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https://www.readbyqxmd.com/read/29142124/truncating-the-gp41-cytoplasmic-tail-of-siv-decreases-sensitivity-to-neutralizing-antibodies-without-increasing-envelope-content-of-virions
#1
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/28987959/reanalysis-of-the-role-of-pronase-treatment-of-b-cells-in-the-flow-cytometric-crossmatch-assay-fc-receptor-is-not-the-primary-target
#2
Nicholas K Brown, James R Meade, Jinguo Wang, Susana R Marino
Pronase, a mixture of nonspecific bacterial proteases, is used to pretreat human lymphocytes to prevent false-positive B cell results in the flow cytometric crossmatch (FCXM) assay. The target of pronase has been reported to be B cell-expressed Fc receptors, which nonspecifically bind IgG. As pronase use in FCXM can induce other complications, including degradation of HLA leading to inappropriate FCXM results, and false-positive T cell results when testing serum from HIV-positive patients, we tested whether specifically blocking Fc receptor CD32 could replace pronase...
October 5, 2017: Human Immunology
https://www.readbyqxmd.com/read/28978939/non-neutralizing-antibodies-targeting-the-v1v2-domain-of-hiv-exhibit-strong-antibody-dependent-cell-mediated-cytotoxic-activity
#3
Luzia M Mayr, Thomas Decoville, Sylvie Schmidt, Géraldine Laumond, Jéromine Klingler, Camille Ducloy, Seiamak Bahram, Susan Zolla-Pazner, Christiane Moog
The development of an effective vaccine against HIV-1 has proven to be challenging. Broadly neutralizing antibodies (bNAbs), whilst exhibiting neutralization breadth and potency, are elicited only in a small subset of infected individuals and have yet to be induced by vaccination. Case-control studies of RV144 identified an inverse correlation of HIV-1 infection risk with antibodies (Abs) to the V1V2 region of gp120 with high antibody-dependent cellular cytotoxicity (ADCC) activity. The neutralizing activity of Abs was not found to contribute to this protective outcome...
October 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28978475/elicitation-of-neutralizing-antibodies-targeting-the-v2-apex-of-the-hiv-envelope-trimer-in-a-wild-type-animal-model
#4
James E Voss, Raiees Andrabi, Laura E McCoy, Natalia de Val, Roberta P Fuller, Terrence Messmer, Ching-Yao Su, Devin Sok, Salar N Khan, Fernando Garces, Laura K Pritchard, Richard T Wyatt, Andrew B Ward, Max Crispin, Ian A Wilson, Dennis R Burton
Recent efforts toward HIV vaccine development include the design of immunogens that can engage B cell receptors with the potential to affinity mature into broadly neutralizing antibodies (bnAbs). V2-apex bnAbs, which bind a protein-glycan region on HIV envelope glycoprotein (Env) trimer, are among the most broad and potent described. We show here that a rare "glycan hole" at the V2 apex is enriched in HIV isolates neutralized by inferred precursors of prototype V2-apex bnAbs. To investigate whether this feature could focus neutralizing responses onto the apex bnAb region, we immunized wild-type rabbits with soluble trimers adapted from these Envs...
October 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28975841/progressive-multifocal-leukoencephalopathy-and-monoclonal-antibodies-a-review
#5
Chandrashekar Bohra, Lubomir Sokol, Samir Dalia
Progressive multifocal leukoencephalopathy (PML) is a viral infection predominantly seen in patients with HIV infection. However, with the increased use of monoclonal antibodies (MAB) for various lymphoproliferative disorders, we are now seeing this infection in non-HIV patients on drugs such as natalizumab, rituximab, and so on. The aim of this article is to review the relationship between the occurrence of PML and MAB used in the treatment of hematological malignancies and autoimmune diseases. Review of articles from PubMed-indexed journals which study PML in relation to the use of MAB...
October 2017: Cancer Control: Journal of the Moffitt Cancer Center
https://www.readbyqxmd.com/read/28968970/identification-of-a-novel-hiv-1-neutralizing-antibody-from-a-crf07_bc-infected-chinese-donor
#6
Youxiang Sun, Yuanyuan Qiao, Yuanmei Zhu, Huihui Chong, Yuxian He
The identification of human monoclonal antibodies (mAbs) able to neutralize a broad spectrum of primary HIV-1 isolates is highly important for understanding the immune response of HIV-1 infection and developing vaccines and therapeutics. In this study, we isolated a novel human mAb termed Y498 from a phage display antibody library constructed with the PBMC samples of a CRF07_BC-infected Chinese donor whose sera exhibited broadly neutralizing activity. Y498 cross-reacted with diverse Env antigens and neutralized 30% of 70 tested HIV-1 isolates...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28947103/interrogation-of-side-chain-biases-for-oligomannose-recognition-by-antibody-2g12-via-structure-guided-phage-display-libraries
#7
Tsung-Yi Lin, Jonathan R Lai
Monoclonal antibodies (mAbs) are essential reagents for deciphering gene or protein function and have been a fruitful source of therapeutic and diagnostic agents. However, developing anticarbohydrate antibodies to target glycans for those purposes has been less successful because the molecular basis for glycan-mAb interactions is poorly understood relative to protein- or peptide-binding mAbs. Here, we report our investigation on glycan-mAb interactions by using the unique architectural scaffold of 2G12, an antibody that targets oligomannoses on the HIV-1 glycoprotein gp120, as the template for engineering highly specific mAbs to target glycans...
October 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28938888/unique-binding-modes-for-the-broad-neutralizing-activity-of-single-chain-variable-fragments-scfv-targeting-cd4-induced-epitopes
#8
Kazuki Tanaka, Takeo Kuwata, Muntasir Alam, Gilad Kaplan, Shokichi Takahama, Kristel Paola Ramirez Valdez, Anna Roitburd-Berman, Jonathan M Gershoni, Shuzo Matsushita
BACKGROUND: The CD4-induced (CD4i) epitopes in gp120 includes the co-receptor binding site, which are formed and exposed after interaction with CD4. Monoclonal antibodies (mAbs) to the CD4i epitopes exhibit limited neutralizing activity because of restricted access to their epitopes. However, small fragment counterparts such as single-chain variable fragments (scFvs) have been reported to neutralize a broad range of viruses compared with the full-size IgG molecule. To identify the CD4i epitope site responsible for this broad neutralization we constructed three scFvs of anti-CD4i mAbs from a human immunodeficiency virus type 1 (HIV-1)-infected elite controller, and investigated the neutralization coverage and precise binding site in the CD4i epitopes...
September 22, 2017: Retrovirology
https://www.readbyqxmd.com/read/28902916/targeted-n-glycan-deletion-at-the-receptor-binding-site-retains-hiv-env-nfl-trimer-integrity-and-accelerates-the-elicited-antibody-response
#9
Viktoriya Dubrovskaya, Javier Guenaga, Natalia de Val, Richard Wilson, Yu Feng, Arlette Movsesyan, Gunilla B Karlsson Hedestam, Andrew B Ward, Richard T Wyatt
Extensive shielding by N-glycans on the surface of the HIV envelope glycoproteins (Env) restricts B cell recognition of conserved neutralizing determinants. Elicitation of broadly neutralizing antibodies (bNAbs) in selected HIV-infected individuals reveals that Abs capable of penetrating the glycan shield can be generated by the B cell repertoire. Accordingly, we sought to determine if targeted N-glycan deletion might alter antibody responses to Env. We focused on the conserved CD4 binding site (CD4bs) since this is a known neutralizing determinant that is devoid of glycosylation to allow CD4 receptor engagement, but is ringed by surrounding N-glycans...
September 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28878072/high-throughput-protein-engineering-improves-the-antigenicity-and-stability-of-soluble-hiv-1-envelope-glycoprotein-sosip-trimers
#10
Jonathan T Sullivan, Chidananda Sulli, Alberto Nilo, Anila Yasmeen, Gabriel Ozorowski, Rogier W Sanders, Andrew B Ward, P J Klasse, John P Moore, Benjamin J Doranz
Soluble envelope glycoprotein (Env) trimers (SOSIP.664 gp140) are attractive HIV-1 vaccine candidates, with structures that mimic the native membrane-bound Env spike (gp160). Since engineering trimers can be limited by the difficulty of rationally predicting beneficial mutations, here we used a more comprehensive mutagenesis approach with the goal of identifying trimer variants with improved antigenic and stability properties. We created 341 cysteine pairs at predicted points of stabilization throughout gp140, 149 proline residue substitutions at every residue of the gp41 ectodomain, and 362 space-filling residue substitutions at every hydrophobic and aromatic residue in gp140...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28835491/hiv-1-cross-reactive-primary-virus-neutralizing-antibody-response-elicited-by-immunization-in-nonhuman-primates
#11
Yimeng Wang, Sijy O'Dell, Hannah L Turner, Chi-I Chiang, Lin Lei, Javier Guenaga, Richard Wilson, Paola Martinez-Murillo, Nicole Doria-Rose, Andrew B Ward, John R Mascola, Richard T Wyatt, Gunilla B Karlsson Hedestam, Yuxing Li
Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross-reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28830557/membrane-anchored-ccl20-augments-hiv-env-specific-mucosal-immune-responses
#12
Xianliang Sun, Han Zhang, Shuiling Xu, Lili Shi, Jingjian Dong, Dandan Gao, Yan Chen, Hao Feng
BACKGROUND: Induction of broad immune responses at mucosal site remains a primary goal for most vaccines against mucosal pathogens. Abundance of evidence indicates that the co-delivery of mucosal adjuvants, including cytokines, is necessary to induce effective mucosal immunity. In the present study, we set out to evaluate the role of a chemokine, CCL20, as an effective mucosal adjuvant for HIV vaccine. METHODS: To evaluate the role of CCL20 as a potent adjuvant for HIV vaccine, we examined its effects on antigen-specific antibody responses, level of antibody-secreting cells, cytokine production and intestinal homing of plasma cells in vaccine immunized mice...
August 23, 2017: Virology Journal
https://www.readbyqxmd.com/read/28816583/mammalian-cell-surface-display-for-monoclonal-antibody-based-facs-selection-of-viral-envelope-proteins
#13
Tim-Henrik Bruun, Veronika Grassmann, Benjamin Zimmer, Benedikt Asbach, David Peterhoff, Alexander Kliche, Ralf Wagner
The elicitation of broadly and efficiently neutralizing antibodies in humans by active immunization is still a major obstacle in the development of vaccines against pathogens such as the human immunodeficiency virus (HIV), influenza virus, hepatitis C virus or cytomegalovirus. Here, we describe a mammalian cell surface display and monoclonal antibody (mAb)-mediated panning technology that allows affinity-based selection of envelope (Env) variants from libraries. To this end, we established an experimental setup featuring: 1) single and site specific integration of Env to link genotype and phenotype, 2) inducible Env expression to avoid cytotoxicity effects, 3) translational coupling of Env and enhanced green fluorescent protein expression to normalize for Env protein levels, and 4) display on HEK cells to ensure native folding and mammalian glycosylation...
October 2017: MAbs
https://www.readbyqxmd.com/read/28799906/of-mice-macaques-and-men-broadly-neutralizing-antibody-immunotherapy-for-hiv-1
#14
REVIEW
Yoshiaki Nishimura, Malcolm A Martin
The neutralizing antibodies targeting the HIV-1 envelope protein have been a major focus for HIV therapy. Early studies with anti-HIV-1 neutralizing monoclonal antibodies (mAbs) administered to infected individuals showed some promise, as they resulted in transient reductions in plasma viremia in some recipients. However, resistant viral variants rapidly emerged. A major development during the past 6 to 7 years has been the isolation and characterization of highly potent and broadly neutralizing mAbs (bNAbs) from infected individuals known as "elite neutralizers...
August 9, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28790381/selective-cytotoxicity-of-a-novel-immunotoxin-based-on-pulchellin-a-chain-for-cells-expressing-hiv-envelope
#15
Mohammad Sadraeian, Francisco E G Guimarães, Ana P U Araújo, David K Worthylake, Louis Jr LeCour, Seth H Pincus
Immunotoxins (ITs), which consist of antibodies conjugated to toxins, have been proposed as a treatment for cancer and chronic infections. To develop and improve the ITs, different toxins such as ricin, have been used, aiming for higher efficacy against target cells. The toxin pulchellin, isolated from the Abrus pulchellus plant, has similar structure and function as ricin. Here we have compared two plant toxins, recombinant A chains from ricin (RAC) and pulchellin (PAC) toxins, for their ability to kill HIV Env-expressing cells...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28701403/monoclonal-antibodies-derived-from-humans-vaccinated-with-the-rv144-hiv-vaccine-containing-the-hvem-binding-domain-of-herpes-simplex-virus-hsv-glycoprotein-d-neutralize-hsv-infection-mediate-antibody-dependent-cellular-cytotoxicity-and-protect-mice-from-ocular
#16
Kening Wang, Georgia D Tomaras, Sinthujan Jegaskanda, M Anthony Moody, Hua-Xin Liao, Kyle N Goodman, Phillip W Berman, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Jaranit Kaewkungwal, Barton F Haynes, Jeffrey I Cohen
The RV144 HIV vaccine trial included a recombinant HIV glycoprotein 120 (gp120) construct fused to a small portion of herpes simplex virus 1 (HSV-1) glycoprotein D (gD) so that the first 40 amino acids of gp120 were replaced by the signal sequence and the first 27 amino acids of the mature form of gD. This region of gD contains most of the binding site for HVEM, an HSV receptor important for virus infection of epithelial cells and lymphocytes. RV144 induced antibodies to HIV that were partially protective against infection, as well as antibodies to HSV...
October 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28658672/identification-of-a-novel-hiv-1-neutralizing-antibody-from-a-crf07_bc-infected-chinese-donor
#17
Youxiang Sun, Yuanyuan Qiao, Yuanmei Zhu, Huihui Chong, Yuxian He
The identification of human monoclonal antibodies (mAbs) able to neutralize a broad spectrum of primary HIV-1 isolates is highly important for understanding the immune response of HIV-1 infection and developing vaccines and therapeutics. In this study, we isolated a novel human mAb termed Y498 from a phage display antibody library constructed with the PBMC samples of a CRF07_BC-infected Chinese donor whose sera exhibited broadly neutralizing activity. Y498 cross-reacted with diverse Env antigens and neutralized 30% of 70 tested HIV-1 isolates...
June 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28637537/occult-hiv-infection-in-a-large-sample-of-health-care-users-in-lombardy-italy-in-2014-2015-implications-for-control-strategies
#18
L Scudeller, F Genco, F Baldanti, G Comolli, G Albonico, M Prestia, V Meroni
We estimated the number of people unaware of their human immunodeficiency virus (HIV) infection in our province, Pavia (population 540 000) in Lombardy, Italy, by means of anonymous unlinked testing of 10 044 serum/plasma samples residual from clinical analyses at the outpatient clinic of Policlinico San Matteo in 2014 and 2015. Ethical and legal approval was obtained prior to study start. Samples were irreversibly anonymised, only retaining gender and 5-year age class. Five sample pools were tested for HIV using LIAISON® XL MUREX HIV Ab/Ag (DiaSorin, Saluggia, Italy)...
August 2017: Epidemiology and Infection
https://www.readbyqxmd.com/read/28615206/plasticity-and-epitope-exposure-of-the-hiv-1-envelope-trimer
#19
Rebecca L R Powell, Maxim Totrov, Vincenza Itri, Xiaomei Liu, Alisa Fox, Susan Zolla-Pazner
We recently showed that mutations in the HIV-1 envelope (Env) destabilize the V3 loop, rendering neutralization-resistant viruses sensitive to V3-directed monoclonal antibodies (MAbs). Here, we investigated the propagation of this effect on other Env epitopes, with special emphasis on V2 loop exposure. Wild-type JR-FL and 19 mutant JR-FL pseudoviruses were tested for neutralization sensitivity to 21 MAbs specific for epitopes in V2, the CD4 binding site (CD4bs), and the CD4-induced (CD4i) region. Certain glycan mutants, mutations in the gp120 hydrophobic core, and mutations in residues involved in intraprotomer interactions exposed epitopes in the V2i region (which overlies the α4β7 integrin binding site) and the V3 crown, suggesting general destabilization of the distal region of the trimer apex...
September 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28614387/global-sensing-of-the-antigenic-structure-of-herpes-simplex-virus-gd-using-high-throughput-array-based-spr-imaging
#20
Tina M Cairns, Noah T Ditto, Huan Lou, Benjamin D Brooks, Doina Atanasiu, Roselyn J Eisenberg, Gary H Cohen
While HSV-2 typically causes genital lesions, HSV-1 is increasingly the cause of genital herpes. In addition, neonatal HSV infections are associated with a high rate of mortality and HSV-2 may increase the risk for HIV or Zika infections, reinforcing the need to develop an effective vaccine. In the GSK Herpevac trial, doubly sero-negative women were vaccinated with a truncated form of gD2 [gD2(284t)], then examined for anti-gD serum titers and clinical manifestations of disease. Surprisingly, few vaccinees were protected against genital HSV-2 but 86% were protected from genital HSV-1...
June 2017: PLoS Pathogens
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