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Broadly neutralizing antibodies

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https://www.readbyqxmd.com/read/28230658/engineering-antibody-like-inhibitors-to-prevent-and-treat-hiv-1-infection
#1
Matthew R Gardner, Michael Farzan
PURPOSE OF REVIEW: Here we discuss recently developed HIV-1 entry inhibitors that can target multiple epitopes on the HIV-1 envelope glycoprotein (Env), with an emphasis on eCD4-Ig. Some of these inhibitors are more potent and broader than any single antibody characterized to date. We also discuss the use of recombinant adeno-associated virus (rAAV) vectors as a platform for long-term expression of these inhibitors. RECENT FINDINGS: Much of the exterior of HIV-1 Env can be targeted by broadly neutralizing antibodies (bNAbs)...
February 21, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28230657/stabilized-hiv-1-envelope-glycoprotein-trimers-for-vaccine-use
#2
Max Medina-Ramírez, Rogier W Sanders, Quentin J Sattentau
PURPOSE OF REVIEW: To provide an update on the latest developments in the field of HIV-1 antibody-based soluble envelope glycoprotein (Env) trimer design for vaccine use. RECENT FINDINGS: The development of soluble native-like HIV-1 Env trimer immunogens has moved the field of antibody-based vaccine design forward dramatically over the past few years with refinement of various stabilizing approaches. However, despite this progress, significant challenges remain...
February 21, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28230655/lessons-learned-from-human-hiv-vaccine-trials
#3
Justin Pollara, David Easterhoff, Genevieve G Fouda
PURPOSE OF REVIEW: The ability to induce broadly neutralizing antibody (bNAb) responses is likely essential for development of a globally effective HIV vaccine. Unfortunately, human vaccine trials conducted to date have failed to elicit broad plasma neutralization of primary virus isolates. Despite this limitation, in-depth analysis of the vaccine-induced memory B-cell repertoire can provide valuable insights into the presence and function of subdominant B-cell responses, and identify initiation of antibody lineages that may be on a path towards development of neutralization breadth...
February 21, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28225819/lipid-interactions-and-angle-of-approach-to-the-hiv-1-viral-membrane-of-broadly-neutralizing-antibody-10e8-insights-for-vaccine-and-therapeutic-design
#4
Adriana Irimia, Andreia M Serra, Anita Sarkar, Ronald Jacak, Oleksandr Kalyuzhniy, Devin Sok, Karen L Saye-Francisco, Torben Schiffner, Ryan Tingle, Michael Kubitz, Yumiko Adachi, Robyn L Stanfield, Marc C Deller, Dennis R Burton, William R Schief, Ian A Wilson
Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater neutralizing breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The 10E8 epitope has been identified as the conserved membrane proximal external region (MPER) of gp41 subunit of the envelope (Env) viral glycoprotein and is a major vaccine target. However, the MPER is proximal to the viral membrane and may be laterally inserted into the membrane in the Env prefusion form. Nevertheless, 10E8 has not been reported to have significant lipid-binding reactivity...
February 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28225449/ifn-%C3%AE-augments-natural-killer-mediated-antibody-dependent-cellular-cytotoxicity-of-hiv-1-infected-autologous-cd4-t-cells-regardless-of-major-histocompatibility-complex-class-1-downregulation
#5
Costin Tomescu, Pablo Tebas, Luis J Montaner
DESIGN: We have previously shown that IFN-α stimulation augments direct natural killer (NK) cell lysis of autologous CD4 primary T cells infected with certain HIV-1 isolates based upon major histocompatibility complex class 1 (MHC-1) downregulation capacity. Here, we investigated if antibody-dependent cellular cytotoxicity (ADCC) could trigger lysis of HIV-1 isolates that were resistant to direct NK lysis and if IFN-α prestimulation of NK cells could further enhance ADCC. METHODS: Using broadly neutralizing monoclonal antibodies against gp120 (VRC01 or PGV04) or plasma from HIV-1-infected patients (ART-suppressed or elite controller) to trigger ADCC, we measured NK cell chromium release cytotoxicity against HIV-1-infected autologous CD4 primary T cells and NK cell CD107a degranulation against gp120-coated CD4 T cells...
March 13, 2017: AIDS
https://www.readbyqxmd.com/read/28222130/dengue-virus-antibody-database-systematically-linking-serotype-specificity-with-epitope-mapping-in-dengue-virus
#6
Sidhartha Chaudhury, Gregory D Gromowski, Daniel R Ripoll, Ilja V Khavrutskii, Valmik Desai, Anders Wallqvist
BACKGROUND: A majority infections caused by dengue virus (DENV) are asymptomatic, but a higher incidence of severe illness, such as dengue hemorrhagic fever, is associated with secondary infections, suggesting that pre-existing immunity plays a central role in dengue pathogenesis. Primary infections are typically associated with a largely serotype-specific antibody response, while secondary infections show a shift to a broadly cross-reactive antibody response. METHODS/PRINCIPAL FINDINGS: We hypothesized that the basis for the shift in serotype-specificity between primary and secondary infections can be found in a change in the antibody fine-specificity...
February 21, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28213514/peripheral-membrane-interactions-boost-the-engagement-by-an-anti-hiv-1-broadly-neutralizing-antibody
#7
Edurne Rujas, José M M Caaveiro, Sara Insausti, Miguel García-Porras, Kouhei Tsumoto, José L Nieva
The 4E10 antibody displays an extreme breadth of HIV-1 neutralization and therefore constitutes a suitable model system for structure- guided vaccine design and immunotherapeutics against AIDS. In this regard, the relevance of auto- reactivity with membrane lipids for the biological function of this antibody is still a subject of controversy. To address this dispute, herein we have compared the membrane-partitioning ability of the 4E10 antibody and several of its variants, which were mutated at the region of the paratope surface in contact with the membrane-interface...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28207490/how-hiv-1-entry-mechanism-and-broadly-neutralizing-antibodies-guide-structure-based-vaccine-design
#8
Marie Pancera, Anita Changela, Peter D Kwong
PURPOSE OF REVIEW: An HIV-1 vaccine that elicits broadly neutralizing antibodies (bNAbs) remains to be developed. Here, we review how knowledge of bNAbs and HIV-1 entry mechanism is guiding the structure-based design of vaccine immunogens and immunization regimens. RECENT FINDINGS: Isolation of bNAbs from HIV-1-infected donors has led to an unprecedented understanding of the sites of vulnerability that these antibodies target on the HIV-1 envelope (Env) as well as of the immunological pathways that these antibody lineages follow to develop broad and potent neutralization...
February 15, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28207489/b-cell-abnormalities-and-impact-on-antibody-response-in-hiv-infection
#9
Alessandra Noto, Giuseppe Pantaleo
PURPOSE OF REVIEW: The purpose of the present review is to provide an update on the current development in the field of broadly neutralizing antibodies (bNabs) and their potential use in the prevention and therapeutic settings, and an evaluation of the B-cell abnormalities that may impair antibody responses in HIV infection. RECENT FINDINGS: Major advances have been achieved in the characterization of bNabs directed against different vulnerable regions of HIV Envelope (Env)...
February 15, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28207488/lessons-learned-from-humoral-responses-of-hiv-patients
#10
Laura E McCoy, Áine McKnight
PURPOSE OF REVIEW: Since 2009 many broadly neutralizing antibodies against HIV have been identified, yet there is still no vaccine capable of inducing such antibodies in humans. This review considers the early observations of HIV sera neutralization in light of more recent studies and highlights areas for future research. RECENT FINDINGS: Large clinical cohort studies using standardized neutralization assays and pseudoviruses derived from primary isolates have shown that 10-30% of HIV infections result in some level of serum neutralization breadth...
February 15, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28207486/particle-based-delivery-of-the-hiv-envelope-protein
#11
Benedikt Asbach, Ralf Wagner
PURPOSE OF REVIEW: A major focus in HIV vaccine research is the development of suitable antigens that elicit broadly neutralizing antibody responses targeting HIV's envelope protein (Env). Delivery of Env in a repetitive manner on particle-based carriers allows higher avidity interactions and is therefore expected to efficiently engage B cells, thus leading to affinity maturation that results in superior antibody responses characterized by improved breadth, potency, and durability. This review summarizes current work that is evaluating diverse types of such particulate carriers for Env delivery...
February 15, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28207485/antigp41-membrane-proximal-external-region-antibodies-and-the-art-of-using-the-membrane-for-neutralization
#12
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...
February 15, 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28202756/a-glycosylation-benchmark-profile-for-hiv-1-envelope-glycoprotein-production-based-on-eleven-env-trimers
#13
Eden P Go, Haitao Ding, Shijian Zhang, Rajesh P Ringe, Nathan Nicely, David Hua, Robert T Steinbock, Michael Golabek, James Alin, S Munir Alam, Albert Cupo, Barton F Haynes, John C Kappes, John P Moore, Joseph G Sodroski, Heather Desaire
HIV-1 envelope glycoprotein (Env) glycosylation is important because individual glycans are components of multiple broadly neutralizing antibody epitopes, while shielding other sites that might otherwise be immunogenic. The glycosylation on Env is influenced by a variety of factors, including the genotype of the protein, the cell line used for its expression, and the details of the construct design. Here, we used a mass spectrometry-based approach to map the complete glycosylation profile at every site in multiple HIV-1 Env trimers, accomplishing two goals: 1) We determined which glycosylation sites contain conserved glycan profiles across many trimeric Envs...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28194154/the-role-of-cd4-t-follicular-helper-cells-in-hiv-infection-from-the-germinal-center-to-the-periphery
#14
REVIEW
John Patrick Thornhill, Sarah Fidler, Paul Klenerman, John Frater, Chansavath Phetsouphanh
T follicular helper cells (TFh) are key components of the adaptive immune system; they are primarily found in germinal centers (GCs) where their interaction with B cells supports humoral immune responses and efficient antibody production. They are defined by the expression of CXC receptor 5, program death-1, ICOS, and secretion of IL-21. Their differentiation is regulated by B-cell lymphoma 6. The relationship and function of circulating TFh to bona fide TFh resident in the GC is much debated. HIV infection impacts the TFh response with evidence of aberrant TFh function observed in acute and chronic infection...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28187204/differentiating-founder-and-chronic-hiv-envelope-sequences
#15
John M Murray, Stephen Maher, Talia Mota, Kazuo Suzuki, Anthony D Kelleher, Rob J Center, Damian Purcell
Significant progress has been made in characterizing broadly neutralizing antibodies against the HIV envelope glycoprotein Env, but an effective vaccine has proven elusive. Vaccine development would be facilitated if common features of early founder virus required for transmission could be identified. Here we employ a combination of bioinformatic and operations research methods to determine the most prevalent features that distinguish 78 subtype B and 55 subtype C founder Env sequences from an equal number of chronic sequences...
2017: PloS One
https://www.readbyqxmd.com/read/28179536/hiv-aids-vaccine-candidates-based-on-replication-competent-recombinant-poxvirus-nyvac-c-kc-expressing-trimeric-gp140-and-gag-derived-vlps-or-lacking-the-viral-molecule-b19-that-inhibits-type-i-interferon-activate-relevant-hiv-1-specific-b-and-t-cell-immune
#16
Juan García-Arriaza, Beatriz Perdiguero, Jonathan L Heeney, Michael S Seaman, David C Montefiori, Nicole L Yates, Georgia D Tomaras, Guido Ferrari, Kathryn E Foulds, Mario Roederer, Steven G Self, Bhavesh Borate, Raphael Gottardo, Sanjay Phogat, Jim Tartaglia, Susan W Barnett, Brian Burke, Anthony D Cristillo, Deborah E Weiss, Carter Lee, Karen V Kibler, Bertram L Jacobs, Ralf Wagner, Song Ding, Giuseppe Pantaleo, Mariano Esteban
The non-replicating attenuated poxvirus vector NYVAC expressing clade C(CN54) HIV-1 Env(gp120), Gag-Pol-Nef antigens (NYVAC-C) showed in phase I clinical trials limited immunogenicity. To enhance the capacity of the NYVAC vector to trigger broad humoral responses and a more balanced activation of CD4(+) and CD8(+) T cells, here we compared the HIV-1-specific immunogenicity elicited in non-human primates immunized with two replicating NYVAC vectors that have been modified by the insertion of K1L and C7L vaccinia viral host-range genes and express clade C(ZM96) trimeric HIV-1 gp140 protein or a Gag(ZM96)-Pol-Nef(CN54) polyprotein as Gag-derived virus-like particles (termed NYVAC-C-KC)...
February 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28179535/a-bivalent-heterologous-dna-virus-like-particles-prime-boost-vaccine-elicits-broad-protection-against-both-groups-1-and-2-influenza-a-viruses
#17
Wenbo Jiang, Shuangshuang Wang, Honglin Chen, Huanhuan Ren, Xun Huang, Guiqin Wang, Ze Chen, Ling Chen, Zhiwei Chen, Paul Zhou
Current seasonal influenza vaccines are efficacious when vaccine strains are matched with circulating strains. But they do not protect antigenic variants and newly emerging pandemic and outbreak strains. Thus there is a critical need for developing so-called "universal" vaccines that protect against all influenza viruses. In the present study we developed a bivalent heterologous DNA-virus-like particles (VLP) prime-boost vaccine strategy. We show that mice immunized with this vaccine were broadly protected against lethal challenge of group 1 (H1, H5 and H9) and group 2 (H3 and H7) viruses with 94% aggregate survival...
February 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28179531/toll-like-receptor-7-agonist-gs-9620-induces-hiv-expression-and-hiv-specific-immunity-in-cells-from-hiv-infected-individuals-on-suppressive-antiretroviral-therapy
#18
Angela Tsai, Alivelu Irrinki, Jasmine Kaur, Tomas Cihlar, George Kukolj, Derek D Sloan, Jeffrey P Murry
Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs)...
February 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28179429/serinc5-inhibits-hiv-1-fusion-pore-formation-by-promoting-functional-inactivation-of-envelope-glycoproteins
#19
Chetan Sood, Mariana Marin, Ajit Chande, Massimo Pizzato, Gregory B Melikyan
The host proteins, SERINC3 and SERINC5, have been recently shown to incorporate into HIV-1 particles and compromise their ability to fuse with target cells - an effect that is antagonized by the viral Nef protein. Env glycoproteins from different HIV-1 isolates exhibit a broad range of sensitivity to SERINC-mediated restriction, and the mechanism by which SERINCs interfere with HIV-1 fusion remains unclear. Here, we show that incorporation of SERINC5 into virions in the absence of Nef inhibits the formation of small fusion pores between viruses and cells...
February 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28176006/development-of-a-high-throughput-colorimetric-zika-virus-infection-assay
#20
Janis A Müller, Mirja Harms, Axel Schubert, Benjamin Mayer, Stephanie Jansen, Jean-Philippe Herbeuval, Detlef Michel, Thomas Mertens, Olli Vapalahti, Jonas Schmidt-Chanasit, Jan Münch
Zika virus (ZIKV) is an emerging pathogen that causes congenital infections which may result in birth defects, such as microcephaly. Currently, no approved treatment or vaccination is available. ZIKV can be readily detected in cell culture where virally infected cells are normally stained by specific antibodies. As ZIKV regularly causes a cytopathic effect, we were wondering whether this viral property can be used to quantitatively determine viral infectivity. We here describe the use of an 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide-(MTT)-based cell viability assay that allows to determine ZIKV-induced cell death...
February 7, 2017: Medical Microbiology and Immunology
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