T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable

HIV controllers (HCs) are individuals who can naturally control HIV infection, partially due to potent HIV-specific CD8+ T cell responses. Here, we examined the hypothesis that superior function of CD8+ T cells from HCs is encoded by their T cell receptors (TCRs). We compared the functional properties of immunodominant HIV-specific TCRs obtained from HLA-B*2705 HCs and chronic progressors (CPs) following expression in primary T cells. T cells transduced with TCRs from HCs and CPs showed equivalent induction of epitope-specific cytotoxicity, cytokine secretion, and antigen-binding properties. Transduced T cells comparably, albeit modestly, also suppressed HIV infection in vitro and in humanized mice. We also performed extensive molecular dynamics simulations that provided a structural basis for similarities in cytotoxicity and epitope cross-reactivity. These results demonstrate that the differential abilities of HIV-specific CD8+ T cells from HCs and CPs are not genetically encoded in the TCRs alone and must depend on additional factors

T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable

HIV controllers (HCs) are individuals who can naturally control HIV infection, partially due to potent HIV-specific CD8+ T cell responses. Here, we examined the hypothesis that superior function of CD8+ T cells from HCs is encoded by their T cell receptors (TCRs). We compared the functional properties of immunodominant HIV-specific TCRs obtained from HLA-B*2705 HCs and chronic progressors (CPs) following expression in primary T cells. T cells transduced with TCRs from HCs and CPs showed equivalent induction of epitope-specific cytotoxicity, cytokine secretion, and antigen-binding properties. Transduced T cells comparably, albeit modestly, also suppressed HIV infection in vitro and in humanized mice. We also performed extensive molecular dynamics simulations that provided a structural basis for similarities in cytotoxicity and epitope cross-reactivity. These results demonstrate that the differential abilities of HIV-specific CD8+ T cells from HCs and CPs are not genetically encoded in the TCRs alone and must depend on additional factors

A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors

Host proteins are essential for HIV entry and replication and can be important nonviral therapeutic targets. Large-scale RNA interference (RNAi)-based screens have identified nearly a thousand candidate host factors, but there is little agreement among studies and few factors have been validated. Here we demonstrate that a genome-wide CRISPR-based screen identifies host factors in a physiologically relevant cell system. We identify five factors, including the HIV co-receptors CD4 and CCR5, that are required for HIV infection yet are dispensable for cellular proliferation and viability. Tyrosylprotein sulfotransferase 2 (TPST2) and solute carrier family 35 member B2 (SLC35B2) function in a common pathway to sulfate CCR5 on extracellular tyrosine residues, facilitating CCR5 recognition by the HIV envelope. Activated leukocyte cell adhesion molecule (ALCAM) mediates cell aggregation, which is required for cell-to-cell HIV transmission. We validated these pathways in primary human CD4 + T cells through Cas9-mediated knockout and antibody blockade. Our findings indicate that HIV infection and replication rely on a limited set of host-dispensable genes and suggest that these pathways can be studied for therapeutic intervention

The Effect of Arabinoxylan and Wheat Bran Incorporation on Dough Rheology and Thermal Processing of Rotary-Moulded Biscuits

Wheat bran incorporation into biscuits may increase their nutritional value, however, it may affect dough rheology and baking performance, due to the effect of bran particles on dough structure and an increase in water absorption. This study analyzed the enrichment effect of wheat bran and arabinoxylans, the most important non-starch polysaccharides found in whole wheat flour, on dough rheology and thermal behaviour during processing of rotary-moulded biscuits. The objective was to understand the contribution of arabinoxylans during biscuit-making and their impact when incorporated as wheat bran. Refined flour was replaced at 25, 50, 75, or 100% by whole flour with different bran particle sizes (fine: 4% > 500 μm; coarse: 72% > 500 μm). The isolated effect of arabinoxylans was examined by preparing model flours, where refined flour was enriched with water-extractable and water-unextractable arabinoxylans. Wheat bran had the greatest impact on dough firmness and arabinoxylans had the greatest impact on the elastic response. The degree of starch gelatinization increased from 24 to 36% in biscuits enriched with arabinoxylans or whole flour and coarse bran. The microstructural analysis (SEM, micro-CT) suggested that fibre micropores may retain water inside their capillaries which can be released in a controlled manner during baking

HIV Controllers Exhibit Effective CD8 + T Cell Recognition of HIV-1-Infected Non-activated CD4 + T Cells

Even with sustained antiretroviral therapy, resting CD4 + T cells remain a persistent reservoir of HIV infection, representing a critical barrier to curing HIV. Here, we demonstrate that CD8 + T cells recognize infected, non-activated CD4 + T cells in the absence of de novo protein production, as measured by immune synapse formation, degranulation, cytokine production, and killing of infected cells. Immune recognition is induced by HLA-I presentation of peptides derived from incoming viral particles, and recognition occurred either following cell-free virus infection or following cell-to-cell spread. CD8 + T cells from HIV controllers mediate more effective immune recognition than CD8 + T cells from progressors. These results indicate that non-activated HIV-infected CD4 + T cells can be targeted by CD8 + T cells directly after HIV entry, before reverse transcription, and thus before the establishment of latency, and suggest a mechanism whereby the immune response may reduce the size of the HIV reservoir. The cure for HIV is not achievable due to HIV reservoirs, mostly in resting CD4 + T cells. Monel et al. show that CD8 + T cells from HIV controllers are able to establish immunological synapses with HIV + resting CD4 + T cells, leading to IFN-?, MIP1-? production, degranulation, and the elimination of the target cells. © 2019 The Author

HIV Controllers Exhibit Effective CD8 + T Cell Recognition of HIV-1-Infected Non-activated CD4 + T Cells

Even with sustained antiretroviral therapy, resting CD4 + T cells remain a persistent reservoir of HIV infection, representing a critical barrier to curing HIV. Here, we demonstrate that CD8 + T cells recognize infected, non-activated CD4 + T cells in the absence of de novo protein production, as measured by immune synapse formation, degranulation, cytokine production, and killing of infected cells. Immune recognition is induced by HLA-I presentation of peptides derived from incoming viral particles, and recognition occurred either following cell-free virus infection or following cell-to-cell spread. CD8 + T cells from HIV controllers mediate more effective immune recognition than CD8 + T cells from progressors. These results indicate that non-activated HIV-infected CD4 + T cells can be targeted by CD8 + T cells directly after HIV entry, before reverse transcription, and thus before the establishment of latency, and suggest a mechanism whereby the immune response may reduce the size of the HIV reservoir. The cure for HIV is not achievable due to HIV reservoirs, mostly in resting CD4 + T cells. Monel et al. show that CD8 + T cells from HIV controllers are able to establish immunological synapses with HIV + resting CD4 + T cells, leading to IFN-?, MIP1-? production, degranulation, and the elimination of the target cells. © 2019 The Author

El impacto de la detección de disfunción endotelial en la aterosclerosis: estudio mediante tomografía por emisión de positrones

El endotelio juega un papel importante en la regulación del líquido intracelular, la permeabilidad vascular, en la modulación del tono vascular focal y la angiogénesis. La disfunción endotelial se manifiesta por la pérdida de la capacidad del endotelio de modular el comportamiento fisiológico del lecho vascular y actualmente se considera un marcador pronóstico de la enfermedad arterial coronaria. La relevancia de estudiar la disfunción endotelial radica en que ésta se ha observado en diversas patologías como diabetes mellitas (DM), dislipidemia, hipertensión arterial sistémica, tabaquismo o en enfermedades inmunológicas como síndrome antifosfolípido y lupus eritematoso sistémico. La Tomografía por Emisión de Positrones (PET) es un método no invasivo que permite cuantificar en términos absolutos el flujo miocárdico en reposo, esfuerzo y durante la estimulación adrenérgica, siendo considerado en la actualidad el estándar de oro para valorar la función endotelial. Por lo tanto el PET es una herramienta diagnóstica muy útil en identificar a los pacientes con disfunción endotelial y en evaluar la respuesta a la terapia administrada en enfermedades que se acompañen de ésta. Permitiendo un control óptimo y prevención de eventos adversos de estas enfermedades

Modelo de estudio mediante microPET para la evaluación del metabolismo glucolítico en el miocardio de rata con 18F-FDG: Experiencia inicial en México

Objetivos: Estandarizar un protocolo de adquisición para el estudio del metabolismo glucolítico miocárdico en ratas adultas. Material y métodos: Se estudiaron 3 ratas macho adultas de la cepa Wistar en tres diferentes protocolos: el primero con acceso a libre demanda de comida y agua; el segundo con ayuno de 12 horas y el tercero con ayuno de 12 horas más la administración de una carga oral de glucosa al 50%. Se adquirieron imágenes del área torácica durante 30 minutos mediante el microPET; a los 30 y 60 minutos después de la administración de una dosis de 370 - 555 MBq de 18F-FDG por vía intraperitoneal. Se realizó un análisis comparativo y cualitativo de las imágenes obtenidas por dos médicos especialistas en el área. Resultados: Se obtuvieron en total 18 estudios cardíacos; 6 para cada protocolo, donde se determinó que las mejores imágenes para fines de evaluación metabólica del miocardio fueron las correspondientes a los 60 minutos postadministración de la 18F-FDG del protocolo sin ayuno. Conclusiones: Es factible establecer en nuestro servicio un protocolo válido para la valoración del metabolismo glucolítico, con el fin de utilizarlo en el estudio de viabilidad miocárdica en la cardiopatía isquémica