Immunodominance of HIV-1 Specific CD8+ T-Cell Responses Is Related to Disease Progression Rate in Vertically Infected Adolescents

BACKGROUND: HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%≥25 were categorized as having no immune suppression (NS), and those with CD4%≤15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of naïve CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. CONCLUSIONS/SIGNIFICANCE: Together, these data suggest that, at least in vertically infected adolescents, the region of HIV-1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions

Molecular Characterization of HIV-1 CRF01_AE in Mekong Delta, Vietnam, and Impact of T-Cell Epitope Mutations on HLA Recognition (ANRS 12159)

To date, 11 HIV-1 subtypes and 48 circulating recombinant forms have been described worldwide. The underlying reason why their distribution is so heterogeneous is not clear. Host genetic factors could partly explain this distribution. The aim of this study was to describe HIV-1 strains circulating in an unexplored area of Mekong Delta, Vietnam, and to assess the impact of optimal epitope mutations on HLA binding.We recruited 125 chronically antiretroviral-naive HIV-1-infected subjects from five cities in the Mekong Delta. We performed high-resolution DNA typing of HLA class I alleles, sequencing of Gag and RT-Prot genes and phylogenetic analysis of the strains. Epitope mutations were analyzed in patients bearing the HLA allele restricting the studied epitope. Optimal wild-type epitopes from the Los Alamos database were used as reference. T-cell epitope recognition was predicted using the immune epitope database tool according to three different scores involved in antigen processing (TAP and proteasome scores) and HLA binding (MHC score). with a Vietnamese specificity held by two different haplotypes. The percentage of homology between Mekong and B consensus HIV-1 sequences was above 85%. Divergent epitopes had TAP and proteasome scores comparable with wild-type epitopes. MHC scores were significantly lower in divergent epitopes with a mean of 2.4 (±0.9) versus 2 (±0.7) in non-divergent ones (p<0.0001).Our study confirms the wide predominance of CRF01_AE in the Mekong Delta where patients harbor a specific HLA pattern. Moreover, it demonstrates the lower MHC binding affinity among divergent epitopes. This weak immune pressure combined with a narrow genetic diversity favors immune escape and could explain why CRF01_AE is still predominant in Vietnam, particularly in the Mekong area

Non-specific interstitial pneumonia in cigarette smokers: a CT study

The goal of this study was to seek indirect evidence that smoking is an aetiological factor in some patients with non-specific interstitial pneumonia (NSIP). Ten current and eight ex-smokers with NSIP were compared to controls including 137 current smokers with no known interstitial lung disease and 11 non-smokers with NSIP. Prevalence and extent of emphysema in 18 smokers with NSIP were compared with subjects meeting GOLD criteria for chronic obstructive pulmonary disease (COPD; group A; n = 34) and healthy smokers (normal FEV1; group B; n = 103), respectively. Emphysema was present in 14/18 (77.8%) smokers with NSIP. Emphysema did not differ in prevalence between NSIP patients and group A controls (25/34, 73.5%), but was strikingly more prevalent in NSIP patients than in group B controls (18/103, 17.5%, P < 0.0005). On multiple logistic regression, the likelihood of emphysema increased when NSIP was present (OR = 18.8; 95% CI = 5.3–66.3; P < 0.0005) and with increasing age (OR = 1.04; 95% CI = 0.99–1.11; P = 0.08). Emphysema is as prevalent in smokers with NSIP as in smokers with COPD, and is strikingly more prevalent in these two groups than in healthy smoking controls. The association between NSIP and emphysema provides indirect support for a smoking pathogenesis hypothesis in some NSIP patients

HLA Alleles Associated with Slow Progression to AIDS Truly Prefer to Present HIV-1 p24

Background: The mechanism behind the association between human leukocyte antigen (HLA) molecules and the rate of HIV-1 disease progression is still poorly understood. Recent data suggest that ‘‘protective’’ HLA molecules, i.e. those associated with a low HIV-1 viral load and relatively slow disease progression, tend to present epitopes from the Gag capsid protein. Although this suggests that preferential targeting of Gag delays disease progression, the apparent preference for Gag could also be a side-effect of the relatively high immunogenicity of the protein. Methods and Findings: To separate cause and effect, we predicted HIV-1 epitopes from the whole genome of HIV-1, and found that protective HLA alleles have a true preference for the p24 Gag protein, while non-protective HLA alleles preferentially target HIV-1 Nef. In line with this, we found a significant negative correlation between the predicted affinity of the best-binding p24 epitopes and the relative hazard of HIV-1 disease progression for a large number of HLA molecules. When the epitopes targeted by protective HLA alleles were mapped to the known p24 structure, we found that mutations in these epitopes are likely to disturb the p24 dimer structure, which is expected to severely reduce the fitness of the virus. Conclusions: Our results suggest that the intrinsic preference of different HLA molecules to present p24 peptides explains why some HLA molecules are more protective than others

Socio-cognitive determinants of consumers’ support for the fair trade movement

Despite the reasonable explanatory power of existing models of consumers’ ethical decision making, a large part of the process remains unexplained. This article draws on previous research and proposes an integrated model that includes measures of the theory of planned behavior, personal norms, self-identity, neutralization, past experience, and attitudinal ambivalence. We postulate and test a variety of direct and moderating effects in the context of a large survey with a representative sample of the U.K. population. Overall, the resulting model represents an empirically robust and holistic attempt to identify the most important determinants of consumers’ support for the fair-trade movement. Implications and avenues for further research are discussed

Modelling the Spread of HIV Immune Escape Mutants in a Vaccinated Population

Because cytotoxic T-lymphocytes (CTLs) have been shown to play a role in controlling human immunodeficiency virus (HIV) infection and because CTL-based simian immunodeficiency virus (SIV) vaccines have proved effective in non-human primates, one goal of HIV vaccine design is to elicit effective CTL responses in humans. Such a vaccine could improve viral control in patients who later become infected, thereby reducing onwards transmission and enhancing life expectancy in the absence of treatment. The ability of HIV to evolve mutations that evade CTLs and the ability of these ‘escape mutants’ to spread amongst the population poses a challenge to the development of an effective and robust vaccine. We present a mathematical model of within-host evolution and between-host transmission of CTL escape mutants amongst a population receiving a vaccine that elicits CTL responses to multiple epitopes. Within-host evolution at each epitope is represented by the outgrowth of escape mutants in hosts who restrict the epitope and their reversion in hosts who do not restrict the epitope. We use this model to investigate how the evolution and spread of escape mutants could affect the impact of a vaccine. We show that in the absence of escape, such a vaccine could markedly reduce the prevalence of both infection and disease in the population. However the impact of such a vaccine could be significantly abated by CTL escape mutants, especially if their selection in hosts who restrict the epitope is rapid and their reversion in hosts who do not restrict the epitope is slow. We also use the model to address whether a vaccine should span a broad or narrow range of CTL epitopes and target epitopes restricted by rare or common HLA types. We discuss the implications and limitations of our findings

Countries with Higher Levels of Gender Equality Show Larger National Sex Differences in Mathematics Anxiety and Relatively Lower Parental Mathematics Valuation for Girls.

Despite international advancements in gender equality across a variety of societal domains, the underrepresentation of girls and women in Science, Technology, Engineering, and Mathematics (STEM) related fields persists. In this study, we explored the possibility that the sex difference in mathematics anxiety contributes to this disparity. More specifically, we tested a number of predictions from the prominent gender stratification model, which is the leading psychological theory of cross-national patterns of sex differences in mathematics anxiety and performance. To this end, we analyzed data from 761,655 15-year old students across 68 nations who participated in the Programme for International Student Assessment (PISA). Most importantly and contra predictions, we showed that economically developed and more gender equal countries have a lower overall level of mathematics anxiety, and yet a larger national sex difference in mathematics anxiety relative to less developed countries. Further, although relatively more mothers work in STEM fields in more developed countries, these parents valued, on average, mathematical competence more in their sons than their daughters. The proportion of mothers working in STEM was unrelated to sex differences in mathematics anxiety or performance. We propose that the gender stratification model fails to account for these national patterns and that an alternative model is needed. In the discussion, we suggest how an interaction between socio-cultural values and sex-specific psychological traits can better explain these patterns. We also discuss implications for policies aiming to increase girls' STEM participation

Genomics meets HIV-1

Genomics is now a core element in the effort to develop a vaccine against HIV-1. Thanks to unprecedented progress in high-throughput genotyping and sequencing, in knowledge about genetic variation in humans, and in evolutionary genomics, it is finally possible to systematically search the genome for common genetic variants that influence the human response to HIV-1. The identification of such variants would help to determine which aspects of the response to the virus are the most promising targets for intervention. However, a key obstacle to progress remains the scarcity of appropriate human cohorts available for genomic research

Quantifying the impact of human immunodeficiency virus-1 escape from cytotoxic T-lymphocytes.

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