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https://www.readbyqxmd.com/read/29321334/mechanism-of-hiv-1-resistance-to-an-electronically-constrained-%C3%AE-helical-peptide-membrane-fusion-inhibitor
#1
Xiyuan Wu, Zixuan Liu, Xiaohui Ding, Danwei Yu, Huamian Wei, Bo Qin, Yuanmei Zhu, Huihui Chong, Sheng Cui, Yuxian He
SC29EK is an electronically constrained α-helical peptide HIV-1 fusion inhibitor highly effective against both wild-type and enfuvirtide (T20)-resistant viruses. In this study, we focused on investigating the mechanism of HIV-1 resistance to SC29EK by two approaches. First, SC29EK-escaping HIV-1 variants were selected and characterized. Three mutant viruses, which possessed two (E43K/E49A) or three (Q39R/N43K/N126K, N43K/E49A/N126K) amino acid substitutions in the N- and C-terminal repeat regions of gp41 were identified as conferring high resistance to SC29EK and cross-resistance to the first-generation (T20, C34) and newly-designed (sifuvirtide, MT-SC29EK, 2P23) fusion inhibitors...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29284009/hiv-1-envelope-sequence-based-diversity-measures-for-identifying-recent-infections
#2
Alexis Kafando, Eric Fournier, Bouchra Serhir, Christine Martineau, Florence Doualla-Bell, Mohamed Ndongo Sangaré, Mohamed Sylla, Annie Chamberland, Mohamed El-Far, Hugues Charest, Cécile L Tremblay
Identifying recent HIV-1 infections is crucial for monitoring HIV-1 incidence and optimizing public health prevention efforts. To identify recent HIV-1 infections, we evaluated and compared the performance of 4 sequence-based diversity measures including percent diversity, percent complexity, Shannon entropy and number of haplotypes targeting 13 genetic segments within the env gene of HIV-1. A total of 597 diagnostic samples obtained in 2013 and 2015 from recently and chronically HIV-1 infected individuals were selected...
2017: PloS One
https://www.readbyqxmd.com/read/29281723/human-immunodeficiency-virus-type-1-hiv-1-evades-antibody-dependent-phagocytosis
#3
Johannes S Gach, Margaux Bouzin, Marcus P Wong, Veronika Chromikova, Andrea Gorlani, Kuan-Ting Yu, Brijesh Sharma, Enrico Gratton, Donald N Forthal
Fc gamma receptor (FcyR)-mediated antibody functions play a crucial role in preventing HIV infection. One such function, antibody-dependent phagocytosis (ADP), is thought to be involved in controlling other viral infections, but its role in HIV infection is unknown. We measured the ability of HIV-specific polyclonal and monoclonal antibodies (mAbs) to mediate the internalization of HIV-1 virions and HIV-1-decorated cells by phagocytes. To measure ADP of virions, we primarily used a green-fluorescent protein-expressing molecular clone of HIV-1JRFL, an R5, clinical isolate, in combination with polyclonal HIVIG or mAbs known to capture and/or neutralize HIV-1...
December 27, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29277995/tilted-uninterrupted-monomeric-hiv-1-gp41-transmembrane-helix-from-residual-dipolar-couplings
#4
Sai Chaitanya Chiliveri, John M Louis, Rodolfo Ghirlando, James L Baber, Ad Bax
Cryo-electron microscopy and X-ray crystallography have shown that the pre- and post-fusion states of the HIV-1 gp41 viral coat protein, although very different from one another, each adopt C3 symmetric structures. A stable homotrimeric structure for the transmembrane domain (TM) also was modeled and supported by experimental data. For a C3 symmetric structure, alignment in an anisotropic medium must be axially symmetric, with the unique axis of the alignment tensor coinciding with the C3 axis. However, NMR residual dipolar couplings (RDCs) measured under three different alignment conditions were found to be incompatible with C3 symmetry...
December 26, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29248499/gp41-a-superfamily-sf2-helicase-from-bacteriophage-bfk20
#5
Nora Halgasova, Radka Matuskova, Daniel Kraus, Adela Tkacova, Lenka Balusikova, Gabriela Bukovska
Gp41 is one of two helicases encoded by the genome of bacteriophage BFK20. The gp41 sequence contains conserved motifs from the SF2 family of helicases. We prepared and studied three recombinant proteins: gp41HN, a wild type-like protein with an N-terminal His-Tag; gp41HC, with an S2A mutation and a C-terminal His-Tag; and gp41dC, a mutant protein with a deleted C-terminal region and His-Tags on both N- and C-termini. We tested the enzymatic activities and DNA binding abilities of these isolated proteins. We found that both gp41HN and gp41HC had strong DNA-dependent ATPase activities, but that the ATPase activity of gp41dC was significantly lower regardless of the presence of DNA...
December 14, 2017: Virus Research
https://www.readbyqxmd.com/read/29239894/temporal-variation-in-hiv-specific-igg-subclass-abs-during-acute-infection-differentiates-spontaneous-controllers-from-chronic-progressors
#6
Saheli Sadanand, Jishnu Das, Amy W Chung, Matthew K Schoen, Sophie Lane, Todd J Suscovich, Hendrik Streeck, Davey Smith, Susan Little, Douglas A Lauffenburger, Douglas Richman, Galit Alter
OBJECTIVE: Given the emerging appreciation for the role of antibody-dependent effector functions and IgG subclass distribution among spontaneous controllers of HIV, we sought to determine whether antibody-associated features diverged in early HIV infection between subjects who ultimately became controllers versus those who became progressors. METHODS: IgG was purified from plasma from nine acutely infected subjects who subsequently controlled HIV spontaneously (controllers) and ten acutely infected individuals who did not control viremia (progressors)...
December 12, 2017: AIDS
https://www.readbyqxmd.com/read/29238342/breastfeeding-behaviors-and-the-innate-immune-system-of-human-milk-working-together-to-protect-infants-against-inflammation-hiv-1-and-other-infections
#7
REVIEW
Bethany M Henrick, Xiao-Dan Yao, Laila Nasser, Ava Roozrogousheh, Kenneth L Rosenthal
The majority of infants' breastfeeding from their HIV-infected mothers do not acquire HIV-1 infection despite exposure to cell-free virus and cell-associated virus in HIV-infected breast milk. Paradoxically, exclusive breastfeeding regardless of the HIV status of the mother has led to a significant decrease in mother-to-child transmission (MTCT) compared with non-exclusive breastfeeding. Although it remains unclear how these HIV-exposed infants remain uninfected despite repeated and prolonged exposure to HIV-1, the low rate of transmission is suggestive of a multitude of protective, short-lived bioactive innate immune factors in breast milk...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29237828/identification-of-novel-structural-determinants-in-mw965-env-that-regulate-the-neutralization-phenotype-and-conformational-masking-potential-of-primary-hiv-1-isolates
#8
Zakiya M Qualls, Alok Choudhary, William Honnen, Raja Prattipati, James E Robinson, Abraham Pinter
The subtype C HIV-1 isolate MW965.26 is a highly neutralization-sensitive tier-1a primary isolate that is widely used in vaccine studies, but the basis for the sensitive neutralization phenotype of this isolate is not known. Substituting the MW965.26 V1/V2 domain into a neutralization-sensitive SF162 Env clone resulted in high resistance to standard anti-V3 monoclonal antibodies, demonstrating that this region possessed strong masking activity in a standard Env backbone and indicating that determinants elsewhere in MW965...
December 13, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29234103/an-exhaustive-search-algorithm-to-aid-nmr-based-structure-determination-of-rotationally-symmetric-transmembrane-oligomers
#9
Jing Yang, Alessandro Piai, Hong-Bin Shen, James J Chou
Nuclear magnetic resonance (NMR) has been an important source of structural restraints for solving structures of oligomeric transmembrane domains (TMDs) of cell surface receptors and viral membrane proteins. In NMR studies, oligomers are assembled using inter-protomer distance restraints. But, for oligomers that are higher than dimer, these distance restraints all have two-fold directional ambiguity, and resolving such ambiguity often requires time-consuming trial-and-error calculations using restrained molecular dynamics (MD) with simulated annealing (SA)...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29201019/therapeutic-application-of-phage-capsule-depolymerases-against-k1-k5-and-k30-capsulated-e-coli-in-mice
#10
Han Lin, Matthew L Paff, Ian J Molineux, James J Bull
Capsule depolymerase enzymes offer a promising class of new antibiotics. In vivo studies are encouraging but it is unclear how well this type of phage product will generalize in therapeutics, or whether different depolymerases against the same capsule function similarly. Here, in vivo efficacy was tested using cloned bacteriophage depolymerases against Escherichia coli strains with three different capsule types: K1, K5, and K30. When treating infections with the cognate capsule type in a mouse thigh model, the previously studied K1E depolymerase rescued poorly, whereas K1F, K1H, K5, and K30 depolymerases rescued well...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29162455/synthesis-and-biological-evaluation-of-water-soluble-derivatives-of-chiral-gossypol-as-hiv-fusion-inhibitors-targeting-gp41
#11
Jian Yang, Long-Long Li, Ju-Rong Li, Jing-Xiang Yang, Fang Zhang, Gang Chen, Rui Yu, Wen-Jie Ouyang, Shu-Wen Wu
A series of novel or known water-soluble derivatives of chiral gossypol were synthesized and screened in vitro for their anti-HIV-1 activity. (-)-gossypol derivative was more active against HIV-1 than the corresponding (+)-gossypol derivative, respectively. Among these derivatives, d-glucosamine derivative of (-)-gossypol, oligopeptide derivative of (-)-gossypol and taurine derivative of (-)-gossypol, such as compounds 1a, 3a and 14a, showed significant inhibitory activities against HIV-1 replication, HIV-1 mediated cell-cell fusion and HIV gp41 6-helix bundle formation as some amino acid derivatives of (-)-gossypol...
August 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29156603/adding-an-artificial-tail-anchor-to-a-peptide-based-hiv-1-fusion-inhibitor-for-improvement-of-its-potency-and-resistance-profile
#12
Shan Su, Zhenxuan Ma, Chen Hua, Weihua Li, Lu Lu, Shibo Jiang
Peptides derived from the C-terminal heptad repeat (CHR) of human immunodeficiency virus type 1 (HIV-1) envelope protein transmembrane subunit gp41, such as T20 (enfuvirtide), can bind to the N-terminal heptad repeat (NHR) of gp41 and block six-helix bundle (6-HB) formation, thus inhibiting HIV-1 fusion with the target cell. However, clinical application of T20 is limited because of its low potency and genetic barrier to resistance. HP23, the shortest CHR peptide, exhibits better anti-HIV-1 activity than T20, but the HIV-1 strains with E49K mutations in gp41 will become resistant to it...
November 20, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29142124/truncating-the-gp41-cytoplasmic-tail-of-siv-decreases-sensitivity-to-neutralizing-antibodies-without-increasing-envelope-content-of-virions
#13
Ellen White, Fan Wu, Elena Chertova, Julian Bess, James D Roser, Jeffrey D Lifson, Vanessa M Hirsch
An incomplete understanding of native HIV and SIV envelope glycoprotein (Env) impedes the development of structural models of Env and vaccine design. This shortcoming is due in part to the low number of Env trimers on virus particles. For SIV, this low expression can be counteracted by truncating the cytoplasmic tail (CT) of Env. CT truncation has been shown to increase Env incorporation into the virion and is commonly used in vaccine and imaging studies, but its effects on viral antigenicity have not been fully elucidated...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29098809/gp41-and-gag-amino-acids-linked-to-hiv-1-protease-inhibitor-based-second-line-failure-in-hiv-1-subtype-a-from-western-kenya
#14
Mia Coetzer, Lauren Ledingham, Lameck Diero, Emmanuel Kemboi, Millicent Orido, Rami Kantor
INTRODUCTION: Failure of protease-inhibitor (PI)-based second-line antiretroviral therapy (ART) with medication adherence but no protease drug resistance mutations (DRMs) is not well understood. This study investigated the involvement of gp41 and gag as alternative mechanisms, not captured by conventional resistance testing and particularly relevant in resource-limited settings where third-line ART is limited. METHODS: We evaluated gp41 and gag for unique amino acids in seven subtype A infected Kenyans failing second-line therapy with no PI resistance yet detectable lopinavir (query dataset), compared to seven similar-setting patients with PI resistance or undetectable lopinavir and 69 publically available subtype A Kenyan whole-genomes sequences...
November 2017: Journal of the International AIDS Society
https://www.readbyqxmd.com/read/29093081/analysis-of-select-hsv-1-proteins-for-restriction-of-human-immunodeficiency-virus-type-1-the-hsv-1-gm-protein-potently-restricts-hiv-1-by-preventing-the-intracellular-transport-and-processing-of-env-gp160
#15
Sachith Polpitiya Arachchige, Wyatt Henke, Ankita Pramanik, Maria Kalamvoki, Edward B Stephens
Proteins encoded by viruses that impair or shutdown specific host cell functions during replication can be used as probes to identify potential proteins/pathways used in the replication of viruses from other families. We screened nine proteins from herpes simplex virus type 1 (HSV-1) for the ability to enhance or restrict human immunodeficiency virus type 1 (HIV-1) replication. We show that several HSV-1 proteins (glycoprotein M (gM), US3 and UL24) potently restricted the replication of HIV-1. Unlike UL24 and US3, which reduced viral protein synthesis, we observed that gM restriction of HIV-1 occurred through interference of the processing and transport of gp160, resulting in a significantly reduced level of mature gp120/gp41 released from cells...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29056482/solution-structure-and-membrane-interaction-of-the-cytoplasmic-tail-of-hiv-1-gp41-protein
#16
R Elliot Murphy, Alexandra B Samal, Jiri Vlach, Jamil S Saad
The cytoplasmic tail of gp41 (gp41CT) remains the last HIV-1 domain with an unknown structure. It plays important roles in HIV-1 replication such as mediating envelope (Env) intracellular trafficking and incorporation into assembling virions, mechanisms of which are poorly understood. Here, we present the solution structure of gp41CT in a micellar environment and characterize its interaction with the membrane. We show that the N-terminal 45 residues are unstructured and not associated with the membrane. However, the C-terminal 105 residues form three membrane-bound amphipathic α helices with distinctive structural features such as variable degree of membrane penetration, hydrophobic and basic surfaces, clusters of aromatic residues, and a network of cation-π interactions...
November 7, 2017: Structure
https://www.readbyqxmd.com/read/29046462/distinct-roles-of-cellular-escrt-i-and-escrt-iii-proteins-in-efficient-entry-and-egress-of-budded-virions-of-autographa-californica-multiple-nucleopolyhedrovirus
#17
Qi Yue, Qianlong Yu, Qi Yang, Ye Xu, Ya Guo, Gary W Blissard, Zhaofei Li
The endosomal sorting complex required for transport (ESCRT) machinery is necessary for budding by many enveloped viruses. Recently, it was demonstrated that Vps4, the key regulator for recycling of the ESCRT-III complex, is required for efficient infection of the baculovirus, Autographa californica multiple nucleopolyhedrovirus (AcMNPV). However, ESCRT assembly, regulation and function are complex and little is known regarding details of participation of specific ESCRT complexes in AcMNPV infection. In this study, the core components of ESCRT-I (Tsg101 and Vps28) and ESCRT-III (Vps2B, Vps20, Vps24, Snf7, Vps46, and Vps60) were cloned from Spodoptera frugiperda Using a viral complementation system and RNAi assays, we found that ESCRT-I and ESCRT-III complexes are required for efficient entry of AcMNPV into insect cells...
October 18, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29046160/construction-and-production-of-hiv-vlp-harboring-mper-v3-for-potential-vaccine-study
#18
Fatemeh Tohidi, Seyed Mehdi Sadat, Azam Bolhassani, Ramin Yaghobi
Vaccine against HIV-1 is not currently available. In present, Virus like particles (VLPs) as effective strategy was used in several vaccine developing. Two conserved sequences; V3 loop of gp120 and the membrane-proximal external region (MPER) of gp41 are dominant sites for vaccine studies. In this study, we used fusion gene of MPER and V3 to product recombinant VLPs and introduced a novel retroviral VLPs harboring high copy of MPER-V3 for HIV-1 vaccine design. The pEGFP-N1 plasmid harboring MPER-V3 sequence with Vpr linker was constructed...
October 17, 2017: Current HIV Research
https://www.readbyqxmd.com/read/29035947/cross-reactivity-of-hiv-vaccine-responses-and-the-microbiome
#19
Wilton B Williams, Qifeng Han, Barton F Haynes
PURPOSE OF REVIEW: A successful HIV-type 1 (HIV-1) vaccine will require immunogens that induce protective immune responses. However, recent studies suggest that the response to HIV-1 and perhaps other viruses may be altered by immune system exposure to intestinal microbiota-antigens. This review will discuss select aspects of these studies. RECENT FINDINGS: Naïve CD4 T and B cell repertoires can be imprinted by intestinal microbiota-antigens to respond to virus epitopes prior to virus infection...
October 14, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28970835/immunologic-insights-on-the-membrane-proximal-external-region-a-major-human-immunodeficiency-virus-type-1-vaccine-target
#20
REVIEW
Luis M Molinos-Albert, Bonaventura Clotet, Julià Blanco, Jorge Carrillo
Broadly neutralizing antibodies (bNAbs) targeting conserved regions within the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein (Env) can be generated by the human immune system and their elicitation by vaccination will be a key point to protect against the wide range of viral diversity. The membrane proximal external region (MPER) is a highly conserved region within the Env gp41 subunit, plays a major role in membrane fusion and is targeted by naturally induced bNAbs. Therefore, the MPER is considered as an attractive vaccine target...
2017: Frontiers in Immunology
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