RESUMEN
The aim of this survey was to describe the attitudes and self-reported practices of French dentists towards antibiotic use and resistance and to compare practices with national guidelines. A nationwide cross-sectional internet-based survey was conducted among the 41,800 French dentists. The online questionnaire was distributed through professional networks from April 2017 to April 2018. Seven-hundred seventy-five dentists participated but only 455 questionnaires were complete enough to be included in the analyses. Amoxicillin was the most frequently prescribed antibiotic (65.8%, 1783/2711), followed by spiramycin + metronidazole fixed-dose combination (11.6%, 312/2711) and amoxicillin-clavulanic acid (10.3%, 279/2711). The main indications for use were abscess (349/423, 82.5%), cervicofacial cellulitis (74.2%, 314/423), and pericoronitis (58.6%, 239/408). Most dentists (90.5%, 381/421) considered that antibiotic resistance is of concern but only half of them (56.3%, 238/423) felt adequately informed about antibiotic use. Many dentists did not comply with the national guidelines: the majority of them declared inappropriate antibiotic prescriptions for 11/17 clinical situations. They did not prescribe antibiotics for 5/6 clinical situations requiring prophylaxis. They reported that the publication of clinical guidelines is the main factor influencing their prescriptions (71.0%, 299/421). They wished to receive regular updates of national guidelines in the form of practical sheets (93.0%, 172/185). French dentists should urgently be targeted by antibiotic stewardship initiatives.
Asunto(s)
Antibacterianos/uso terapéutico , Odontólogos/estadística & datos numéricos , Farmacorresistencia Microbiana , Adulto , Programas de Optimización del Uso de los Antimicrobianos , Actitud del Personal de Salud , Estudios Transversales , Femenino , Francia , Adhesión a Directriz , Encuestas de Atención de la Salud , Humanos , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina , Prescripciones/estadística & datos numéricosRESUMEN
Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia accompanied by the disruption of carbohydrate, lipid, and proteins metabolism and development of long-term microvascular, macrovascular, and neuropathic changes. This review presents the results of spectroscopic studies on the glycation of tissues and cell proteins in organisms with naturally developing and model diabetes and in vitro glycated samples in a wide range of electromagnetic waves, from visible light to terahertz radiation. Experiments on the refractometric measurements of glycated and oxygenated hemoglobin in broad wavelength and temperature ranges using digital holographic microscopy and diffraction tomography are discussed, as well as possible application of these methods in the diabetes diagnostics. It is shown that the development and implementation of multimodal approaches based on a combination of phase diagnostics with other methods is another promising direction in the diabetes diagnostics. The possibilities of using optical clearing agents for monitoring the diffusion of substances in the glycated tissues and blood flow dynamics in the pancreas of animals with induced diabetes have also been analyzed.
Asunto(s)
Diabetes Mellitus/diagnóstico por imagen , Hemoglobina Glucada/ultraestructura , Animales , Velocidad del Flujo Sanguíneo , Glicosilación , Holografía/métodos , Humanos , Microscopía/métodos , Espectrofotometría Infrarroja/métodos , Espectroscopía de Terahertz/métodos , Tomografía/métodosRESUMEN
Thanks to significant advances in real-time terahertz imaging in terms of resolution and image quality, adapting and extending optical methods for 3D imaging at the millimeter scale is now promising. The shape-from-focus algorithm is a post-processing tool used in optical microscopy to reconstruct the external shape surface of a convex surface object. Images acquired at different distances from the object-side focal plane are implemented in this algorithm. We localize the best focus position in the stack of images for each pixel and then reconstruct the object in 3D due to the short depth of field. In this Letter, we propose an application of this algorithm in active and real-time terahertz imaging. We achieve the experimental reconstruction in 3D with a terahertz waves imaging system composed of a powerful source and a real-time terahertz camera.
RESUMEN
Two-dimensional (2D) terahertz imaging and 3D visualization suffer from severe artifacts since an important part of the terahertz beam is reflected, diffracted, and refracted at each interface. These phenomena are due to refractive index mismatch and reflection in the case of non-orthogonal incidence. This paper proposes an experimental procedure that reduces these deleterious optical refraction effects for a cylinder and a prism made with polyethylene material. We inserted these samples in a low absorption liquid medium to match the sample index. We then replaced the surrounding air with a liquid with an optimized refractive index, with respect to the samples being studied. Using this approach we could more accurately recover the original sample shape by time-of-flight tomography.
RESUMEN
INTRODUCTION: We describe here an unusual presentation of a plasmablastic lymphoma in a patient suffering from an osteoradionecrosis of the jaw. PRESENTATION OF CASE: We report the case of a 64-year-old patient who was followed up on oncology because of an oropharyngeal cancer treated by a combined procedure of both surgery and radio-chemotherapy procedure. This patient developed an osteoradionecrosis of the jaw. In the vicinity of this necrotic area appeared an ulceration which could evoke a new necrotic area. Given the persistence of this ulceration, a biopsy was performed which highlighted a plasmablastic lymphoma oral localization. DISCUSSION: The plasmablastic lymphoma, belonging to the diffuse large B-cell lymphoma family, is a very aggressive and unusual form of cancer with poor prognosis. If it is found mainly in patients with positive HIV, in whom it was first described, it is also found in immunosuppressed patients such as transplanted patients or patients suffering from leukaemia. CONCLUSION: Plasmablastic lymphoma is a rare and an aggressive pathology in immunocompetent patients.
RESUMEN
Additive manufacturing (AM) technology is not only used to make 3D objects but also for rapid prototyping. In industry and laboratories, quality controls for these objects are necessary though difficult to implement compared to classical methods of fabrication because the layer-by-layer printing allows for very complex object manufacturing that is unachievable with standard tools. Furthermore, AM can induce unknown or unexpected defects. Consequently, we demonstrate terahertz (THz) imaging as an innovative method for 2D inspection of polymer materials. Moreover, THz tomography may be considered as an alternative to x-ray tomography and cheaper 3D imaging for routine control. This paper proposes an experimental study of 3D polymer objects obtained by additive manufacturing techniques. This approach allows us to characterize defects and to control dimensions by volumetric measurements on 3D data reconstructed by tomography.
RESUMEN
The dissemination of individual tumor cells is a common phenomenon in solid cancers. Detection of tumor cells in bone marrow disseminated tumor cells (DTC) and in peripheral blood circulating tumor cells (CTC) in nonmetastatic situation is of high prognostic significance. Compared to breast, colon and prostate cancers, the studies on CTC and DTC in head and neck cancers are sparse. The objective of our study was to detect DTC in drains after neck dissection. Fourteen patients undergoing surgery for stages III and IV head and neck cancers were enrolled in this study--twelve presenting with squamous cell carcinoma and two with adenocarcinoma. Redon drain analysis was performed by the Cellsearch method using immunomagnetic and fluorescence approaches. A positivity threshold value was set at 2DTC/7.5 ml of the sample. Tumor cells were detected in drains of 69 % of patients a few days after surgery. The range of quantification was 3-2,094 DTC/5 ml and we showed morphological differences between the two types of carcinoma cells. DTC were detected after neck dissection both in squamous cell carcinoma and in adenocarcinoma. Potential clinical significance of tumor cells needs to be further investigated as their presence could affect pre-surgical and post-operative treatments.
Asunto(s)
Carcinoma de Células Escamosas/diagnóstico , Drenaje , Neoplasias de Cabeza y Cuello/diagnóstico , Disección del Cuello/métodos , Estadificación de Neoplasias , Células Neoplásicas Circulantes/patología , Complicaciones Posoperatorias , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/cirugía , Femenino , Neoplasias de Cabeza y Cuello/secundario , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Pronóstico , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
In this paper, the impact of low-frequency noise on terahertz-computed tomography (THz-CT) is analyzed for several measurement configurations and pyroelectric detectors. We acquire real noise data from a continuous millimeter-wave tomographic scanner in order to figure out its impact on reconstructed images. Second, noise characteristics are quantified according to two distinct acquisition methods by (i) extrapolating from experimental acquisitions a sinogram for different noise backgrounds and (ii) reconstructing the corresponding spatial distributions in a slice using a CT reconstruction algorithm. Then we describe the low-frequency noise fingerprint and its influence on reconstructed images. Thanks to the observations, we demonstrate that some experimental choices can dramatically affect the 3D rendering of reconstructions. Thus, we propose some experimental methodologies optimizing the resulting quality and accuracy of the 3D reconstructions, with respect to the low-frequency noise characteristics observed during acquisitions.
RESUMEN
BACKGROUND: Reconstruction of the mandible with microvascularized fibula transplants is actually a well-established procedure, yet the major component is the limited diameter of the diaphysis that can induce oral rehabilitation's failure, especially in dentate patients. In this paper, we report our surgical procedure allowing preservation of the mandibular height. The primary objective was to assess aesthetic and functional improvements of preservation of an osseous mandibular rim with a fibula free flap reconstruction. PATIENTS AND METHODS: Five patients (all males, mean age of 60 years) were treated with this method. Aetiologies were tumour in 3 cases, and osteoradionecrosis in the two others cases. We described all step of our surgical procedure and the functional, aesthetic and carcinologic results were evaluated. The follow up varies from 6 to 30 months. RESULTS: One patient died at 12 days from unrelated affection. For the other patients, both the aesthetics and functional outcomes were better than in case of mandibular interruption surgery. In fact, the mandibular contour of the mandibule was preserved and the height of mandible was restored. One patient is in progress of dental rehabilitation with osseous implants. Carcinologically, no local recurrence was observed. CONCLUSION: This technique is reliable and enables to optimize oral rehabilitation with endosteal implants. Nevertheless, we consider that the 3D scanner is essential before the intervention to evaluate the osseous reach. Moreover, if necessarily the procedure can be modified intraoperatively.
Asunto(s)
Peroné/trasplante , Colgajos Tisulares Libres , Neoplasias Mandibulares/cirugía , Reconstrucción Mandibular/métodos , Anciano , Carcinoma de Células Escamosas/cirugía , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We investigate in this paper a new reconstruction method in order to perform 3D Terahertz (THz) tomography using a continuous wave acquisition setup in transmission mode. This method is based on the Maximum Likelihood for TRansmission tomography (ML-TR) first developed for X-ray imaging. We optimize the Ordered Subsets Convex (OSC) implementation of the ML-TR by including the Gaussian propagation model of THz waves and take into account the intensity distributions of both blank calibration scan and dark-field measured on THz detectors. THz ML-TR reconstruction quality and accuracy are discussed and compared to other tomographic reconstructions.
Asunto(s)
Algoritmos , Procesamiento de Imagen Asistido por Computador , Fantasmas de Imagen , Tomografía Computarizada por Rayos X/métodos , Tomografía por Rayos X/métodos , Humanos , ProbabilidadRESUMEN
The authors describe a pooled analysis of 23 French patients presenting with oral metastasis between 1981 and 2008. The reviewed cases were collected from the medical records of two cancer institutes. The inclusion criteria were: the histology of the metastases must be known; the primary location must be known; metastasis and primary location must be physically separated; and oral primary locations were excluded. This sample represent 0.48% of all oral malignancies treated during the period. The sex-ratio was 2.3:1 in favour of men, the mean age was 64.5 years (±13.2). Lungs and kidneys represent 52.2% of the primary cancer locations. In most cases, the primary cancer was a carcinoma or an adenocarcinoma (82.6%). The most affected oral regions were the gingiva and alveolar mucosa (60.7%), followed by the tongue (17.9%). The mean survival was 16.6 months. This sample is characterized by the relative absence of specific symptoms and quite different distribution in primary sites. Even if oral metastases are rare, their semiological value necessitates the histopathological examination of any oral tumour, and a systematic search in all patients with cancer history.
Asunto(s)
Mucosa Bucal/patología , Neoplasias de la Boca/secundario , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/secundario , Femenino , Francia , Humanos , Neoplasias Maxilomandibulares/patología , Neoplasias Maxilomandibulares/secundario , Neoplasias Maxilomandibulares/terapia , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Neoplasias de la Boca/terapia , Estudios Retrospectivos , Sarcoma/secundario , Tasa de SupervivenciaRESUMEN
In this paper, a model of the beam propagation is developed according to the physical properties of THz waves used in THz computed tomography (CT) scan imaging. This model is first included in an acquisition simulator to observe and estimate the impact of the Gaussian beam intensity profile on the projection sets. Second, the model is introduced in several inversion methods as a convolution filter to perform efficient tomographic reconstructions of simulated and real acquired objects. Results obtained with three reconstruction methods (BFP, SART and OSEM) are compared to the techniques proposed in this paper. We will demonstrate an increase of the overall quality and accuracy of the 3D reconstructions.
Asunto(s)
Algoritmos , Tomografía Computarizada de Haz Cónico/métodos , Interpretación de Imagen Asistida por Computador/métodos , Imagenología Tridimensional/métodos , Modelos Estadísticos , Simulación por Computador , Aumento de la Imagen/métodos , Reproducibilidad de los Resultados , Dispersión de Radiación , Sensibilidad y Especificidad , Radiación TerahertzRESUMEN
UNLABELLED: Surgical treatment of oropharyngeal tumours usually requires mandibular osteotomy. Using this technique allows a better exposure and an easier excision, but this approach often generates complications. Since 1995, we used a less aggressive surgical technique, with a suprahyoid pharyngotomy when the oral approach was not sufficient, thus sparing the mandible. OBJECTIVE: The purpose of this study is to evaluate this technical evolution, ensuring that mandibular preservation doesn't affect quality of exeresis, local control and survival, while allowing a lower complication rate. MATERIAL AND METHODS: All patients who have had a surgical treatment for an oropharyngeal carcinoma between 1995 and 2001 in our center were included in this study. RESULTS: Mandibular sparing was used for 55 patients; 19 patients underwent mandibulotomy. The surgical procedure's quality was classified as clear, close, or insufficient margins. All adjuvant treatments were noted, functional and carcinologic results were evaluated. No significant differences are found for exeresis quality and local control. There are less complications (p = 0.045) and less surgical revisions (p = 0.023) in the preservation group. Survival and functional results are better in the preservation group, but without significant difference. For oropharyngeal tumours, survival is dependent on tumoural aggressivity, on general condition and co-morbidity and on the development of a second tumour. Results in local control rate (83.7% at 1 year) are satisfying compared to literature. CONCLUSION: Mandibular preservation is an efficient and safe procedure, even for T3/T4 tumours. Most of oropharyngeal tumours can be removed without mandibulotomy. The suprahyoid approach provides a good exposure when oral approach is insufficient, thus avoiding mandibulotomy and its complications.
Asunto(s)
Carcinoma de Células Escamosas/cirugía , Mandíbula/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Neoplasias Orofaríngeas/cirugía , Osteotomía/métodos , Adulto , Anciano , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/patología , Pronóstico , Estudios RetrospectivosRESUMEN
Cell-mediated immunity directed against human papillomavirus 16 (HPV-16) antigens was studied in 16 patients affected with classic vulvar intra-epithelial neoplasia (VIN), also known as bowenoid papulosis (BP). Ten patients had blood lymphocyte proliferative T cell responses directed against E6/2 (14-34) and/or E6/4 (45-68) peptides, which were identified in the present study as immunodominant among HPV-16 E6 and E7 large peptides. Ex vivo enzyme-linked immunospot-interferon (IFN)-gamma assay was positive in three patients who had proliferative responses. Twelve months later, proliferative T cell responses remained detectable in only six women and the immunodominant antigens remained the E6/2 (14-34) and E6/4 (45-68) peptides. The latter large fragments of peptides contained many epitopes able to bind to at least seven human leucocyte antigen (HLA) class I molecules and were strong binders to seven HLA-DR class II molecules. In order to build a therapeutic anti-HPV-16 vaccine, E6/2 (14-34) and E6/4 (45-68) fragments thus appear to be good candidates to increase HPV-specific effector T lymphocyte responses and clear classic VIN (BP) disease lesions.
Asunto(s)
Epítopos de Linfocito T/inmunología , Papillomavirus Humano 16/inmunología , Proteínas Oncogénicas Virales/inmunología , Infecciones por Papillomavirus/inmunología , Proteínas Represoras/inmunología , Linfocitos T/inmunología , Neoplasias de la Vulva/inmunología , Neoplasias de la Vulva/virología , Adulto , Anciano , Secuencia de Aminoácidos , Proliferación Celular , Epítopos de Linfocito T/metabolismo , Femenino , Antígenos HLA-D/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Interferón gamma/metabolismo , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Activación de Linfocitos/inmunología , Persona de Mediana Edad , Proteínas E7 de Papillomavirus , Infecciones por Papillomavirus/virología , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Unión Proteica/inmunología , Linfocitos T/citología , Linfocitos T/metabolismo , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: The human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome induce account for over 40 million deaths in the past 20 years. Given that the currently available treatments to prevent HIV transmission and disease are not effective in eradicating the virus, vaccination likely represents the only efficacious adapted response to the global impact of this infection. This paper reviews the challenges encountered in the development of an HIV vaccine as well as the different vaccine approaches and main HIV vaccine candidates evaluated in clinical trials. CURRENT KNOWLEDGE AND KEY POINTS: In spite the tremendous progress in HIV research, the major challenges that are encountered in the development of an HIV vaccine remain of scientific order and include viral specificities, absence of correlates of immune protection and limitations of existing animal models. Over 30 vaccine candidates have been evaluated in clinical trials. These vaccine approaches include the use of recombinant envelope proteins, DNA vaccines, live-vectored recombinant vaccines, subunit vaccines and prime-boost regimens combining various vaccine candidates. Although the protective efficacy of these candidate vaccines has yet to be demonstrated, some vaccination regiments appear to dampen initial viremia and prolong disease-free survival. FUTURE PROSPECTS AND PROJECTS: Faced with the challenges in developing an HIV vaccine, international consortia and new methodologies have been proposed in order to accelerate the development and screening process of new candidate HIV vaccines. Moreover, in the absence of a protective vaccine, the impact of a vaccine that confers partial protection needs to be seriously considered.
Asunto(s)
Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , Vacunas contra el SIDA/genética , Diseño de Fármacos , Variación Genética , Infecciones por VIH/genética , HumanosRESUMEN
This paper addresses a passive system capable of converting a linearly polarized THz beam into a radially polarized one. This is obtained by extending to THz frequencies and waveguides an already proven concept based on mode selection in optical fibers. The approach is validated at 0.1 THz owing to the realization of a prototype involving a circular waveguide and two tapers that exhibits a radially polarized beam at its output. By a simple homothetic size reduction, the system can be easily adapted to higher THz frequencies.
Asunto(s)
Refractometría/instrumentación , Transductores , Diseño Asistido por Computadora , Diseño de Equipo , Análisis de Falla de Equipo , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Radiación TerahertzRESUMEN
Little is known about the role of specific hepatitis C virus (HCV) CD8+ T cells in liver damage, especially for the progression of fibrosis, during the highly variable course of chronic C hepatitis. The aim of this study was to investigate the presence of HCV-specific CD8+ T cells in the liver of patients with chronic C hepatitis and to examine their clinical significance by relating the response to liver fibrosis and progression rate, serum viral load, serum aminotransferase levels, inflammatory activity and in situ characteristics of the intrahepatic infiltrate. Fifteen patients were prospectively included in the study. Intrahepatic lymphocytes were tested for interferon gamma (IFNg) production in response to HCV class I-restricted epitopic peptides using enzyme-linked immunospot analysis. Liver biopsy samples were evaluated for fibrosis, fibrosis progression rate, activity, and in situ number of CD8+ cytotoxic lymphocytes and apoptotic cells. An IFNg-specific CD8+ T-cell response was detected in the liver samples of 47% of patients which was significantly related to a lower stage of fibrosis (P = 0.02) and a lower progression rate of fibrosis (P = 0.01). It was neither related to the number of cytotoxic lymphocytes infiltrating the liver nor to hepatocyte apoptosis. In conclusion, our results indicate that the presence of HCV-specific IFNg-secreting T cells in the liver of patients with chronic C hepatitis is associated with low liver fibrosis and fibrosis progression rate, suggesting that these IFNg-secreting T cells might limit the progression of liver damage.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Hepatitis C Crónica/inmunología , Interferón gamma/inmunología , Cirrosis Hepática/inmunología , Adulto , Anciano , Linfocitos T CD8-positivos/metabolismo , Femenino , Hepatitis C Crónica/enzimología , Hepatitis C Crónica/patología , Humanos , Inmunofenotipificación , Interferón gamma/metabolismo , Hígado/enzimología , Hígado/inmunología , Hígado/metabolismo , Cirrosis Hepática/enzimología , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Transaminasas/sangreRESUMEN
The anti-Hu syndrome is the most common paraneoplastic neurologic syndrome but the exact mechanism of immune mediated neuronal injury remains unknown. Anti-Hu antibodies do not appear to play a pivotal role in the pathogenesis of the disease. To assess cell-mediated immunity, we selected 51 peptides from the Hu-D sequence and tested their ability to bind to six common HLA class I molecules. Stable complexes with purified HLA molecules were obtained with 19/51 (37%) selected peptides. Subsequently, the ability of the 19 HLA-binding peptides to stimulate T cells from 10 patients and 10 control subjects was evaluated by detecting IFN-gamma secretion. An anti-peptide T-cell response was observed in 7/10 Hu-positive patients but also in 3/10 control subjects. Overall, a significant T-cell activation occurred in response to 74% (14 out of 19) of the selected peptides in the Hu-positive patients vs. 16% (3 out of 19) in the control group (p < 0.001). In addition, T cells of patients tested within 3 months of the onset of anti-Hu syndrome responded to 82% (14 out of 17) of assessed Hu-D peptides vs. 37% (7 out of 19) in patients tested 1 year or more after developing the syndrome (p < 0.01). Thus, the present study suggests a role of cellular immunity during the course of anti-Hu syndrome.
Asunto(s)
Carcinoma de Células Pequeñas/inmunología , Inmunidad Celular/inmunología , Proteínas del Tejido Nervioso/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Proteínas de Unión al ARN/inmunología , Linfocitos T/inmunología , Carcinoma de Células Pequeñas/complicaciones , Células Cultivadas , Proteínas ELAV , Antígenos HLA-A/inmunología , Antígenos HLA-A/metabolismo , Humanos , Interferón gamma/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Síndromes Paraneoplásicos del Sistema Nervioso/complicaciones , Fragmentos de Péptidos/inmunología , Proteínas de Unión al ARN/metabolismo , Estadísticas no Paramétricas , Síndrome , Linfocitos T/metabolismoRESUMEN
Cytotoxic T-lymphocyte (CTL) responses directed to different human immunodeficiency virus (HIV) epitopes vary in their protective efficacy. In particular, HIV-infected cells are much more sensitive to lysis by anti-Gag/p17(77-85)/HLA-A2 than to that by anti-polymerase/RT(476-484)/HLA-A2 CTL, because of a higher density of p17(77-85) complexes. This report describes multiple processing steps favoring the generation of p17(77-85) complexes: (i) the exact COOH-terminal cleavage of epitopes by cellular proteases occurred faster and more frequently for p17(77-85) than for RT(476-484), and (ii) the binding efficiency of the transporter associated with antigen processing was greater for p17(77-85) precursors than for the RT(476-484) epitope. Surprisingly, these peptides, which differed markedly in their antigenicity, displayed qualitatively and quantitatively similar immunogenicity, suggesting differences in the mechanisms governing these phenomena. Here, we discuss the mechanisms responsible for such differences.
Asunto(s)
Presentación de Antígeno/inmunología , Cisteína Endopeptidasas , Epítopos de Linfocito T/inmunología , Productos del Gen gag/inmunología , Antígenos VIH/inmunología , Infecciones por VIH/inmunología , Transcriptasa Inversa del VIH/inmunología , VIH-1/inmunología , Antígeno HLA-A2/inmunología , Epítopos Inmunodominantes/inmunología , Complejos Multienzimáticos , Linfocitos T Citotóxicos/inmunología , Proteínas Virales , Secuencia de Aminoácidos , Transporte Biológico , Endopeptidasas/metabolismo , Epítopos de Linfocito T/metabolismo , Productos del Gen gag/metabolismo , Antígenos VIH/metabolismo , Transcriptasa Inversa del VIH/metabolismo , Humanos , Epítopos Inmunodominantes/metabolismo , Complejo Mayor de Histocompatibilidad , Datos de Secuencia Molecular , Complejo de la Endopetidasa Proteasomal , Precursores de Proteínas/metabolismo , Proteínas/metabolismo , Productos del Gen gag del Virus de la Inmunodeficiencia HumanaRESUMEN
The HIV early regulatory Nef protein downregulates surface expression of major histocompatibility class I (MHC I) molecules on various immortalized cell lines and on T lymphocytes. MHC I-restricted presentation induces CD8+ T cell responses, which have a major role in limiting HIV infection. Induction of primary immune responses requires dendritic cells, which are major candidates as the first cells that can internalize the virus and present it to T cells in mucosal contamination. To test the effect of Nef on MHC I-restricted antigen presentation by dendritic cells, we used recombinant vaccinia viruses. Flow cytometric analysis of double labeling for a vaccinia protein and MHC I showed that HIV-1 Lai Nef indeed downregulated MHC I surface expression on dendritic cells. MHC I-restricted presentation to a Nef-specific CD8+ cell clone from an infected patient was decreased in an interferon gamma ELISpot assay. Presentation of a reverse transcriptase epitopic peptide on sorted Nef-infected cells was decreased in a peptide concentration-dependent way, confirming the role of MHC I downregulation in the impairment of the CD8+ cell-specific response. Therefore, Nef downregulates MHC I surface expression on human dendritic cells, impairing presentation to HIV-specific CD8+ cells. This action of Nef probably induces a deleterious delay in the early CD8+ responses during the first days of infection and at the onset of new viral mutants.