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https://www.readbyqxmd.com/read/29346393/computational-study-of-hiv-gp120-as-a-target-for-polyanionic-entry-inhibitors-exploiting-the-v3-loop-region
#1
Louis R Hollingsworth, Anne M Brown, Richard D Gandour, David R Bevan
Multiple approaches are being utilized to develop therapeutics to treat HIV infection. One approach is designed to inhibit entry of HIV into host cells, with a target being the viral envelope glycoprotein, gp120. Polyanionic compounds have been shown to be effective in inhibiting HIV entry, with a mechanism involving electrostatic interactions with the V3 loop of gp120 being proposed. In this study, we applied computational methods to elucidate molecular interactions between the repeat unit of the precisely alternating polyanion, Poly(4,4'-stilbenedicarboxylate-alt-maleic acid) (DCSti-alt-MA) and the V3 loop of gp120 from strains of HIV against which these polyanions were previously tested (IIIb, BaL, 92UG037, JR-CSF) as well as two strains for which gp120 crystal structures are available (YU2, 2B4C)...
2018: PloS One
https://www.readbyqxmd.com/read/29345922/efficient-fusion-at-neutral-ph-by-human-immunodeficiency-virus-gp41-trimers-containing-the-fusion-peptide-and-transmembrane-domain
#2
Shuang Liang, Punsisi Ratnayake, Craig Keinath, Lihui Jia, Robert Wolfe, Ahinsa Ranaweera, David P Weliky
Human immunodeficiency virus (HIV) is membrane-enveloped and an initial infection step is joining/fusion of viral and cell membranes. This step is catalyzed by gp41 which is a single-pass integral viral membrane protein. The protein contains a ~170-residue ectodomain located outside the virus that is important for fusion, and includes the fusion peptide (FP), N-helix, loop, C-helix, and viral membrane-proximal external region (MPER). The virion initially has non-covalent complexes between three gp41 ectodomains and three gp120 proteins...
January 18, 2018: Biochemistry
https://www.readbyqxmd.com/read/29343613/restricted-hiv-1-env-glycan-engagement-by-lectin-reengineered-davei-protein-chimera-is-sufficient-for-lytic-inactivation-of-the-virus
#3
Bibek Parajuli, Kriti Acharya, Harry C Bach, Bijay Parajuli, Shiyu Zhang, Amos B Smith, Cameron F Abrams, Irwin Chaiken
We previously reported first generation recombinant DAVEI construct, a dual action virus entry inhibitor composed of cyanovirin-N (CVN) fused to a membrane proximal external region (MPER) or its derivative peptide Trp3. DAVEI exhibits potent and irreversible inactivation of HIV-1 viruses by dual engagement of gp120 and gp41. However, the promiscuity of CVN to associate with multiple glycosylation sites in gp120 and its multivalency limit current understanding of the molecular arrangement of the DAVEI molecules on trimeric spike...
January 17, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29343576/increased-epitope-complexity-correlated-with-antibody-affinity-maturation-and-a-novel-binding-mode-revealed-by-structures-of-rabbit-antibodies-against-the-third-variable-loop-v3-of-hiv-1-gp120
#4
Ruimin Pan, Yali Qin, Marisa Banasik, William Lees, Adrian J Shepherd, Michael W Cho, Xiang-Peng Kong
The V3 loop of HIV-1 gp120 is an immunodominant region targeted by neutralizing antibodies (nAbs). Despite limited breadth, better characterization of the structural details of the interactions between these nAbs and their target epitopes would enhance our understanding of the mechanism of neutralization and facilitate designing better immunogens to induce nAbs with greater breadth. Recently, we isolated two anti-V3 neutralizing monoclonal antibodies (mAbs), 10A3 and 10A37, from a rabbit immunized with gp120 of the M group consensus sequence...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29343575/high-resolution-sequencing-of-viral-populations-during-early-siv-infection-reveals-evolutionary-strategies-for-rapid-escape-from-emerging-env-specific-antibody-responses
#5
Sergio Ita, Alison K Hill, Evan C Lam, Fay J Dufort, Xiao Yang, Ruchi Newman, Sivan Leviyang, Ismael B Fofana, Welkin E Johnson
Primate lentiviruses, including the human and simian immunodeficiency viruses (HIV and SIV), produce infections marked by persistent, ongoing viral replication. This occurs despite the presence of virus-specific adaptive immune responses, including antibodies targeting the viral envelope glycoprotein (Env), and evolution of antibody-escape variants is a well-documented feature of lentiviral infection. Here, we examined the evolutionary dynamics of the SIV env gene during early infection (≤ 29 weeks post-infection) in a cohort of four SIVmac251-infected rhesus macaques...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29337418/specific-non-covalent-interactions-determine-optimal-structure-of-a-buried-ligand-moiety-qm-mm-and-pure-qm-modeling-of-complexes-of-the-small-molecule-cd4-mimetics-and-hiv1-gp120
#6
Francesca Moraca, David Rinaldo, Amos Brittain Smith, Cameron Abrams
The small molecule CD4 mimetics (smCD4mc) are a class of highly potent HIV-1 entry inhibitors characterized by a unique SAR. They share a halogenated phenyl ring (region 1) that deeply inserts into an otherwise water-filled cavity at the CD4 binding site on the gp120 surface, so-called F43 cavity. Conservative modifications to region 1 away from this halogenated phenyl motif have all lead to loss of activity, despite they are predicted to bind equally well via standard empirical computational approaches making difficult to further optimize this region of the compounds to increase binding to gp120...
January 16, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29324755/hiv-1-co-receptor-tropism-and-liver-fibrosis-in-hiv-infected-patients
#7
Annalisa Saracino, Alessandro Cozzi-Lepri, Milensu Shanyinde, Francesca Ceccherini Silberstein, Silvia Nozza, Antonio Di Biagio, Giovanni Cassola, Giuseppe Bruno, Maria Capobianchi, Massimo Puoti, Laura Monno, Antonella d'Arminio Monforte
BACKGROUND: In vitro, gp120 of both X4 and R5 HIV-1 strains activates human hepatic stellate cells, but if it can promote liver fibrosis in vivo is unknown. We aimed to evaluate if patients carrying X4 or R5 strains have a different liver fibrosis (LF) progression over time. METHODS: A total of 1,137 HIV-infected patients in ICONA cohort (21% females, 7% HCV co-infected) with an available determination of HIV-1 co-receptor tropism (CRT), a Fibrosis-4 Index for Liver Fibrosis (FIB-4) <3...
2018: PloS One
https://www.readbyqxmd.com/read/29323175/functional-antibody-response-against-v1v2-and-v3-of-hiv-gp120-in-the-vax003-and-vax004-vaccine-trials
#8
Preetha Balasubramanian, Constance Williams, Mariya B Shapiro, Faruk Sinangil, Keith Higgins, Arthur Nádas, Maxim Totrov, Xiang-Peng Kong, Andrew J Fiore-Gartland, Nancy L Haigwood, Susan Zolla-Pazner, Catarina E Hioe
Immunization with HIV AIDSVAX gp120 vaccines in the phase III VAX003 and VAX004 trials did not confer protection. To understand the shortcomings in antibody (Ab) responses induced by these vaccines, we evaluated the kinetics of Ab responses to the V1V2 and V3 regions of gp120 and the induction of Ab-mediated antiviral functions during the course of 7 vaccinations over a 30.5-month period. Plasma samples from VAX003 and VAX004 vaccinees and placebo recipients were measured for ELISA-binding Abs and for virus neutralization, Ab-dependent cellular phagocytosis (ADCP), and Ab-dependent cellular cytotoxicity (ADCC)...
January 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321330/glycosyl-phosphatidylinositol-anchored-anti-hiv-env-single-chain-variable-fragments-interfere-with-hiv-1-env-processing-and-viral-infectivity
#9
Anisha Misra, Emile Gleeson, Weiming Wang, Chaobaihui Ye, Paul Zhou, Jason T Kimata
In previous studies, we demonstrated that single-chain variable fragments (scFv) from anti-HIV Env monoclonal antibodies act as entry inhibitors when tethered to the surface of target cells by a glycosyl-phosphitidylinositol (GPI) anchor. Interestingly, even if a virus escapes inhibition at entry, its replication is ultimately controlled. We hypothesized that in addition to functioning as entry inhibitors, anti-HIV GPI-scFvs may also interact with Env in an infected cell, thereby interfering with infectivity of newly produced virions...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29311557/publisher-correction-the-%C3%AE-20-%C3%AE-21-of-gp120-is-a-regulatory-switch-for-hiv-1-env-conformational-transitions
#10
Alon Herschhorn, Christopher Gu, Francesca Moraca, Xiaochu Ma, Mark Farrell, Amos B Smith, Marie Pancera, Peter D Kwong, Arne Schön, Ernesto Freire, Cameron Abrams, Scott C Blanchard, Walther Mothes, Joseph G Sodroski
The original version of this Article contained an error in the spelling of the author Amos B. Smith, III, which was incorrectly given as Amos B. SmithIII. This has now been corrected in both the PDF and HTML versions of the Article.
January 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29306566/bispecific-chimeric-antigen-receptors-targeting-the-cd4-binding-site-and-high-mannose-glycans-of-gp120-optimized-for-anti-human-immunodeficiency-virus-potency-and-breadth-with-minimal-immunogenicity
#11
Mustafa H Ghanem, Sara Bolivar-Wagers, Barna Dey, Agnes Hajduczki, Diego A Vargas-Inchaustegui, David T Danielson, Virgilio Bundoc, Li Liu, Edward A Berger
BACKGROUND AIMS: Chimeric antigen receptors (CARs) offer great potential toward a functional cure of human immunodeficiency virus (HIV) infection. To achieve the necessary long-term virus suppression, we believe that CARs must be designed for optimal potency and anti-HIV specificity, and also for minimal probability of virus escape and CAR immunogenicity. CARs containing antibody-based motifs are problematic in the latter regard due to epitope mutation and anti-idiotypic immune responses against the variable regions...
January 3, 2018: Cytotherapy
https://www.readbyqxmd.com/read/29284009/hiv-1-envelope-sequence-based-diversity-measures-for-identifying-recent-infections
#12
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
#13
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/29280955/immune-modulation-of-nyvac-based-hiv-vaccines-by-combined-deletion-of-viral-genes-that-act-on-several-signalling-pathways
#14
Carmen Elena Gómez, Beatriz Perdiguero, Cristina Sánchez-Corzo, Carlos Oscar S Sorzano, Mariano Esteban
An HIV-1 vaccine continues to be a major target to halt the AIDS pandemic. The limited efficacy of the RV144 phase III clinical trial with the canarypox virus-based vector ALVAC and a gp120 protein component led to the conclusion that improved immune responses to HIV antigens are needed for a more effective vaccine. In non-human primates, the New York vaccinia virus (NYVAC) poxvirus vector has a broader immunogenicity profile than ALVAC and has been tested in clinical trials. We therefore analysed the HIV immune advantage of NYVAC after removing viral genes that act on several signalling pathways (Toll-like receptors-TLR-interferon, cytokines/chemokines), as well as genes of unknown immune function...
December 27, 2017: Viruses
https://www.readbyqxmd.com/read/29273432/the-alpha-helix-1-from-the-first-conserved-region-of-hiv1-gp120-is-reconstructed-in-the-short-nq21-peptide
#15
Vladislav Victorovich Khrustalev, Tatyana Aleksandrovna Khrustaleva, Ekaterina Yurievna Kahanouskaya, Yulia Anatolyevna Rudnichenko, Hanna Vitalyevna Bandarenka, Alexander Migranovich Arutyunyan, Kseniya Victorovna Girel, Nadia Vladimirovna Khinevich, Alexander Leonidovich Ksenofontov, Larisa Valentinovna Kordyukova
Investigations of short peptides that can be used in the next phase of synthetic HIV1 vaccine development are an urgent goal, as well as investigations of peptides that can be used in immunological tests with the aim to check the titer of antibodies against the alpha helix 1 from the first conserved region of HIV1 gp120 that are known to cause antibody-dependent cellular cytotoxicity (ADCC). The aim of this work was to study the structure of the NQ21 peptide corresponding to the less mutable part of the first conserved region of HIV1 gp120 (residues 94-114)...
December 19, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29248757/envelope-glycoproteins-sampling-states-2-3-are-susceptible-to-adcc-by-sera-from-hiv-1-infected-individuals
#16
Jérémie Prévost, Jonathan Richard, Shilei Ding, Beatriz Pacheco, Roxanne Charlebois, Beatrice H Hahn, Daniel E Kaufmann, Andrés Finzi
Recent analysis of HIV-1 envelope glycoproteins (Env) dynamics showed that the unliganded Env trimer can potentially sample three conformations: a metastable "closed" conformation (State 1), an "open" CD4-bound conformation (State 3), and an intermediate "partially open" conformation (State 2). HIV-1 evolved several mechanisms to avoid "opening" its Env in order to evade immune responses such as antibody-dependent cellular cytotoxicity (ADCC), which preferentially targets Envs in the CD4-bound conformation on the surface of infected cells...
December 14, 2017: Virology
https://www.readbyqxmd.com/read/29239894/temporal-variation-in-hiv-specific-igg-subclass-abs-during-acute-infection-differentiates-spontaneous-controllers-from-chronic-progressors
#17
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/29237847/a-trimeric-hiv-1-envelope-gp120-immunogen-induces-potent-and-broad-anti-v1v2-loop-antibodies-against-hiv-1-in-rabbits-and-rhesus-macaques
#18
Andrew T Jones, Venkateswarlu Chamcha, Sannula Kesavardhana, Xiaoying Shen, David Beaumont, Raksha Das, Linda S Wyatt, Celia C LaBranche, Sherry Stanfield-Oakley, Guido Ferrari, David C Montefiori, Bernard Moss, Georgia D Tomaras, Raghavan Varadarajan, Rama Rao Amara
Trimeric HIV-1 envelope (Env) immunogens are attractive due to their ability to display quaternary epitopes targeted by broadly neutralizing antibodies while obscuring unfavorable epitopes. Results from the RV144 trial highlighted the importance of vaccine induced HIV-1 Env V1V2 directed antibodies, with key regions of the V2 loop as targets for vaccine-mediated protection. We recently reported that a trimeric JRFL-gp120 immunogen, generated by inserting a N-terminal trimerization domain in the V1 loop region of a cyclically permuted gp120 (cycP-gp120), induces neutralizing activity against multiple tier-2 HIV-1 isolates in guinea pigs in a DNA prime/protein boost approach...
December 13, 2017: Journal of Virology
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
#19
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/29222332/stabilization-of-the-gp120-v3-loop-through-hydrophobic-interactions-reduces-the-immunodominant-v3-directed-non-neutralizing-response-to-hiv-1-envelope-trimers
#20
Steven W de Taeye, Alba Torrents de la Peña, Andrea Vecchione, Enzo Scutigliani, Kwinten Sliepen, Judith A Burger, Patricia van der Woude, Anna Schorcht, Edith E Schermer, Marit J van Gils, Celia C LaBranche, David C Montefiori, Ian A Wilson, John P Moore, Andrew B Ward, Rogier W Sanders
To provide protective immunity against circulating primary HIV-1 strains, a vaccine most likely has to induce broadly neutralizing antibodies (bNAbs) to the HIV-1 envelope (Env) glycoprotein spike. Recombinant Env trimers such as the prototype BG505 SOSIP.664 that closely mimic the native Env spike can induce autologous neutralizing antibodies (NAbs) against relatively resistant (tier-2) primary viruses. Ideally, Env immunogens should present bNAb epitopes, but limit the presentation of immunodominant non-NAb epitopes that might induce off-target and potentially interfering responses...
December 8, 2017: Journal of Biological Chemistry
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