Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
1.
J Immunol ; 202(4): 1200-1209, 2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30635392

RESUMEN

The classical pathway of complement (CP) can mediate C3 opsonization of Ags responsible for the costimulation and activation of cognate B lymphocytes. In this manner, the complement system acts as a bridge between the innate and adaptive immune systems critical for establishing a humoral response. However, aberrant complement activation is often observed in autoimmune diseases in which C3 deposition on self-antigens may serve to activate self-reactive B cell clones. In this study, we use BIVV009 (Sutimlimab), a clinical stage, humanized mAb that specifically inhibits the CP-specific serine protease C1s to evaluate the impact of upstream CP antagonism on activation and proliferation of normal and autoimmune human B cells. We report that BIVV009 significantly inhibited complement-mediated activation and proliferation of primary human B cells. Strikingly, CP antagonism suppressed human Ig-induced activation of B cells derived from patients with rheumatoid arthritis. These results suggest that clinical use of CP inhibitors in autoimmune patients may not only block complement-mediated tissue damage, but may also prevent the long-term activation of autoimmune B cells and the production of autoantibodies that contribute to the underlying pathologic condition of these diseases.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Artritis Reumatoide/tratamiento farmacológico , Linfocitos B/efectos de los fármacos , Complemento C1s/antagonistas & inhibidores , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Linfocitos B/inmunología , Linfocitos B/patología , Proliferación Celular/efectos de los fármacos , Activación de Complemento/efectos de los fármacos , Complemento C1s/inmunología , Humanos
2.
Proc Natl Acad Sci U S A ; 113(6): E782-90, 2016 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-26802124

RESUMEN

Epstein-Barr virus (EBV) is an oncogenic herpesvirus that has been causally linked to the development of B-cell and epithelial malignancies. Early after infection, EBV induces a transient period of hyperproliferation that is suppressed by the activation of the DNA damage response and a G1/S-phase growth arrest. This growth arrest prevents long-term outgrowth of the majority of infected cells. We developed a method to isolate and characterize infected cells that arrest after this early burst of proliferation and integrated gene expression and metabolic profiling to gain a better understanding of the pathways that attenuate immortalization. We found that the arrested cells have a reduced level of mitochondrial respiration and a decrease in the expression of genes involved in the TCA cycle and oxidative phosphorylation. Indeed, the growth arrest in early infected cells could be rescued by supplementing the TCA cycle. Arrested cells were characterized by an increase in the expression of p53 pathway gene targets, including sestrins leading to activation of AMPK, a reduction in mTOR signaling, and, consequently, elevated autophagy that was important for cell survival. Autophagy was also critical to maintain early hyperproliferation during metabolic stress. Finally, in assessing the metabolic changes from early infection to long-term outgrowth, we found concomitant increases in glucose import and surface glucose transporter 1 (GLUT1) levels, leading to elevated glycolysis, oxidative phosphorylation, and suppression of basal autophagy. Our study demonstrates that oncogene-induced senescence triggered by a combination of metabolic and genotoxic stress acts as an intrinsic barrier to EBV-mediated transformation.


Asunto(s)
Linfocitos B/virología , Transformación Celular Viral , Herpesvirus Humano 4/fisiología , Estrés Fisiológico , Autofagia/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Linfocitos B/ultraestructura , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Transformación Celular Viral/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Desoxiglucosa/farmacología , Dimetilformamida/farmacología , Herpesvirus Humano 4/efectos de los fármacos , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Metabolómica , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Complejos Multiproteicos/metabolismo , Oncogenes , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismo , Transcriptoma/genética , Proteína p53 Supresora de Tumor/metabolismo
3.
Proc Natl Acad Sci U S A ; 112(6): 1767-72, 2015 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-25624487

RESUMEN

Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and the leading viral cause of birth defects after congenital infection. The glycoprotein complexes gH/gL/gO and gH/gL/UL128/UL130/UL131A (Pentamer) are key targets of the human humoral response against HCMV and are required for HCMV entry into fibroblasts and endothelial/epithelial cells, respectively. We expressed and characterized soluble forms of gH/gL, gH/gL/gO, and Pentamer. Mass spectrometry and mutagenesis analysis revealed that gL-Cys144 forms disulfide bonds with gO-Cys351 in gH/gL/gO and with UL128-Cys162 in the Pentamer. Notably, Pentamer harboring the UL128-Cys162Ser/gL-Cys144Ser mutations had impaired syncytia formation and reduced interference of HCMV entry into epithelial cells. Electron microscopy analysis showed that HCMV gH/gL resembles HSV gH/gL and that gO and UL128/UL130/UL131A bind to the same site at the gH/gL N terminus. These data are consistent with gH/gL/gO and Pentamer forming mutually exclusive cell entry complexes and reveal the overall location of gH/gL-, gH/gL/gO-, and Pentamer-specific neutralizing antibody binding sites. Our results provide, to our knowledge, the first structural view of gH/gL/gO and Pentamer supporting the development of vaccines and antibody therapeutics against HCMV.


Asunto(s)
Citomegalovirus/inmunología , Citomegalovirus/fisiología , Glicoproteínas de Membrana/metabolismo , Complejos Multiproteicos/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Internalización del Virus , Anticuerpos Neutralizantes/inmunología , Sitios de Unión/genética , Western Blotting , Cromatografía de Afinidad , Secuencia Conservada/genética , Citomegalovirus/metabolismo , Disulfuros/metabolismo , Citometría de Flujo , Humanos , Procesamiento de Imagen Asistido por Computador , Espectrometría de Masas , Glicoproteínas de Membrana/química , Microscopía Electrónica , Complejos Multiproteicos/química , Mutagénesis , Mutagénesis Sitio-Dirigida , Mutación/genética , Unión Proteica , Proteínas del Envoltorio Viral/química
4.
Materials (Basel) ; 17(12)2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38930180

RESUMEN

The elasto-optic properties of liquids on the basis of the first principles of acousto-optics were theoretically investigated. A relationship for calculating the elasto-optic constant of liquids using only the refractive index was obtained. The refractive index values corresponding to the maximum elasto-optic constant for polar and nonpolar liquids were determined. Calculations for about 100 liquids were performed and compared with known experimental data. This study significantly extends our understanding of the acousto-optic effect and has practical applications for predicting the elasto-optic constant of a liquid and estimating its wavelength dispersion.

5.
Materials (Basel) ; 16(5)2023 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-36902935

RESUMEN

The paper presents the application of the acousto-optic tunable filter (AOTF) in surface plasmon resonance (SPR) spectroscopy to measure the optical thickness of thin dielectric coatings. The technique presented uses combined angular and spectral interrogation modes to obtain the reflection coefficient under the condition of SPR. Surface electromagnetic waves were excited in the Kretschmann geometry, with the AOTF serving as a monochromator and polarizer of light from a white broadband radiation source. The experiments highlighted the high sensitivity of the method and the lower amount of noise in the resonance curves compared with the laser light source. This optical technique can be implemented for nondestructive testing in the production of thin films in not only the visible, but also the infrared and terahertz ranges.

6.
MAbs ; 15(1): 2212673, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37216961

RESUMEN

Immune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer but are only efficacious in a small subset of patients. Targeting suppressive mechanisms acting on innate immune cells could significantly improve the incidence of clinical response by facilitating a multi-lineage response against the tumor involving both adaptive and innate immune systems. Here, we show that intra-tumoral interleukin (IL)-38 expression is a feature of a large frequency of head and neck, lung and cervical squamous cancers and correlates with reduced immune cell numbers. We generated IMM20324, an antibody that binds human and mouse IL-38 proteins and inhibits the binding of IL-38 to its putative receptors, interleukin 1 receptor accessory protein-like 1 (IL1RAPL) and IL-36R. In vivo, IMM20324 demonstrated a good safety profile, delayed tumor growth in a subset of mice in an EMT6 syngeneic model of breast cancer, and significantly inhibited tumor expansion in a B16.F10 melanoma model. Notably, IMM20324 treatment resulted in the prevention of tumor growth following re-implantation of tumor cells, indicating the induction of immunological memory. Furthermore, exposure of IMM20324 correlated with decreased tumor volume and increased levels of intra-tumoral chemokines. Together, our data suggest that IL-38 is expressed in a high frequency of cancer patients and allows tumor cells to suppress anti-tumor immunity. Blockade of IL-38 activity using IMM20324 can re-activate immunostimulatory mechanisms in the tumor microenvironment leading to immune infiltration, the generation of tumor-specific memory and abrogation of tumor growth.


Asunto(s)
Melanoma Experimental , Linfocitos T , Humanos , Ratones , Animales , Melanoma Experimental/tratamiento farmacológico , Memoria Inmunológica , Microambiente Tumoral , Línea Celular Tumoral , Interleucinas
7.
Sci Immunol ; 7(75): eabl9943, 2022 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-35771946

RESUMEN

Monoclonal antibodies are an efficacious therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, rapid viral mutagenesis led to escape from most of these therapies, outlining the need for an antibody cocktail with a broad neutralizing potency. Using an unbiased interrogation of the memory B cell repertoire of patients with convalescent COVID-19, we identified human antibodies with broad antiviral activity in vitro and efficacy in vivo against all tested SARS-CoV-2 variants of concern, including Delta and Omicron BA.1 and BA.2. Here, we describe an antibody cocktail, IMM-BCP-01, that consists of three patient-derived broadly neutralizing antibodies directed at nonoverlapping surfaces on the SARS-CoV-2 Spike protein. Two antibodies, IMM20184 and IMM20190, directly blocked Spike binding to the ACE2 receptor. Binding of the third antibody, IMM20253, to its cryptic epitope on the outer surface of RBD altered the conformation of the Spike Trimer, promoting the release of Spike monomers. These antibodies decreased Omicron SARS-CoV-2 infection in the lungs of Syrian golden hamsters in vivo and potently induced antiviral effector response in vitro, including phagocytosis, ADCC, and complement pathway activation. Our preclinical data demonstrated that the three-antibody cocktail IMM-BCP-01 could be a promising means for preventing or treating infection of SARS-CoV-2 variants of concern, including Omicron BA.1 and BA.2, in susceptible individuals.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Anticuerpos Antivirales , Cricetinae , Humanos , Glicoproteína de la Espiga del Coronavirus/genética
8.
Materials (Basel) ; 14(19)2021 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-34639915

RESUMEN

The acousto-optic (AO) diffraction of terahertz (THz) radiation in liquefied sulfur hexafluoride (SF6) was investigated in various temperature regimes. It was found that with the increase in the temperature from +10 to +23 °C, the efficiency of the AO diffraction became one order higher at the same amplitude of the driving electrical signal. At the same time, the efficiency of the AO diffraction per 1 W of the sound power as well as the angular bandwidth of the efficient AO interaction were temperature independent within the measurement error. Increase of the resonant sound frequency with decreasing temperature and strong narrowing of the sound frequency bandwidth of the efficient AO interaction were detected.

9.
Front Genet ; 12: 674783, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34306019

RESUMEN

Amaryllidaceae is a large family with more than 1,600 species, belonging to 75 genera. The largest genus-Allium-is vast, comprising about a thousand species. Allium species (as well as other members of the Amaryllidaceae) are widespread and diversified, they are adapted to a wide range of habitats from shady forests to open habitats like meadows, steppes, and deserts. The genes present in chloroplast genomes (plastomes) play fundamental roles for the photosynthetic plants. Plastome traits could thus be associated with geophysical abiotic characteristics of habitats. Most chloroplast genes are highly conserved and are used as phylogenetic markers for many families of vascular plants. Nevertheless, some studies revealed signatures of positive selection in chloroplast genes of many plant families including Amaryllidaceae. We have sequenced plastomes of the following nine Allium (tribe Allieae of Allioideae) species: A. zebdanense, A. moly, A. victorialis, A. macleanii, A. nutans, A. obliquum, A. schoenoprasum, A. pskemense, A. platyspathum, A. fistulosum, A. semenovii, and Nothoscordum bivalve (tribe Leucocoryneae of Allioideae). We compared our data with previously published plastomes and provided our interpretation of Allium plastome genes' annotations because we found some noteworthy inconsistencies with annotations previously reported. For Allium species we estimated the integral evolutionary rate, counted SNPs and indels per nucleotide position as well as compared pseudogenization events in species of three main phylogenetic lines of genus Allium to estimate whether they are potentially important for plant physiology or just follow the phylogenetic pattern. During examination of the 38 species of Allium and the 11 of other Amaryllidaceae species we found that rps16, rps2, infA, ccsA genes have lost their functionality multiple times in different species (regularly evolutionary events), while the pseudogenization of other genes was stochastic events. We found that the "normal" or "pseudo" state of rps16, rps2, infA, ccsA genes correlates well with the evolutionary line of genus the species belongs to. The positive selection in various NADH dehydrogenase (ndh) genes as well as in matK, accD, and some others were found. Taking into account known mechanisms of coping with excessive light by cyclic electron transport, we can hypothesize that adaptive evolution in genes, coding subunits of NADH-plastoquinone oxidoreductase could be driven by abiotic factors of alpine habitats, especially by intensive light and UV radiation.

10.
Vaccine X ; 8: 100098, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33937741

RESUMEN

Patients who recover from SARS-CoV-2 infections produce antibodies and antigen-specific T cells against multiple viral proteins. Here, an unbiased interrogation of the anti-viral memory B cell repertoire of convalescent patients has been performed by generating large, stable hybridoma libraries and screening thousands of monoclonal antibodies to identify specific, high-affinity immunoglobulins (Igs) directed at distinct viral components. As expected, a significant number of antibodies were directed at the Spike (S) protein, a majority of which recognized the full-length protein. These full-length Spike specific antibodies included a group of somatically hypermutated IgMs. Further, all but one of the six COVID-19 convalescent patients produced class-switched antibodies to a soluble form of the receptor-binding domain (RBD) of S protein. Functional properties of anti-Spike antibodies were confirmed in a pseudovirus neutralization assay. Importantly, more than half of all of the antibodies generated were directed at non-S viral proteins, including structural nucleocapsid (N) and membrane (M) proteins, as well as auxiliary open reading frame-encoded (ORF) proteins. The antibodies were generally characterized as having variable levels of somatic hypermutations (SHM) in all Ig classes and sub-types, and a diversity of VL and VH gene usage. These findings demonstrated that an unbiased, function-based approach towards interrogating the COVID-19 patient memory B cell response may have distinct advantages relative to genomics-based approaches when identifying highly effective anti-viral antibodies directed at SARS-CoV-2.

11.
mSphere ; 2(6)2017.
Artículo en Inglés | MEDLINE | ID: mdl-29202043

RESUMEN

Epstein-Barr virus (EBV), an oncogenic herpesvirus, infects and transforms primary B cells into immortal lymphoblastoid cell lines (LCLs), providing a model for EBV-mediated tumorigenesis. EBV transformation stimulates robust homotypic aggregation, indicating that EBV induces molecules that mediate cell-cell adhesion. We report that EBV potently induced expression of the adhesion molecule CD226, which is not normally expressed on B cells. We found that early after infection of primary B cells, EBV promoted an increase in CD226 mRNA and protein expression. CD226 levels increased further from early proliferating EBV-positive B cells to LCLs. We found that CD226 expression on B cells was independent of B-cell activation as CpG DNA failed to induce CD226 to the extent of EBV infection. CD226 expression was high in EBV-infected B cells expressing the latency III growth program, but low in EBV-negative and EBV latency I-infected B-lymphoma cell lines. We validated this correlation by demonstrating that the latency III characteristic EBV NF-κB activator, latent membrane protein 1 (LMP1), was sufficient for CD226 upregulation and that CD226 was more highly expressed in lymphomas with increased NF-κB activity. Finally, we found that CD226 was not important for LCL steady-state growth, survival in response to apoptotic stress, homotypic aggregation, or adhesion to activated endothelial cells. These findings collectively suggest that EBV induces expression of a cell adhesion molecule on primary B cells that may play a role in the tumor microenvironment of EBV-associated B-cell malignancies or facilitate adhesion in the establishment of latency in vivo. IMPORTANCE Epstein-Barr virus (EBV) is a common human herpesvirus that establishes latency in B cells. While EBV infection is asymptomatic for most individuals, immune-suppressed individuals are at significantly higher risk of a form of EBV latent infection in which infected B cells are reactivated, grow unchecked, and generate lymphomas. This form of latency is modeled in the laboratory by infecting B cells from the blood of normal human donors in vitro. In this model, we identified a protein called CD226 that is induced by EBV but is not normally expressed on B cells. Rather, it is known to play a role in aggregation and survival signaling of non-B cells in the immune system. Cultures of EBV-infected cells adhere to one another in "clumps," and while the proteins that are responsible for this cellular aggregation are not fully understood, we hypothesized that this form of cellular aggregation may provide a survival advantage. In this article, we characterize the mechanism by which EBV induces this protein and its expression on lymphoma tissue and cell lines and characterize EBV-infected cell lines in which CD226 has been knocked out.

12.
Elife ; 62017 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-28425914

RESUMEN

Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection. We used BH3 profiling to query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL-2) to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1 mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis.


Asunto(s)
Apoptosis , Linfocitos B/fisiología , Linfocitos B/virología , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Herpesvirus Humano 4/fisiología , Interacciones Huésped-Patógeno , Antígenos de Histocompatibilidad Menor/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Supervivencia Celular , Células Cultivadas , Humanos , Ratones
13.
Nat Commun ; 6: 8176, 2015 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-26365435

RESUMEN

Human cytomegalovirus (HCMV) poses a significant threat to immunocompromised individuals and neonates infected in utero. Glycoprotein B (gB), the herpesvirus fusion protein, is a target for neutralizing antibodies and a vaccine candidate due to its indispensable role in infection. Here we show the crystal structure of the HCMV gB ectodomain bound to the Fab fragment of 1G2, a neutralizing human monoclonal antibody isolated from a seropositive subject. The gB/1G2 interaction is dominated by aromatic residues in the 1G2 heavy chain CDR3 protruding into a hydrophobic cleft in the gB antigenic domain 5 (AD-5). Structural analysis and comparison with HSV gB suggest the location of additional neutralizing antibody binding sites on HCMV gB. Finally, immunoprecipitation experiments reveal that 1G2 can bind to HCMV virion gB suggesting that its epitope is exposed and accessible on the virus surface. Our data will support the development of vaccines and therapeutic antibodies against HCMV infection.


Asunto(s)
Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Antígenos Virales/metabolismo , Fragmentos Fab de Inmunoglobulinas/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Proteínas Virales de Fusión/metabolismo , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/ultraestructura , Anticuerpos Antivirales/química , Anticuerpos Antivirales/ultraestructura , Antígenos Virales/química , Antígenos Virales/ultraestructura , Cristalización , Cristalografía por Rayos X , Citomegalovirus/inmunología , Humanos , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/ultraestructura , Inmunoprecipitación , Microscopía Electrónica , Mutagénesis Sitio-Dirigida , Conformación Proteica , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/ultraestructura , Proteínas Virales de Fusión/química , Proteínas Virales de Fusión/ultraestructura
14.
PLoS One ; 9(1): e87299, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24498068

RESUMEN

B-cell activation and proliferation can be induced by a variety of extracellular stimuli. The fate of an activated B cell following mitogen stimulation can be dictated by the strength or duration of the signal, the expression of downstream signaling components necessary to promote proliferation, and the cell intrinsic sensors and regulators of the proliferative program. Previously we have identified the DNA damage response (DDR) signaling pathway as a cell intrinsic sensor that is activated upon latent infection of primary human B cells by Epstein-Barr virus (EBV). Here we have assessed the role of the DDR as a limiting factor in the proliferative response to non-viral B-cell mitogens. We report that TLR9 activation through CpG-rich oligonucleotides induced B-cell hyper-proliferation and an ATM/Chk2 downstream signaling pathway. However, B-cell activation through the CD40 pathway coupled with interleukin-4 (IL-4) promoted proliferation less robustly and only a modest DDR. These two mitogens, but not EBV, modestly induced intrinsic apoptosis that was independent from the DDR. However, all three mitogens triggered a DDR-dependent G1/S phase cell cycle arrest preventing B-cell proliferation. The extent of G1/S arrest, as evidenced by release through Chk2 inhibition, correlated with B-cell proliferation rates. These findings have implications for the regulation of extra-follicular B-cell activation as it may pertain to the development of auto-immune diseases or lymphoma.


Asunto(s)
Linfocitos B/metabolismo , Quinasa de Punto de Control 2/genética , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Mitógenos/genética , Puntos de Control de la Fase S del Ciclo Celular/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Antígenos CD40/genética , Antígenos CD40/metabolismo , Proliferación Celular , Quinasa de Punto de Control 2/metabolismo , Daño del ADN/genética , Humanos , Interleucina-4/genética , Interleucina-4/metabolismo , Activación de Linfocitos/genética , Mitógenos/metabolismo , Transducción de Señal/genética
15.
Future Virol ; 6(7): 813-830, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21927617

RESUMEN

Human DNA tumor viruses induce host cell proliferation in order to establish the necessary cellular milieu to replicate viral DNA. The consequence of such viral-programmed induction of proliferation coupled with the introduction of foreign replicating DNA structures makes these viruses particularly sensitive to the host DNA damage response machinery. In fact, sensors of DNA damage are often activated and modulated by DNA tumor viruses in both latent and lytic infection. This article focuses on the role of the DNA damage response during the life cycle of human DNA tumor viruses, with a particular emphasis on recent advances in our understanding of the role of the DNA damage response in EBV, Kaposi's sarcoma-associated herpesvirus and human papillomavirus infection.

16.
Cell Host Microbe ; 8(6): 510-22, 2010 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-21147465

RESUMEN

Epstein-Barr virus (EBV), an oncogenic herpesvirus that causes human malignancies, infects and immortalizes primary human B cells in vitro into indefinitely proliferating lymphoblastoid cell lines, which represent a model for EBV-induced tumorigenesis. The immortalization efficiency is very low, suggesting that an innate tumor suppressor mechanism is operative. We identify the DNA damage response (DDR) as a major component of the underlying tumor suppressor mechanism. EBV-induced DDR activation was not due to lytic viral replication, nor did the DDR marks colocalize with latent episomes. Rather, a transient period of EBV-induced hyperproliferation correlated with DDR activation. Inhibition of the DDR kinases ATM and Chk2 markedly increased transformation efficiency of primary B cells. Further, the viral latent oncoprotein EBNA3C was required to attenuate the EBV-induced DDR. We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR that is attenuated by viral latency products to induce cell immortalization.


Asunto(s)
Linfocitos B/virología , Proteínas de Ciclo Celular/fisiología , Daño del ADN , Proteínas de Unión al ADN/fisiología , Herpesvirus Humano 4/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Supresoras de Tumor/fisiología , Proteínas de la Ataxia Telangiectasia Mutada , Linfocitos B/patología , Proliferación Celular , Transformación Celular Viral , Células Cultivadas , Quinasa de Punto de Control 2 , Antígenos Nucleares del Virus de Epstein-Barr/fisiología , Humanos , Transducción de Señal
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA