Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses

Ajuts: R01/R56 NIH Grant AI-52779 (GDT), NIH F31 Fellowship (1F31AI106519-01)(TLP), Center for AIDS Research (P30 AI 64518) i Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, grant number UM1-AI100645-01 (AM)Abstract.Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control

A 10 year case study on the changing determinants of University student satisfaction in the UK

Higher Education (HE), once the prerogative of a tiny elite, is now accessible to larger numbers of people around the world than ever before yet despite the fact that an understanding of student satisfaction has never been more important for today’s universities, the concept remains poorly understood. Here we use published data from the UK’s National Student Survey (NSS), representing data from 2.3 million full-time students collected from 2007 to 2016, as a case study of the benefits and limitations of measuring student satisfaction that might have applicability for other countries, particularly those that, like the UK, have experienced significant growth in student numbers. The analyses showed that the factor structure of the NSS remained generally stable and that the ability of the NSS to discriminate between different subjects at different universities actually improved over the ten-year sample period. The best predictors of overall satisfaction were 'Teaching Quality' and 'Organisation & Management', with 'Assessment & Feedback' having relatively weak predictive ability, despite the sector's tangible efforts to improve on this metric. The tripling of student fees in 2012 for English students (but not the rest of the UK) was used as a ‘natural experiment’ to investigate the sensitivity of student satisfaction ratings to the real economic costs of HE. The tuition fee increase had no identifiable negative effect, with student satisfaction steadily improving throughout the decade. Although the NSS was never designed to measure perceived value-for money, its insensitivity to major changes in the economic costs of HE to the individual suggest that the conventional concept of student satisfaction is incomplete. As such we propose that the concept of student satisfaction: (i) needs to be widened to take into account the broader economic benefits to the individual student by including measures of perceived value-for-money and (ii) should measure students’ level of satisfaction in the years post-graduation, by which time they may have a greater appreciation of the value of their degree in the workplace

Identification of Effective Subdominant Anti-HIV-1 CD8+ T Cells Within Entire Post-infection and Post-vaccination Immune Responses

Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called “beneficial” regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control

The million-dollar question: can internships boost employment?

Higher education institutions are increasingly concerned with the professional insertion of graduates in the labour market and with the design of institutional mechanisms to facilitate students? transition from higher education to work, particularly given the context of scarcity of financial resources and the rise of graduate unemployment. This issue has been addressed, inter alia, through the creation of study programmes with internships. Despite the public discourse encouraging the use of such strategies, there is a general consensus regarding the absence of empirical studies on the professional value of these strategies. This article aims to assess two interrelated questions: the extent to which measures of graduate unemployment rate tend to decrease after the introduction of internships in Portuguese study programmes; and the extent to which this effect applies to the different institutions that comprise the Portuguese tertiary education landscape. It also seeks to contribute to the debate on the relevance of the structure and nature of internships, which are factors frequently neglected in the literature

Quality of written narrative feedback and reflection in a modified mini-clinical evaluation exercise: an observational study

Contains fulltext : 109243.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Research has shown that narrative feedback, (self) reflections and a plan to undertake and evaluate improvements are key factors for effective feedback on clinical performance. We investigated the quantity of narrative comments comprising feedback (by trainers), self-reflections (by trainees) and action plans (by trainer and trainee) entered on a mini-CEX form that was modified for use in general practice training and to encourage trainers and trainees to provide narrative comments. In view of the importance of specificity as an indicator of feedback quality, we additionally examined the specificity of the comments. METHOD: We collected and analysed modified mini-CEX forms completed by GP trainers and trainees. Since each trainee has the same trainer for the duration of one year, we used trainer-trainee pairs as the unit of analysis. We determined for all forms the frequency of the different types of narrative comments and rated their specificity on a three-point scale: specific, moderately specific, not specific. Specificity was compared between trainee-trainer pairs. RESULTS: We collected 485 completed modified mini-CEX forms from 54 trainees (mean of 8.8 forms per trainee; range 1-23; SD 5.6). Trainer feedback was more frequently provided than trainee self-reflections, and action plans were very rare. The comments were generally specific, but showed large differences between trainee-trainer pairs. CONCLUSION: The frequency of self-reflection and action plans varied, all comments were generally specific and there were substantial and consistent differences between trainee-trainer pairs in the specificity of comments. We therefore conclude that feedback is not so much determined by the instrument as by the users. Interventions to improve the educational effects of the feedback procedure should therefore focus more on the users than on the instruments

Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses

Ajuts: R01/R56 NIH Grant AI-52779 (GDT), NIH F31 Fellowship (1F31AI106519-01)(TLP), Center for AIDS Research (P30 AI 64518) i Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, grant number UM1-AI100645-01 (AM)Abstract.Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control

CD8+ T cell responses to PTE peptides based on to the entire HIV proteome were measured in HIV-positive HVTN participants (502—vaccinees, black closed circles; placebos, black open circles) and (503—vaccinees, grey closed circles; placebos, grey open circles) at week 5 post-infection by intracellular staining for IFN-γ.

<p><b>A.</b><b>B.</b> Correlation between CD8+ T cell inhibition (CD8+/CD4+ cell ratio = 2:1) of a clade-matched virus and magnitude of CD8+ T cell response to the entire HIV proteome, colour-coded as indicated in A. Five subjects are not shown in B, due to lack of viral inhibition data for the 2:1 ratio.</p

Distribution of responses to Gag peptides in HIV-positive MVA.HIVA vaccinees.

<p>Distribution of responses to Gag peptides in HIV-positive MVA.HIVA vaccinees.</p