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91.
Bonsignori M Hwang KK Chen X Tsao CY Morris L Gray E Marshall DJ Crump JA Kapiga SH Sam NE Sinangil F Pancera M Yongping Y Zhang B Zhu J Kwong PD O'Dell S Mascola JR Wu L Nabel GJ Phogat S Seaman MS Whitesides JF Moody MA Kelsoe G Yang X Sodroski J Shaw GM Montefiori DC Kepler TB Tomaras GD Alam SM Liao HX Haynes BF 《Journal of virology》2011,85(19):9998-10009
V2/V3 conformational epitope antibodies that broadly neutralize HIV-1 (PG9 and PG16) have been recently described. Since an elicitation of previously known broadly neutralizing antibodies has proven elusive, the induction of antibodies with such specificity is an important goal for HIV-1 vaccine development. A critical question is which immunogens and vaccine formulations might be used to trigger and drive the development of memory B cell precursors with V2/V3 conformational epitope specificity. In this paper we identified a clonal lineage of four V2/V3 conformational epitope broadly neutralizing antibodies (CH01 to CH04) from an African HIV-1-infected broad neutralizer and inferred their common reverted unmutated ancestor (RUA) antibodies. While conformational epitope antibodies rarely bind recombinant Env monomers, a screen of 32 recombinant envelopes for binding to the CH01 to CH04 antibodies showed monoclonal antibody (MAb) binding to the E.A244 gp120 Env and to chronic Env AE.CM243; MAbs CH01 and CH02 also bound to transmitted/founder Env B.9021. CH01 to CH04 neutralized 38% to 49% of a panel of 91 HIV-1 tier 2 pseudoviruses, while the RUAs neutralized only 16% of HIV-1 isolates. Although the reverted unmutated ancestors showed restricted neutralizing activity, they retained the ability to bind to the E.A244 gp120 HIV-1 envelope with an affinity predicted to trigger B cell development. Thus, E.A244, B.9021, and AE.CM243 Envs are three potential immunogen candidates for studies aimed at defining strategies to induce V2/V3 conformational epitope-specific antibodies. 相似文献
92.
Hansman GS Biertümpfel C Georgiev I McLellan JS Chen L Zhou T Katayama K Kwong PD 《Journal of virology》2011,85(13):6687-6701
Noroviruses are the dominant cause of outbreaks of gastroenteritis worldwide, and interactions with human histo-blood group antigens (HBGAs) are thought to play a critical role in their entry mechanism. Structures of noroviruses from genogroups GI and GII in complex with HBGAs, however, reveal different modes of interaction. To gain insight into norovirus recognition of HBGAs, we determined crystal structures of norovirus protruding domains from two rarely detected GII genotypes, GII.10 and GII.12, alone and in complex with a panel of HBGAs, and analyzed structure-function implications related to conservation of the HBGA binding pocket. The GII.10- and GII.12-apo structures as well as the previously solved GII.4-apo structure resembled each other more closely than the GI.1-derived structure, and all three GII structures showed similar modes of HBGA recognition. The primary GII norovirus-HBGA interaction involved six hydrogen bonds between a terminal αfucose1-2 of the HBGAs and a dimeric capsid interface, which was composed of elements from two protruding subdomains. Norovirus interactions with other saccharide units of the HBGAs were variable and involved fewer hydrogen bonds. Sequence analysis revealed a site of GII norovirus sequence conservation to reside under the critical αfucose1-2 and to be one of the few patches of conserved residues on the outer virion-capsid surface. The site was smaller than that involved in full HBGA recognition, a consequence of variable recognition of peripheral saccharides. Despite this evasion tactic, the HBGA site of viral vulnerability may provide a viable target for small molecule- and antibody-mediated neutralization of GII norovirus. 相似文献
93.
Joseph T. Wu Kathy Leung Ranawaka A. P. M. Perera Daniel K. W. Chu Cheuk Kwong Lee Ivan F. N. Hung Che Kit Lin Su-Vui Lo Yu-Lung Lau Gabriel M. Leung Benjamin J. Cowling J. S. Malik Peiris 《PLoS pathogens》2014,10(4)
Seroprevalence survey is the most practical method for accurately estimating infection attack rate (IAR) in an epidemic such as influenza. These studies typically entail selecting an arbitrary titer threshold for seropositivity (e.g. microneutralization [MN] 1∶40) and assuming the probability of seropositivity given infection (infection-seropositivity probability, ISP) is 100% or similar to that among clinical cases. We hypothesize that such conventions are not necessarily robust because different thresholds may result in different IAR estimates and serologic responses of clinical cases may not be representative. To illustrate our hypothesis, we used an age-structured transmission model to fully characterize the transmission dynamics and seroprevalence rises of 2009 influenza pandemic A/H1N1 (pdmH1N1) during its first wave in Hong Kong. We estimated that while 99% of pdmH1N1 infections became MN1∶20 seropositive, only 72%, 62%, 58% and 34% of infections among age 3–12, 13–19, 20–29, 30–59 became MN1∶40 seropositive, which was much lower than the 90%–100% observed among clinical cases. The fitted model was consistent with prevailing consensus on pdmH1N1 transmission characteristics (e.g. initial reproductive number of 1.28 and mean generation time of 2.4 days which were within the consensus range), hence our ISP estimates were consistent with the transmission dynamics and temporal buildup of population-level immunity. IAR estimates in influenza seroprevalence studies are sensitive to seropositivity thresholds and ISP adjustments which in current practice are mostly chosen based on conventions instead of systematic criteria. Our results thus highlighted the need for reexamining conventional practice to develop standards for analyzing influenza serologic data (e.g. real-time assessment of bias in ISP adjustments by evaluating the consistency of IAR across multiple thresholds and with mixture models), especially in the context of pandemics when robustness and comparability of IAR estimates are most needed for informing situational awareness and risk assessment. The same principles are broadly applicable for seroprevalence studies of other infectious disease outbreaks. 相似文献
94.
95.
Young Do Kwon Judith M. LaLonde Yongping Yang Mark A. Elban Akihiro Sugawara Joel R. Courter David M. Jones Amos B. Smith III Asim K. Debnath Peter D. Kwong 《PloS one》2014,9(1)
Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization. 相似文献
96.
Natalia Casta?o-Rodríguez Nadeem O. Kaakoush Khean-Lee Goh Kwong Ming Fock Hazel M. Mitchell 《PloS one》2014,9(6)
BackgroundCurrently, it is well established that cancer arises in chronically inflamed tissue. A number of NOD-like receptors (NLRs) form inflammasomes, intracellular multiprotein complexes critical for generating mature pro-inflammatory cytokines (IL-1β and IL-18). As chronic inflammation of the gastric mucosa is a consequence of Helicobacter pylori infection, we investigated the role of genetic polymorphisms and expression of genes involved in the NLR signalling pathway in H. pylori infection and related gastric cancer (GC).ResultsCARD8-rs11672725, NLRP3-rs10754558, NLRP3-rs4612666, NLRP12-rs199475867 and NLRX1-rs10790286 showed significant associations with GC. On multivariate analysis, CARD8-rs11672725 remained a risk factor (OR: 4.80, 95% CI: 1.39–16.58). Further, NLRP12-rs2866112 increased the risk of H. pylori infection (OR: 2.13, 95% CI: 1.22–3.71). Statistical analyses assessing the joint effect of H. pylori infection and the selected polymorphisms revealed strong associations with GC (CARD8, NLRP3, CASP1 and NLRP12 polymorphisms). In gene expression analyses, five genes encoding NLRs were significantly regulated in H. pylori-challenged cells (NLRC4, NLRC5, NLRP9, NLRP12 and NLRX1). Interestingly, persistent up-regulation of NFKB1 with simultaneous down-regulation of NLRP12 and NLRX1 was observed in H. pylori GC026-challenged cells. Further, NF-κB target genes encoding pro-inflammatory cytokines, chemokines and molecules involved in carcinogenesis were markedly up-regulated in H. pylori GC026-challenged cells.ConclusionsNovel associations between polymorphisms in the NLR signalling pathway (CARD8, NLRP3, NLRP12, NLRX1, and CASP1) and GC were identified in Chinese individuals. Our genetic polymorphisms and gene expression results highlight the relevance of the NLR signalling pathway in gastric carcinogenesis and its close interaction with NF-κB. 相似文献
97.
98.
Priyamvada Acharya William D. Tolbert Neelakshi Gohain Xueji Wu Lei Yu Tongyun Liu Wensheng Huang Chih-chin Huang Young Do Kwon Robert K. Louder Timothy S. Luongo Jason S. McLellan Marie Pancera Yongping Yang Baoshan Zhang Robin Flinko James S. Foulke Jr. Mohammad M. Sajadi Roberta Kamin-Lewis James E. Robinson Lo?c Martin Peter D. Kwong Yongjun Guan Anthony L. DeVico George K. Lewis Marzena Pazgier 《Journal of virology》2014,88(21):12895-12906
99.
Objective
To determine the predictors of the extent of carotid atherosclerosis in patients treated with radiotherapy (RT) for nasopharyngeal carcinoma (NPC).Methods
The present study investigated 129 post-RT NPC patients. Carotid atherosclerotic parameters, such as carotid intima-media thickness, carotid arterial stiffness and carotid plaque burden (plaque score, the presence of plaque and ≥50% stenosis) were assessed using ultrasonography. The association between carotid atherosclerotic parameters and nine potential predictors, including age, gender, post-RT duration, radiation dose, chemotherapy, diabetes mellitus, hypertension, hypercholesterolemia, and smoking, were determined using multiple regression. The cutoff values of age, post-RT duration and number of cardiovascular risk factors for the presence of carotid plaque or ≥50% carotid stenosis were analyzed using receiver operating characteristic (ROC) curve analysis. Multiple testing was corrected using Benjamini-Hochberg false discovery rate.Results
Age, post-RT duration and number of cardiovascular risk factors were significantly associated with carotid plaque burden (corrected P value, Pcor<0.05). Age of 44.5 years (sensitivity = 99.2% and specificity = 50%, Pcor<0.01) and post-RT duration of 8.5 years (sensitivity = 75.7% and specificity = 64.3%, Pcor<0.001) were the cutoff values for detecting carotid plaque, while post-RT duration of 13.5 years (sensitivity = 66.7% and specificity = 71.6%, Pcor<0.001) and 1.5 cardiovascular risk factors (sensitivity = 40.7% and specificity = 84.3%, Pcor<0.05) were the cutoff values for screening ≥50% carotid stenosis.Conclusions
Age, post-RT duration and number of cardiovascular risk factors are significant predictors of carotid atherosclerosis in post-RT NPC patients. Post-RT NPC patients, who are at least 45 years old, with post-RT duration of 9 years or above, and/or have ≥2 cardiovascular risk factors, are more susceptible to carotid atherosclerosis. 相似文献100.
Tanja K. Kiener Qiang Jia Tao Meng Vincent Tak Kwong Chow Jimmy Kwang 《PLoS neglected tropical diseases》2014,8(5)
Hand, foot and mouth disease caused by enterovirus 71(EV71) leads to the majority of neurological complications and death in young children. While putative inactivated vaccines are only now undergoing clinical trials, no specific treatment options exist yet. Ideally, EV71 specific intravenous immunoglobulins could be developed for targeted treatment of severe cases. To date, only a single universally neutralizing monoclonal antibody against a conserved linear epitope of VP1 has been identified. Other enteroviruses have been shown to possess major conformational neutralizing epitopes on both the VP2 and VP3 capsid proteins. Hence, we attempted to isolate such neutralizing antibodies against conformational epitopes for their potential in the treatment of infection as well as differential diagnosis and vaccine optimization. Here we describe a universal neutralizing monoclonal antibody that recognizes a conserved conformational epitope of EV71 which was mapped using escape mutants. Eight escape mutants from different subgenogroups (A, B2, B4, C2, C4) were rescued; they harbored three essential mutations either at amino acid positions 59, 62 or 67 of the VP3 protein which are all situated in the “knob” region. The escape mutant phenotype could be mimicked by incorporating these mutations into reverse genetically engineered viruses showing that P59L, A62D, A62P and E67D abolish both monoclonal antibody binding and neutralization activity. This is the first conformational neutralization epitope mapped on VP3 for EV71. 相似文献