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1.
EBioMedicine ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31477561

RESUMO

BACKGROUND: Early detection of influenza activity followed by timely response is a critical component of preparedness for seasonal influenza epidemic and influenza pandemic. However, most relevant studies were conducted at the regional or national level with regular seasonal influenza trends. There are few feasible strategies to forecast influenza activity at the local level with irregular trends. METHODS: Multi-source electronic data, including historical percentage of influenza-like illness (ILI%), weather data, Baidu search index and Sina Weibo data of Chongqing, China, were collected and integrated into an innovative Self-adaptive AI Model (SAAIM), which was constructed by integrating Seasonal Autoregressive Integrated Moving Average model and XGBoost model using a self-adaptive weight adjustment mechanism. SAAIM was applied to ILI% forecast in Chongqing from 2017 to 2018, of which the performance was compared with three previously available models on forecasting. FINDINGS: ILI% showed an irregular seasonal trend from 2012 to 2018 in Chongqing. Compared with three reference models, SAAIM achieved the best performance on forecasting ILI% of Chongqing with the mean absolute percentage error (MAPE) of 11·9%, 7·5%, and 11·9% during the periods of the year 2014-2016, 2017, and 2018 respectively. Among the three categories of source data, historical influenza activity contributed the most to the forecast accuracy by decreasing the MAPE by 19·6%, 43·1%, and 11·1%, followed by weather information (MAPE reduced by 3·3%, 17·1%, and 2·2%), and Internet-related public sentiment data (MAPE reduced by 1·1%, 0·9%, and 1·3%). INTERPRETATION: Accurate influenza forecast in areas with irregular seasonal influenza trends can be made by SAAIM with multi-source electronic data.

2.
Emerg Microbes Infect ; 8(1): 841-856, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169078

RESUMO

The Middle East respiratory syndrome coronavirus (MERS-CoV) has spread through 27 countries and infected more than 2,200 people since its first outbreak in Saudi Arabia in 2012. The high fatality rate (35.4%) of this novel coronavirus and its persistent wide spread infectiousness in animal reservoirs have generated tremendous global public health concern. However, no licensed therapeutic agents or vaccines against MERS-CoV are currently available and only a limited few have entered clinical trials. Among all the potential targets of MERS-CoV, the spike glycoprotein (S) has been the most well-studied due to its critical role in mediating viral entry and in inducing a protective antibody response in infected individuals. The most notable studies include the recent discoveries of monoclonal antibodies and development of candidate vaccines against the S glycoprotein. Structural characterization of MERS-CoV S protein bound with these monoclonal antibodies has provided insights into the mechanisms of humoral immune responses against MERS-CoV infection. The current review aims to highlight these developments and discuss possible hurdles and strategies to translate these discoveries into ultimate medical interventions against MERS-CoV infection.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Coronavirus/prevenção & controle , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Vacinas Virais/imunologia , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Glicoproteína da Espícula de Coronavírus/administração & dosagem , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
3.
PLoS Pathog ; 15(6): e1007819, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31194843

RESUMO

Recently identified broadly neutralizing antibodies (bnAbs) show great potential for clinical interventions against HIV-1 infection. However, resistant strains may impose substantial challenges. Here, we report on the identification and characterization of a panel of HIV-1 strains with broad and potent resistance against a large number of bnAbs, particularly those targeting the CD4-binding site (CD4bs). Site-directed mutagenesis revealed that several key epitope mutations facilitate resistance and are located in the inner domain, loop D, and ß23/loop V5/ß24 of HIV-1 gp120. The resistance is largely correlated with binding affinity of antibodies to the envelope trimers expressed on the cell surface. Our results therefore demonstrate the existence of broadly resistant HIV-1 strains against CD4bs neutralizing antibodies. Treatment strategies based on the CD4bs bnAbs must overcome such resistance to achieve optimal clinical outcomes.

4.
Emerg Microbes Infect ; 8(1): 760-772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31130102

RESUMO

The recently identified Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe and fatal acute respiratory illness in humans. However, no approved prophylactic and therapeutic interventions are currently available. The MERS-CoV envelope spike protein serves as a crucial target for neutralizing antibodies and vaccine development, as it plays a critical role in mediating viral entry through interactions with the cellular receptor, dipeptidyl peptidase 4 (DPP4). Here, we constructed a recombinant rare serotype of the chimpanzee adenovirus 68 (AdC68) that expresses full-length MERS-CoV S protein (AdC68-S). Single intranasal immunization with AdC68-S induced robust and sustained neutralizing antibody and T cell responses in BALB/c mice. In a human DPP4 knock-in (hDPP4-KI) mouse model, it completely protected against lethal challenge with a mouse-adapted MERS-CoV (MERS-CoV-MA). Passive transfer of immune sera to naïve hDPP4-KI mice also provided survival advantages from lethal MERS-CoV-MA challenge. Analysis of sera absorption and isolated monoclonal antibodies from immunized mice demonstrated that the potent and broad neutralizing activity was largely attributed to antibodies targeting the receptor binding domain (RBD) of the S protein. These results show that AdC68-S can induce protective immune responses in mice and represent a promising candidate for further development against MERS-CoV infection in both dromedaries and humans.


Assuntos
Infecções por Coronavirus/prevenção & controle , Portadores de Fármacos/administração & dosagem , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/imunologia , Adenoviridae/genética , Administração Intranasal , Animais , Animais Geneticamente Modificados , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Humanos , Imunização Passiva , Camundongos Endogâmicos BALB C , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Glicoproteína da Espícula de Coronavírus/genética , Análise de Sobrevida , Linfócitos T/imunologia , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
5.
Cell Rep ; 27(9): 2593-2607.e5, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141685

RESUMO

The HIV-1 envelope glycoprotein (Env) maintains a delicate balance between mediating viral entry and escaping antibody neutralization. Adaptation during transmission of neutralization-sensitive Envs with an "open" conformation remains poorly understood. By passaging a replication-competent simian-human immunodeficiency virus carrying a highly neutralization-sensitive Env (SHIVCNE40) in rhesus macaques, we show that SHIVCNE40 develops enhanced replication kinetics associated with neutralization resistance against antibodies and autologous serum. A gp41 substitution, E658K, functions as the major determinant for these properties. Structural modeling and functional verification indicate that the substitution disrupts an intermolecular salt bridge with the neighboring protomer, thereby promoting fusion and facilitating immune evasion. This effect is applicable across diverse HIV-1 subtypes. Our results highlight the critical role of gp41 in shaping the neutralization profile and the overall conformation of Env during viral adaptation. The unique intermolecular salt bridge could potentially be utilized for rational vaccine design involving more stable HIV-1 envelope trimers.

7.
Cell Rep ; 26(12): 3360-3368.e5, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893607

RESUMO

We previously reported a human monoclonal antibody, ZK2B10, capable of protection against Zika virus (ZIKV) infection and microcephaly in developing mouse embryos. Here, we report the structural features and mechanism of action of ZK2B10. The crystal structure at a resolution of 2.32 Å revealed that the epitope is located on the lateral ridge of DIII of the envelope glycoprotein. Cryo-EM structure with mature ZIKV showed that the antibody binds to DIIIs around the icosahedral 2-fold, 3-fold, and 5-fold axes, a distinct feature compared to those reported for DIII-specific antibodies. The binding of ZK2B10 to ZIKV has no detectable effect on viral attachment to target cells or on conformational changes of the E glycoprotein in the acidic environment, suggesting that ZK2B10 functions at steps between the formation of the fusion intermediate and membrane fusion. These results provide structural and mechanistic insights into how ZK2B10 mediates protection against ZIKV infection.

8.
J Biol Chem ; 294(12): 4290-4303, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30737282

RESUMO

Most neutralizing antibodies against highly pathogenic avian influenza A virus H5N1 recognize the receptor-binding site (RBS) on the globular head domain and the stem of H5N1 hemagglutinin (HA). Through comprehensive analysis of multiple human protective antibodies, we previously identified four vulnerable sites (VS1-VS4) on the globular head domain. Among them, the VS1, occupying the opposite side of the RBS on the same HA, was defined by the epitope of antibody 65C6. In this study, we report the crystal structures of two additional human H5N1 antibodies isolated from H5N1-infected individuals, 3C11 and AVFluIgG01, bound to the head at 2.33- and 2.30-Å resolution, respectively. These two new antibody epitopes have large overlap with and extend beyond the original VS1. Site-directed mutagenesis experiments identified eight pivotal residues (Ser-126b, Lys-165, Arg-166, Ser-167, Tyr-168, Asn-169, Thr-171, and Asn-172) critical for 65C6-, 3C11-, and AVFluIgG01-binding and neutralization activities. These residues formed a unique "Y"-shaped surface on H5N1 globular head and are highly conserved among H5N1 viruses. Our results further support the existence of a vulnerable site distinct from the RBS and the stem region of H5N1 HA, and future design of immunogens should take this particular site into consideration.

9.
Bioinformatics ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30295703

RESUMO

Motivation: Human immunodeficiency virus type 1 (HIV-1) genome integration is closely related to clinical latency and viral rebound. In addition to human DNA sequences that directly interact with the integration machinery, the selection of HIV integration sites has also been shown to depend on the heterogeneous genomic context around a large region, which greatly hinders the prediction and mechanistic studies of HIV integration. Results: We have developed an attention-based deep learning framework, named DeepHINT, to simultaneously provide accurate prediction of HIV integration sites and mechanistic explanations of the detected sites. Extensive tests on a high-density HIV integration site dataset showed that DeepHINT can outperform conventional modeling strategies by automatically learning the genomic context of HIV integration from primary DNA sequence alone or together with epigenetic information. Systematic analyses on diverse known factors of HIV integration further validated the biological relevance of the prediction results. More importantly, in-depth analyses of the attention values output by DeepHINT revealed intriguing mechanistic implications in the selection of HIV integration sites, including potential roles of several DNA-binding proteins. These results established DeepHINT as an effective and explainable deep learning framework for the prediction and mechanistic study of HIV integration. Availability: DeepHINT is available as an open-source software and can be downloaded from https://github.com/nonnerdling/DeepHINT. Supplementary information: Supplementary data are available at Bioinformatics online.

10.
Medchemcomm ; 9(7): 1226-1231, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30109011

RESUMO

AIDS has evolved from a fatal infectious disease to a manageable chronic disease under the treatment of anti-AIDS medications. HIV fusion inhibitors with high activity, low side effects and strong selectivity are promising drugs against HIV. Only one fusion inhibitor is currently approved, thereby highly active long-acting fusion inhibitors need to be developed for long-term AIDS treatment. Here, we synthesised MT-SC22EK (a small HIV fusion inhibitor) derivatives containing 1-2 staples to improve its stability. Antiviral activity studies showed that MT-SC22EK-2 with two staples exhibited potent inhibitory activity against HIV-1 standard strains and Chinese epidemic strains, and at the same time, MT-SC22EK-2 presented strong anti-T20 resistance. Surprisingly, MT-SC22EK-2 possessed excellent protease stability with a half-life of 3665 min. MT-SC22EK-2 is a potential HIV fusion inhibitor considered as a long-acting anti-HIV drug candidate.

11.
J Biol Chem ; 293(42): 16503-16517, 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30154240

RESUMO

The highly pathogenic avian influenza virus H5N1 is a major threat to global public health and therefore a high-priority target of current vaccine development. The receptor-binding site (RBS) on the globular head of hemagglutinin (HA) in the viral envelope is one of the major target sites for antibody recognition against H5N1 and other influenza viruses. Here, we report the identification and characterization of a pair of human RBS-specific antibodies, designated FLD21.140 and AVFluIgG03, that are mutually complementary in their neutralizing activities against a diverse panel of H5N1 viruses. Crystallographic analysis and site-directed mutagenesis revealed that the two antibodies share a similar RBS-binding mode, and their individual specificities are governed by residues at positions 133a, 144, and 145. Specifically, FLD21.140 preferred Leu-133a/Lys-144/Ser-145, whereas AVFluIgG03 favored Ser-133a/Thr-144/Pro-145 residue triplets, both of which perfectly matched the most prevalent residues in viruses from epidemic-originating regions. Of note, according to an analysis of 3758 H5 HA sequences available in the Influenza Virus Database at the National Center for Biotechnology Information, the residues Leu-133a/Ser-133a and Ser-145/Pro-145 constituted more than 87.6 and 99.3% of all residues at these two positions, respectively. Taken together, our results provide a structural understanding for the neutralizing complementarity of these two antibodies and improve our understanding of the RBS-specific antibody response against H5N1 infection in humans.

12.
Cell Rep ; 24(2): 441-452, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29996104

RESUMO

The major mechanism of antibody-mediated neutralization of the Middle East respiratory syndrome coronavirus (MERS-CoV) involves competition with the cellular receptor dipeptidyl peptidase 4 (DPP4) for binding to the receptor-binding domain (RBD) of the spike (S) glycoprotein. Here, we report a unique epitope and unusual neutralizing mechanism of the isolated human antibody MERS-4. Structurally, MERS-4 approached the RBD from the outside of the RBD-DPP4 binding interface. Such binding resulted in the folding of the ß5-ß6 loop toward a shallow groove on the RBD interface critical for accommodating DPP4. The key residues for binding are identified through site-directed mutagenesis. Structural modeling revealed that MERS-4 binds to RBD only in the "up" position in the S trimer. Furthermore, MERS-4 demonstrated synergy with several reported antibodies. These results indicate that MERS-4 neutralizes MERS-CoV by indirect rather than direct competition with DPP4. This mechanism provides a valuable addition for the combined use of antibodies against MERS-CoV infection.

13.
Cell Rep ; 23(5): 1424-1434, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29719255

RESUMO

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that is generally benign in humans. However, an emergent strain of ZIKV has become widespread, causing severe pre- and post-natal neurological defects. There is now an urgent need for prophylactic and therapeutic agents. To address this, we investigated six human monoclonal antibodies with ZIKV epitope specificity and neutralizing activity in mouse models of ZIKV infection and microcephaly. A single intraperitoneal injection of these antibodies conveyed distinct levels of adult and in utero protection from ZIKV infection, which closely mirrored their respective in vitro neutralizing activities. One antibody, ZK2B10, showed the most potent neutralization activity, completely protected uninfected mice, and markedly reduced tissue pathology in infected mice. Thus, ZK2B10 is a promising candidate for the development of antibody-based interventions and informs the rational design of ZIKV vaccine.

14.
J Biol Chem ; 293(3): 830-846, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29187598

RESUMO

Recent discoveries of broadly neutralizing antibodies (bnAbs) in HIV-1-infected individuals have led to the identification of several major "vulnerable sites" on the HIV-1 envelope (Env) glycoprotein. These sites have provided precise targets for HIV-1 vaccine development, but identifying and utilizing many of these targets remain technically challenging. Using a yeast surface display-based approach, we sought to identify epitope-focused antigenic domains (EADs) containing one of the "vulnerable sites," the CD4-binding site (CD4bs), through screening and selection of a combinatorial antigen library of the HIV-1 envelope glycoprotein with the CD4bs bnAb VRC01. We isolated multiple EADs and found that their trimeric forms have biochemical and structural features that preferentially bind and activate B cells that express VRC01 in vitro More importantly, these EADs could induce detectable levels of neutralizing antibodies against genetically related autologous and heterologous subtype B viruses in guinea pigs. Our results demonstrate that an epitope-focused approach involving a screen of a combinatorial antigen library is feasible. The EADs identified here represent a promising collection of possible targets in the rational design of HIV-1 vaccines and lay the foundation for harnessing the specific antigenicity of CD4bs for protective immunogenicity in vivo.


Assuntos
Anticorpos Neutralizantes/imunologia , Antígenos CD4/imunologia , HIV-1/metabolismo , Animais , Sítios de Ligação , Cobaias , HIV-1/imunologia , Humanos , Ligação Proteica , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
15.
JCI Insight ; 2(12)2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28614803

RESUMO

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that shares a considerable degree of homology with dengue virus (DENV). Here, we examined longitudinal antibody response against ZIKV during natural infection in 2 convalescent individuals. By decomposing the antibody recognition into DI/DII and DIII of the E glycoprotein, we showed their development in humans followed a spatiotemporal hierarchy. Plasma binding to DI/DII appeared to peak and wane during early infection with extensive cross-reactivity with DI/DII of DENV. Binding to DIII, however, peaked early but persisted months into the infection without detectable cross-reactivity with DIII of DENV. A clear trend of increase in DIII-specific neutralizing activity was observed over the course of infection. mAbs isolated during early infection are largely DI/DII specific, weakly neutralizing, and highly cross-reactive with DENV, while those from later infection are more diverse in recognition, potently neutralizing, and ZIKV specific. The most potent neutralizing mAb targeting the DIII provided 100% protection in mice from lethal ZIKV infection and could therefore serve as a promising candidate for antibody-based therapy and prevention. The dynamic features unveiled here will assist us to better understand the pathogenesis of ZIKV infection and inform rational design of vaccines.

16.
J Acquir Immune Defic Syndr ; 74(2): 229-241, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27749600

RESUMO

Transcription activator-like effector nuclease (TALEN) represents a valuable tool for genomic engineering due to its single-nucleotide precision, high nuclease activity, and low cytotoxicity. We report here systematic design and characterization of 28 novel TALENs targeting multiple regions of CCR5 gene (CCR5-TALEN) which encodes the co-receptor critical for entry of human immunodeficiency virus type I (HIV-1). By systemic characterization of these CCR5-TALENs, we have identified one (CCR5-TALEN-515) with higher nuclease activity, specificity, and lower cytotoxicity compared with zinc-finger nuclease (CCR5-ZFN) currently undergoing clinical trials. Sequence analysis of target cell line GHOST-CCR5-CXCR4 and human primary CD4 T cells showed that the double-strand breaks at the TALEN targeted sites resulted in truncated or nonfunctional CCR5 proteins thereby conferring protection against HIV-1 infection in vitro. None of the CCR5-TALENs had detectable levels of off-target nuclease activity against the homologous region in CCR2 although substantial level was identified for CCR5-ZFN in the primary CD4 T cells. Our results suggest that the CCR5-TALENs identified here are highly functional nucleases that produce protective genetic alterations to human CCR5. Application of these TALENs directly to the primary CD4 T cells and CD34 hematopoietic stem cells (HSCs) of infected individuals could help to create an immune system resistant to HIV-1 infection, recapitulating the success of "Berlin patient" and serving as an essential first step towards a "functional" cure of AIDS.


Assuntos
Técnicas de Inativação de Genes/métodos , HIV-1/fisiologia , Receptores CCR5/deficiência , Receptores de HIV/deficiência , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/metabolismo , Adulto , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , HIV-1/crescimento & desenvolvimento , Humanos , Deleção de Sequência
17.
Sci Rep ; 6: 25856, 2016 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-27181584

RESUMO

Ebola virus infections cause a deadly hemorrhagic disease for which no vaccines or therapeutics has received regulatory approval. Here we show isolation of three (Q206, Q314 and Q411) neutralizing monoclonal antibodies (mAbs) against the surface glycoprotein (GP) of Ebola virus identified in West Africa in 2014 through sequential immunization of Chinese rhesus macaques and antigen-specific single B cell sorting. These mAbs demonstrated potent neutralizing activities against both pseudo and live Ebola virus independent of complement. Biochemical, single particle EM, and mutagenesis analysis suggested Q206 and Q411 recognized novel epitopes in the head while Q314 targeted the glycan cap in the GP1 subunit. Q206 and Q411 appeared to influence GP binding to its receptor NPC1. Treatment with these mAbs provided partial but significant protection against disease in a mouse model of Ebola virus infection. These novel mAbs could serve as promising candidates for prophylactic and therapeutic interventions against Ebola virus infection.


Assuntos
Anticorpos Neutralizantes/isolamento & purificação , Ebolavirus/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Macaca mulatta/imunologia , Glicoproteínas de Membrana/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/isolamento & purificação , Anticorpos Antivirais/farmacologia , Linfócitos B/imunologia , Modelos Animais de Doenças , Ebolavirus/efeitos dos fármacos , Epitopos/imunologia , Imunização Passiva , Macaca mulatta/virologia , Glicoproteínas de Membrana/química , Camundongos , Vacinação
18.
Retrovirology ; 13: 12, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26883323

RESUMO

BACKGROUND: Majority of HIV-1 infection is established by one transmitted/founder virus and understanding how the neutralizing antibodies develop against this virus is critical for our rational design an HIV-1 vaccine. RESULTS: We report here antibody profiling of sequential plasma samples against transmitted/founder HIV-1 envelope glycoprotein in an epidemiologically linked transmission pair using our previously reported antigen library approach. We have decomposed the antibody recognition into three major subdomains on the envelope and showed their development in vivo followed a spatiotemporal hierarchy: starting with the ectodomain of gp41 at membrane proximal region, then the V3C3V4 and the V1V2 of gp120 at the membrane distal region. While antibodies to these subdomains appeared to undergo avidity maturation, the early anti-gp41 antibodies failed to translate into detectable autologous neutralization. Instead, it was the much delayed anti-V3C3V4 and anti-V1V2 antibodies constituted the major neutralizing activities. CONCLUSIONS: Our results indicate that the initial antibody response was severely misguided by the transmitted/founder virus and future vaccine design would need to avoid the ectodomain of gp41 and focus on the neutralizing targets in the V3C3V4 and V1V2 subdomains of gp120.


Assuntos
Imunidade Adaptativa , Anticorpos Neutralizantes/sangue , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , HIV-1/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , Estudos de Coortes , Anticorpos Anti-HIV/imunologia , Infecções por HIV/transmissão , Humanos , Masculino , Análise Espaço-Temporal
20.
Nat Commun ; 6: 8855, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26635249

RESUMO

Understanding the mechanism of protective antibody recognition against highly pathogenic avian influenza A virus H5N1 in humans is critical for the development of effective therapies and vaccines. Here we report the crystal structure of three H5-specific human monoclonal antibodies bound to the globular head of hemagglutinin (HA) with distinct epitope specificities, neutralization potencies and breadth. A structural and functional analysis of these epitopes combined with those reported elsewhere identifies four major vulnerable sites on the globular head of H5N1 HA. Chimeric and vulnerable site-specific mutant pseudoviruses are generated to delineate broad neutralization specificities of convalescent sera from two individuals who recovered from the infection with H5N1 virus. Our results show that the four vulnerable sites on the globular head rather than the stem region are the major neutralizing targets, suggesting that during natural H5N1 infection neutralizing antibodies against the globular head work in concert to provide protective antibody-mediated immunity.


Assuntos
Anticorpos Antivirais/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Influenza Humana/imunologia , Adulto , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/química , Aves , Mapeamento de Epitopos , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Virus da Influenza A Subtipo H5N1/química , Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/patogenicidade , Influenza Aviária/virologia , Influenza Humana/virologia , Masculino , Estrutura Terciária de Proteína , Virulência
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