB) confirmatory test and BED-CEIA were performed. The performance of the two methods on recent HIV-1 diagnosis was evaluated and compared...
2018: BioMed Research International
Xiujuan Zhang, Yuanmei Zhu, Hao Hu, Senyan Zhang, Pengfei Wang, Huihui Chong, Jinsheng He, Xinquan Wang, Yuxian He
The deep hydrophobic pocket of HIV-1 gp41 has been considered a drug target, but short-peptides targeting this site usually lack potent antiviral activity. By applying the M-T hook structure, we previously generated highly potent short-peptide fusion inhibitors that specifically targeted the pocket site, such as MT-SC22EK, HP23L, and LP-11. Here, the crystal structures of HP23L and LP-11 bound to the target mimic peptide N36 demonstrated the critical intrahelical and interhelical interactions, especially verifying that the hook-like conformation was finely adopted while the methionine residue was replaced by the oxidation-less prone residue leucine, and that addition of an extra glutamic acid significantly enhanced the binding and inhibitory activities...
2018: Frontiers in Cellular and Infection Microbiology
Quang N Nguyen, David R Martinez, Jonathon E Himes, R Whitney Edwards, Qifeng Han, Amit Kumar, Riley Mangan, Nathan I Nicely, Guanhua Xie, Nathan Vandergrift, Xiaoying Shen, Justin Pollara, Sallie R Permar
BACKGROUND: The initial envelope (Env)-specific antibody response in acutely HIV-1-infected individuals and simian immunodeficiency virus (SIV)-infected rhesus monkeys (RMs) is dominated by non-neutralizing antibodies targeting Env gp41. In contrast, natural primate SIV hosts, such as African green monkeys (AGMs), develop a predominant Env gp120-specific antibody response to SIV infection. However, the fine-epitope specificity and function of SIV Env-specific plasma IgG, and their potential role on autologous virus co-evolution in SIV-infected AGMs and RMs remain unclear...
March 9, 2018: Retrovirology
Vani G S Narasimhulu, Anna K Bellamy-McIntyre, Annamarie E Laumaea, Chan-Sien Lay, David N Harrison, Hannah A D King, Heidi E Drummer, Pantelis Poumbourios
HIV-1 is spread by cell-free virions and by cell-cell viral transfer. We asked whether the structure and function of a broad neutralizing antibody (bNAb) epitope, the membrane-proximal ectodomain region (MPER) of the viral gp41 transmembrane glycoprotein, differ in cell-free and cell-cell-transmitted viruses and whether this difference could be related to Ab neutralization sensitivity. Whereas cell-free viruses bearing W666A and I675A substitutions in the MPER lacked infectivity, cell-associated mutant viruses were able to initiate robust spreading infection...
April 20, 2018: Journal of Biological Chemistry
Lara Ajamian, Luca Melnychuk, Patrick Jean-Pierre, Gerasimos J Zaharatos
Flagellin's potential as a vaccine adjuvant has been increasingly explored over the last three decades. Monomeric flagellin proteins are the only known agonists of Toll-like receptor 5 (TLR5). This interaction evokes a pro-inflammatory state that impacts upon both innate and adaptive immunity. While pathogen associated molecular patterns (PAMPs) like flagellin have been used as stand-alone adjuvants that are co-delivered with antigen, some investigators have demonstrated a distinct advantage to incorporating antigen epitopes within the structure of flagellin itself...
February 27, 2018: Viruses
Victoria Oakes, Johana Torralba, Edurne Rujas, José L Nieva, Carmen Domene, Beatriz Apellaniz
The 10E8 antibody achieves near-pan neutralization of HIV-1 by targeting the remarkably conserved gp41 membrane-proximal external region (MPER) and the connected transmembrane domain (TMD) of the HIV-1 envelope glycoprotein (Env). Thus, recreating the structure that generates 10E8-like antibodies is a major goal of the rational design of anti-HIV vaccines. Unfortunately, high-resolution information of this segment in the native Env is lacking, limiting our understanding of the behavior of the crucial 10E8 epitope residues...
June 2018: Biochimica et Biophysica Acta
Alexander M Andrianov, Ivan A Kashyn, Alexander V Tuzikov
An integrated computational approach to in silico drug design was used to identify novel HIV-1 fusion inhibitor scaffolds mimicking broadly neutralizing antibody (bNab) 10E8 targeting the membrane proximal external region (MPER) of the HIV-1 gp41 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb 10E8 active towards the gp41 MPER segment, (ii) shape and pharmacophore-based identification of the 10E8-mimetic candidates by a web-oriented virtual screening platform pepMMsMIMIC, (iii) high-throughput docking of the identified compounds with the gp41 MPER peptide, and (iv) molecular dynamics simulations of the docked structures followed by binding free energy calculations...
January 15, 2018: Journal of Bioinformatics and Computational Biology
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