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Broadly neutralizing antibodies

Nuria González, Krisha McKee, Rebecca M Lynch, Ivelin S Georgiev, Laura Jimenez, Eulalia Grau, Eloísa Yuste, Peter D Kwong, John R Mascola, José Alcamí
BACKGROUND: Only a small fraction of HIV-1-infected patients develop broadly neutralizing antibodies (bNAbs), a process generally associated to chronic antigen stimulation. It has been described that rare aviremic HIV-1-infected patients can generate bNAbs but this issue remains controversial. To address this matter we have assessed bNAb responses in a large cohort of long-term non-progressors (LTNPs) with low or undetectable viremia. METHODS: Samples from the LTNP cohort of the Spanish AIDS Research Network (87 elite and 42 viremic controllers) and a control population of 176 viremic typical-progressors (TPs) were screened for bNAbs using Env-recombinant viruses...
2018: PloS One
Daniela Fera, Matthew S Lee, Kevin Wiehe, R Ryan Meyerhoff, Alessandro Piai, Mattia Bonsignori, Baptiste Aussedat, William E Walkowicz, Therese Ton, Jeffrey O Zhou, Samuel Danishefsky, Barton F Haynes, Stephen C Harrison
HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide ("Man9 -V3") for structural studies of an HIV Env third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage ("DH270"), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man9 -V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs-the conserved GDIR motif and the N332 glycan...
March 16, 2018: Nature Communications
Zhaojian Xiang, Weike Li, Lixue Wang, Jicai Yi, Kaiwen Chen, Mei Hong
Organic anion-transporting polypeptides (OATPs; gene symbol SLCO) are membrane transporters that mediate the transport of wide ranges of compounds. Expression of different OATP members has been reported in the kidney, liver, placenta, brain, and intestine. Due to their broad substrate spectra and wide distribution within human body, these transporters have been proposed to play key roles in the influx transport of many oral drugs. Inflammation is known to regulate the expression and functions of many drug-metabolizing enzymes and drug transporters...
March 16, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
D Lapuente, M Storcksdieck Genannt Bonsmann, A Maaske, V Stab, V Heinecke, K Watzstedt, R Heß, A M Westendorf, W Bayer, C Ehrhardt, M Tenbusch
A universal influenza vaccine must provide protection against antigenically divergent influenza viruses either through broadly neutralizing antibodies or cross-reactive T cells. Here, intranasal immunizations with recombinant adenoviral vectors (rAd) encoding hemagglutinin (HA) and nucleoprotein (NP) in combination with rAd-Interleukin-(IL)-1β or rAd-IL-18 were evaluated for their efficacy in BALB/c mice. Mucosal delivery of rAd-IL-1β enhanced HA-specific antibody responses including strain-specific neutralizing antibodies...
March 15, 2018: Mucosal Immunology
John L M Law, Michael Logan, Jason Wong, Juthika Kundu, Darren Hockman, Amir Landi, Chao Chen, Kevin Crawford, Mark Wininger, Janelle Johnson, Catalina Mesa Prince, Elzbieta Dudek, Ninad Mehta, D Lorne Tyrrell, Michael Houghton
Current evidence supports a protective role for virus neutralizing antibodies in immunity against HCV infection. Many cross-neutralizing monoclonal antibodies have been identified. These antibodies have been shown to protect or clear infection in animal models. Previous clinical trials have shown a gpE1/gpE2 vaccine can induce antibodies that neutralize the in vitro infectivity of all the major HCVcc genotypes around the world. However, cross-neutralization appeared to favour certain genotypes with significant but lower neutralization against others...
March 14, 2018: Journal of Virology
Shelly Popowich, Ashish Gupta, Betty Chow-Lockerbie, Lisanework Ayalew, Neil Ambrose, Davor Ojkic, Thushari Gunawardana, Shanika Kurukulasuriya, Philip Willson, Suresh K Tikoo, Susantha Gomis
Historically, fowl adenovirus (FAdV) associated inclusion body hepatitis (IBH) was considered a secondary disease in broiler chickens associated with immunosuppression. However, we previously reported the occurrence of IBH as a primary disease in the broiler chicken industry in Canada as a result of infections with various FAdV serotypes. Therefore, the objectives of this study were to develop an immunization strategy in broiler breeders using live FAdV 11-1047 and FAdV8a-TR59 to confer homologous and heterologous protection in broiler progeny against IBH and to study the efficacy of natural exposure of naïve broiler breeders to a vaccine virus from live FAdV vaccinated birds as an immunization technique...
March 5, 2018: Research in Veterinary Science
E N Ilina, M V Larina, T K Aliev, D A Dolgikh, M P Kirpichnikov
Rabies virus is a prototypical neurotropic virus that causes one of the most dangerous zoonotic diseases in humans. Humanized or fully human monoclonal antibodies (mAb) that neutralize rabies virus would be the basis for powerful post-exposure prophylaxis of rabies in humans, having several significant benefits in comparison with human or equine rabies polyclonal immunoglobulins. The most advanced antibodies should broadly neutralize natural rabies virus isolates, bind with conserved antigenic determinants of the rabies virus glycoprotein, and show high neutralizing potency in assays in vivo...
January 2018: Biochemistry. Biokhimii︠a︡
Aitor Nogales, Michael S Piepenbrink, Jiong Wang, Sandra Ortega, Madhubanti Basu, Christopher F Fucile, John J Treanor, Alexander F Rosenberg, Martin S Zand, Michael C Keefer, Luis Martinez-Sobrido, James J Kobie
Influenza's propensity for antigenic drift and shift, and to elicit predominantly strain specific antibodies (Abs) leaves humanity susceptible to waves of new strains with pandemic potential for which limited or no immunity may exist. Subsequently new clinical interventions are needed. To identify hemagglutinin (HA) epitopes that if targeted may confer universally protective humoral immunity, we examined plasmablasts from a subject that was immunized with the seasonal influenza inactivated vaccine, and isolated a human monoclonal Ab (mAb), KPF1...
March 12, 2018: Scientific Reports
Stanislav O Fedechkin, Natasha L George, Jacob T Wolff, Lawrence M Kauvar, Rebecca M DuBois
Respiratory syncytial virus (RSV) is a top cause of severe lower respiratory tract disease and mortality in young children and the elderly. The viral envelope G glycoprotein contributes to pathogenesis through its roles in host cell attachment and modulation of host immunity. Although the G glycoprotein is a target of protective RSV-neutralizing antibodies, its development as a vaccine antigen has been hindered by its heterogeneous glycosylation and sequence variability outside a conserved central domain (CCD)...
March 9, 2018: Science Immunology
J V Camp, R Haider, D Porea, L E Oslobanu, P Forgách, N Nowotny
A serosurvey for Tahyna virus (TAHV), a mosquito-borne California encephalitis orthobunyavirus (Peribunyaviridae) endemic to Europe, was performed to estimate the activity of TAHV on a broad geographic scale. Sera from wild boar (Sus scrofa), roe deer (Capreolus capreolus) and red deer (Cervus elaphus) were collected from Austria, Hungary and Romania. Samples were tested for neutralizing antibodies against TAHV using a virus microneutralization assay. The results demonstrate that TAHV transmission to mammals is widespread in Europe, particularly in the wild boar population where the mean rate of seroconversion is 15...
March 8, 2018: Zoonoses and Public Health
Hao D Cheng, Sebastian K Grimm, Morgan Sa Gilman, Luc Christian Gwom, Devin Sok, Christopher Sundling, Gina Donofrio, Gunilla B Karlsson Hedestam, Mattia Bonsignori, Barton F Haynes, Timothy P Lahey, Isaac Maro, C Fordham von Reyn, Miroslaw K Gorny, Susan Zolla-Pazner, Bruce D Walker, Galit Alter, Dennis R Burton, Merlin L Robb, Shelly J Krebs, Michael S Seaman, Chris Bailey-Kellogg, Margaret E Ackerman
Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth...
March 8, 2018: JCI Insight
Yanmin Wan, Guobin Kang, Chithra Sreenivasan, Lance Daharsh, Junfeng Zhang, Wenjin Fan, Dan Wang, Hideaki Moriyama, Feng Li, Qingsheng Li
Two lineages of Influenza D virus (IDV) have been found to infect cattle and promote bovine respiratory disease complex (BRDC), one of the most commonly diagnosed causes of morbidity and mortality within the cattle industry. Furthermore, IDV can infect other economically important domestic livestock including pigs and has the potential to infect humans, which necessitates the need for an efficacious vaccine. In this study, we designed a DNA vaccine expressing consensus hemagglutinin-esterase-fusion (HEF) protein (FluD-Vax) and tested its protective efficacy against two lineages of IDV (D/OK and D/660) in guinea pigs...
March 7, 2018: Journal of Virology
Jesse L Huang, Attila Nagy, Vera B Ivleva, Daniel Blackstock, Frank Arnold, Cindy X Cai
One approach to mitigate product clipping during HIV mAb CAP256-VRC26.25 cell culture development is the addition of protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF) to the cell culture media. AEBSF can undergo hydrolysis to form an inactive compound, 4-(2-aminoethyl) benzenesulfonic acid. Using mass spectrometry detection, a kinetic profiling of AEBSF hydrolysis was generated for conditions simulating that of cell culture at pH 7.0/37 C. It was found that increasing pH and/or temperature could accelerate AEBSF hydrolysis...
March 6, 2018: Analytical Chemistry
Adam Vigil, Angeles Estélles, Lawrence M Kauvar, Scott K Johnson, Ralph A Tripp, Michael Wittekind
Although antibodies that effectively neutralize a broad set of influenza viruses exist in the human antibody repertoire, they are rare. We used a single cell screening technology to identify rare monoclonal antibodies (mAbs) that recognized a broad set of influenza B viruses (IBV). The screen yielded 23 mAbs with diverse germ line origins that recognized hemagglutinins (HAs) derived from influenza strains of both the Yamagata and Victoria lineages of IBV. Of the 23 mAbs, three exhibited low expression in a transient transfection system, four were neutralizers that bound to the HA head region, eleven were stalk-binding non-neutralizers, and five were stalk-binding neutralizers with four of these five representing unique antibody sequences...
March 5, 2018: Antimicrobial Agents and Chemotherapy
Kshitij Wagh, Michael S Seaman, Marshall Zingg, Tomas Fitzsimons, Dan H Barouch, Dennis R Burton, Mark Connors, David D Ho, John R Mascola, Michel C Nussenzweig, Jeffrey Ravetch, Rajeev Gautam, Malcolm A Martin, David C Montefiori, Bette Korber NCT02960581.
March 5, 2018: PLoS Pathogens
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...
March 1, 2018: Journal of Biological Chemistry
James J Steinhardt, Javier Guenaga, Hannah L Turner, Krisha McKee, Mark K Louder, Sijy O'Dell, Chi-I Chiang, Lin Lei, Andrey Galkin, Alexander K Andrianov, Nicole A Doria-Rose, Robert T Bailer, Andrew B Ward, John R Mascola, Yuxing Li
HIV-1 broadly neutralizing antibodies (bNAbs) are being explored as passively administered therapeutic and preventative agents. However, the extensively diversified HIV-1 envelope glycoproteins (Env) rapidly acquire mutations to evade individual bNAbs in monotherapy regimens. The use of a "single" agent to simultaneously target distinct Env epitopes is desirable to overcome viral diversity. Here, we report the use of tandem single-chain variable fragment (ScFv) domains of two bNAbs, specific for the CD4-binding site and V3 glycan patch, to form anti-HIV-1 bispecific ScFvs (Bi-ScFvs)...
February 28, 2018: Nature Communications
Manickam Ashokkumar, Shambhu G Aralaguppe, Srikanth P Tripathy, Luke Elizabeth Hanna, Ujjwal Neogi
Adequate information on the precise molecular and biological composition of the viral strains that establish HIV-infection in the human host will provide effective means of immunization against HIV-infection. In an attempt to identify and differentiate the biological properties and infectious potential of the transmitted founder (TF) virus from the population of the early transmitted virus, patient-derived 250 envelope glycoprotein, gp120 were cloned in pMN-K7-Luc-IRESs-NefΔgp120 to obtain chimeric viruses...
February 28, 2018: Journal of Virology
Estefania Fernandez, Nurgun Kose, Melissa A Edeling, Jagat Adhikari, Gopal Sapparapu, Susana M Lazarte, Christopher A Nelson, Jennifer Govero, Michael L Gross, Daved H Fremont, James E Crowe, Michael S Diamond
Japanese encephalitis virus (JEV) remains a leading cause of viral encephalitis worldwide. Although JEV-specific antibodies have been described, an assessment of their ability to neutralize multiple genotypes of JEV has been limited. Here, we describe the development of a panel of mouse and human neutralizing monoclonal antibodies (MAbs) that inhibit infection in cell culture of four different JEV genotypes tested. Mechanism-of-action studies showed that many of these MAbs inhibited infection at a postattachment step, including blockade of virus fusion...
February 27, 2018: MBio
Ke Chen, Liang Cheng, Weikun Qian, Zhengdong Jiang, Liankang Sun, Yanfei Zhao, Yongsheng Zhou, Lizhi Zhao, Pengli Wang, Wanxing Duan, Qingyong Ma, Wei Yang
Pancreatic cancer is the fourth leading cause of cancer-associated mortality worldwide, with an overall 5-year survival rate <8%. We studied the therapeutic effect of itraconazole (ITZ), a commonly used broad-spectrum anti-fungal agent, in the treatment of pancreatic cancer, and to reveal the underlying anticancer mechanisms. Effects of ITZ on cell proliferation, apoptosis, invasion and migration were observed by MTT assays and colony formation assays, flow cytometry, wound scratch assays and transwell assays, respectively...
February 26, 2018: Oncology Reports
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