Una mirada retrospectiva sobre Quevedo y lo grotesco (autocrítica, autobombo y perplejidad)

Este ensayo examina retrospectivamente el problema de la relación entre Quevedo y lo grotesco. El autor reflexiona principalmente sobre el impacto ejercido por su Quevedo and the Grotesque (1978, 1982) en conexión con los muchos cambios que se han dado dentro del campo de los estudios hispánicos y de la enseñanza universitaria en general desde su aparición. Explora la compleja relación afectiva / intelectual que se desarrolla entre los estudiosos y los autores y temas que investigan, junto con la manera en que esa relación es afectada por la dinámica socioeconómica de la academia. Examina cómo el ethos de la investigación erudita ha evolucionado durante las últimas cuatro décadas, incluyendo la creciente brecha que separa los estudios hispánicos tal como se practican en los Estados Unidos y España. El autor desarrolla varias hipótesis para explicar por qué la parte de su libro que él considera su contribución más importante pasó esencialmente desapercibida por los críticos. También señala las partes del libro que considera las más débiles y sugiere maneras en que se pudieran haber mejorado. Finalmente, reflexiona sobre el modo en que los estudiosos tienden a ser definidos casi exclusivamente por sus colegas en términos de ciertos (a menudo tempranos) aportes, lo cual lleva a una tergiversación de su trayectoria profesional completa.This essay engages in a retrospective examination of the problem of Quevedo’s relationship to the grotesque. The author reflects primarily on the impact exercised by his Quevedo and the Grotesque (1978, 1982) in connection with the many changes that have occurred in the field of Hispanic studies and the teaching profession at the university level in general since its appearance. It explores the complex affective / intellectual relationship that develops between scholars and the authors and subjects they study and how that relationship is affected by the socio-economic dynamics of the academy. It examines how the ethos of scholarship has evolved in the last four decades, including the growing divide that separates Hispanic studies as practiced in the United States and Spain. The author develops hypotheses to explain why the part of his book that he considers its most original contribution went essentially unnoticed by critics. He also points to the parts of the book he considers to be its weakest and suggests ways in which they could have been improved. Finally, he reflects on the way scholars tend to be defined almost exclusively by their colleagues in terms of certain (often early) contributions, thereby leading to a misrepresentation of their full professional trajectory

Influenza A virus challenge models in cynomolgus macaques using the authentic inhaled aerosol and intra-nasal routes of infection

Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections

Interactions of Viruses With Equine Monocyte-Derived Dendritic Cells.

Dendritic cells (DC) are important modulators of the immune response with the ability to present antigen to naive T cells. DC can be generated in vitro from blood monocytes (MoDC), which represent an appropriate model to study DC biology. In addition, they are important targets for many viruses and this interaction is crucial for the establishment of an anti-viral immunity. Equine arteritis virus (EAV) and Equine encephalosis virus (EEV) cause infectious diseases in equids. Little is known of the effect both viruses have on host immune cells, particularly DC. An optimized system was established to generate equine MoDC (eqMoDC) in vitro. Purified recombinant equine cytokines (GM-CSF and IL-4) were used for the differentiation of Mo to immature MoDC (iMoDC) and a cocktail of stimuli was used for DC maturation. The phenotype of DC, studied using flow cytometry and microarray analysis, and functional assays, such as endocytosis/phagocytosis, mixed leukocyte reactions, antigen presentation and cross presentation, were applied to characterise immature and mature MoDC (mMoDC). To study the interaction with EAV and EEV, MoDC were infected with strains of different genotypes and pathogenicity and virus replication was determined through titration and real-time quantitative PCR (qPCR). Both viruses were able to infect Mo and MoDC but showed differences in their replication pattern. EAV demonstrated a productive replication leading to lysis of cells whereas EEV displayed a possible restricted or restricted-persistent replication. Mature MoDC were the most susceptible to these viruses, unlike iMoDC which were the least susceptible cells thereby preserving their phenotypic and functional characteristics. The replication of EAV resulted in an apoptosis mediated cell death, which inevitably inhibited the differentiation and function of DC. On the other hand, EEV drove the differentiation of Mo. Both viruses inhibited the ability of mMoDC to activate T cells, which is a mechanism used to evade host anti-viral immunity

Interactions of Viruses With Equine Monocyte-Derived Dendritic Cells.

Dendritic cells (DC) are important modulators of the immune response with the ability to present antigen to naive T cells. DC can be generated in vitro from blood monocytes (MoDC), which represent an appropriate model to study DC biology. In addition, they are important targets for many viruses and this interaction is crucial for the establishment of an anti-viral immunity. Equine arteritis virus (EAV) and Equine encephalosis virus (EEV) cause infectious diseases in equids. Little is known of the effect both viruses have on host immune cells, particularly DC. An optimized system was established to generate equine MoDC (eqMoDC) in vitro. Purified recombinant equine cytokines (GM-CSF and IL-4) were used for the differentiation of Mo to immature MoDC (iMoDC) and a cocktail of stimuli was used for DC maturation. The phenotype of DC, studied using flow cytometry and microarray analysis, and functional assays, such as endocytosis/phagocytosis, mixed leukocyte reactions, antigen presentation and cross presentation, were applied to characterise immature and mature MoDC (mMoDC). To study the interaction with EAV and EEV, MoDC were infected with strains of different genotypes and pathogenicity and virus replication was determined through titration and real-time quantitative PCR (qPCR). Both viruses were able to infect Mo and MoDC but showed differences in their replication pattern. EAV demonstrated a productive replication leading to lysis of cells whereas EEV displayed a possible restricted or restricted-persistent replication. Mature MoDC were the most susceptible to these viruses, unlike iMoDC which were the least susceptible cells thereby preserving their phenotypic and functional characteristics. The replication of EAV resulted in an apoptosis mediated cell death, which inevitably inhibited the differentiation and function of DC. On the other hand, EEV drove the differentiation of Mo. Both viruses inhibited the ability of mMoDC to activate T cells, which is a mechanism used to evade host anti-viral immunity

Equine Arteritis Virus in Monocytic Cells Suppresses Differentiation and Function of Dendritic Cells

Equine viral arteritis is an infectious disease of equids caused by equine arteritis virus (EAV), an RNA virus of the family Arteriviridae. Dendritic cells (DC) are important modulators of the immune response with the ability to present antigen to naïve T cells and can be generated in vitro from monocytes (MoDC). DC are important targets for many viruses and this interaction is crucial for the establishment—or rather not—of an anti-viral immunity. Little is known of the effect EAV has on host immune cells, particularly DC. To study the interaction of eqDC with EAV in vitro, an optimized eqMoDC system was used, which was established in a previous study. MoDC were infected with strains of different genotypes and pathogenicity. Virus replication was determined through titration and qPCR. The effect of the virus on morphology, phenotype and function of cells was assessed using light microscopy, flow cytometry and in vitro assays. This study confirms that EAV replicates in monocytes and MoDC. The replication was most efficient in mature MoDC, but variable between strains. Only the virulent strain caused a significant down-regulation of certain proteins such as CD14 and CD163 on monocytes and of CD83 on mature MoDC. Functional studies conducted after infection showed that EAV inhibited the endocytic and phagocytic capacity of Mo and mature MoDC with minimal effect on immature MoDC. Infected MoDC showed a reduced ability to stimulate T cells. Ultimately, EAV replication resulted in an apoptosis-mediated cell death. Thus, EAV evades the host anti-viral immunity both by inhibition of antigen presentation early after infection and through killing infected DC during replication

Effect of epitope variant co-delivery on the depth of CD8 T cell responses induced by HIV-1 conserved mosaic vaccines

To stop the HIV-1 pandemic, vaccines must induce responses capable of controlling vast HIV-1 variants circulating in the population as well as those evolved in each individual following transmission. Numerous strategies have been proposed, of which the most promising include focusing responses on the vulnerable sites of HIV-1 displaying the least entropy among global isolates and using algorithms that maximize vaccine match to circulating HIV-1 variants by vaccine cocktails of optimized complementing sequences. In this study, we investigated CD8 T cell responses induced by a bi-valent mosaic of highly conserved HIVconsvX regions delivered by a combination of simian adenovirus ChAdOx1 and poxvirus MVA. We compared partially and fully mono- and bi-valent prime-boost regimens and their ability to elicit T cells recognizing natural epitope variants using an interferon-γ enzyme-linked immunospot (ELISPOT) assay. We used 11 well-defined CD8 T cell epitopes in two mouse haplotypes and, for each epitope, assessed recognition of the two vaccine forms together with the other most frequent epitope variants in the HIV-1 database. We conclude that for the magnitude and depth of epitope recognition, CD8 T cell responses benefitted in most comparisons from the combined bi-valent mosaic and envisage the main advantage of the bi-valent vaccine during its deployment to diverse populations

Efficient Induction of T Cells against Conserved HIV-1 Regions by Mosaic Vaccines Delivered as Self-Amplifying mRNA

Focusing T cell responses on the most vulnerable parts of HIV-1, the functionally conserved regions of HIV-1 proteins, is likely a key prerequisite for vaccine success. For a T cell vaccine to efficiently control HIV-1 replication, the vaccine-elicited individual CD8+ T cells and as a population have to display a number of critical traits. If any one of these traits is suboptimal, the vaccine is likely to fail. Fine-tuning of individual protective characteristics of T cells will require iterative stepwise improvements in clinical trials. Although the second-generation tHIVconsvX immunogens direct CD8+ T cells to predominantly protective and conserved epitopes, in the present work, we have used formulated self-amplifying mRNA (saRNA) to deliver tHIVconsvX to the immune system. We demonstrated in BALB/c and outbred mice that regimens employing saRNA vaccines induced broadly specific, plurifunctional CD8+ and CD4+ T cells, which displayed structured memory subpopulations and were maintained at relatively high frequencies over at least 22 weeks post-administration. This is one of the first thorough analyses of mRNA vaccine-elicited T cell responses. The combination of tHIVconsvX immunogens and the highly versatile and easily manufacturable saRNA platform may provide a long-awaited opportunity to define and optimize induction of truly protective CD8+ T cell parameters in human volunteers. Keywords: RNA vaccine, HIV vaccine, conserved regions, tHIVconsvX, simian adenovirus, MVA, T cell vaccine, heterologous prime-boost, in vivo killing, T cell

HIVconsv vaccine-induced human T-cell responses.

<p>(A) Schematic representations of the HIVconsv immunogen and six pools of a total of 199 overlapping peptides used for the IFN-γ ELISPOT assay. HIVconsv is a chimeric protein assembled from 14 highly conserved regions of the HIV-1 proteome, the HIV-1 protein origins of which are colour-coded below. Each of the regions uses a consensus amino acid sequence of the HIV-1 clade indicated above the schematics. The C-terminal epitopes include Mamu-A*01- and H-2^d-restricted immunodominant CTL epitopes and a Pk tag recognized by a monoclonal antibody, which together facilitate the quality control of the vaccines. (B) Fresh <i>ex vivo</i> net total (sum of six pools) IFN-γ ELISPOT assay frequencies of HIVconsv-specific T cells of returning healthy HIV-1-negative volunteers of trial HIV-CORE 002, who received either the CM (top) and DDDCM (bottom) vaccine regimen, are shown separately. Time points ‘S’ (screen) and 0–28 weeks were previously published [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181382#pone.0181382.ref068" target="_blank">68</a>] and are shown for completeness. ‘1y’ and ‘2y’ indicate 1 and 2 years after the last M (MVA.HIVconsv) vaccine administration at weeks 8 (CM) and 20 (DDDCM) indicated below the graphs. Volunteers’ ID numbers are shown on the graph legend. (C) Fresh <i>ex vivo</i> net total IFN-γ ELISPOT assay frequencies of HIVconsv-specific T cells after 1 and 2 years. The horizontal bars represent median frequencies for each regimen separately. The two time points and regimens were not statistically separable.</p

Functionality and memory subtypes of vaccine-elicited human CD4⁺ and CD8⁺ T cells.

<p>Frozen and thawed PBMCs from 6 months (6m), and 1 (1y) and 2 (2y) years after the last vaccine administration were stimulated with personalized 15-mer peptide pools and subjected to ICS assay. The pie charts refer to the plurifunctionality of the responses defined by Boolean gating. The results from six individuals are shown. For the best responder 416, memory phenotypes were investigated by flow cytometry using IFN-⅟ release to identify antigen-specific cells. Memory subsets are defined as T_N−naïve T cells (CD45RA^hiCCR7^hiCD27^hi). T_CM—central memory (CD45RA^loCCR7^hiCD27^hi), T_TM—transitional memory (CD45RA^loCCR7^loCD27^hi), T_EM—effector memory (CD45RA^loCCR7^loCD27^lo), and T_TD—terminally differentiated (CD45RA^hiCCR7^loCD27^lo).</p