T cell epitope mapping of JC polyoma virus-encoded proteome reveals reduced T cell responses in HLA-DRB1*04:01+ donors

JC polyomavirus (JCV) infection is highly prevalent and usually kept in a persistent state without clinical signs and symptoms. It is only during immunocompromise and especially impaired CD4(+) T cell function in the brain, as seen in AIDS patients or natalizumab-treated multiple sclerosis patients, that JCV may cause progressive multifocal leukoencephalopathy (PML), an often life-threatening brain disease. Since CD4(+) T cells likely play an important role in controlling JCV infection, we here describe the T cell response to JCV in a group of predominantly HLA-DR-heterozygotic healthy donors (HD) by using a series of overlapping 15-mer peptides spanning all JCV-encoded open reading frames. We identified immunodominant epitopes and compared T cell responses with anti-JCV VP1 antibody production and with the presence of urinary viral shedding. We observed positive JCV-specific T cell responses in 28.6% to 77.6%, humoral immune response in 42.6% to 89.4%, and urinary viral shedding in 36.4% to 45.5% of HD depending on the threshold. Four immunodominant peptides were mapped, and at least one immunogenic peptide per HLA-DRB1 allele was detected in DRB1*01(+), DRB1*07(+), DRB1*11(+), DRB1*13(+), DRB1*15(+), and DRB1*03(+) individuals. We show for the first time that JCV-specific T cell responses may be directed not only against JCV VP1 and large T antigen but also against all other JCV-encoded proteins. Heterozygotic DRB1*04:01(+) individuals showed very low T cell responses to JCV together with normal anti-VP1 antibody levels and no urinary viral shedding, indicating a dominant-negative effect of this allele on global JCV-directed T cell responses. Our data are potentially relevant for the development of vaccines against JCV

Construction and validation of a plaque discrimination score from the anatomical and histological differences in coronary atherosclerosis: the Liverpool IVUS-V-HEART (Intra Vascular UltraSound-Virtual-Histology Evaluation of Atherosclerosis Requiring Treatment) study

Aims: New markers to help stratify coronary atherosclerosis are needed. Although attempts have been made to differentiate active lesions from those that are stable, none of these has ever been formalised into a discriminatory score. The aim of this study was to analyse the differences between culprit ACS lesions and culprit stable angina lesions with intravascular ultrasound-derived virtual histology and to construct and validate a plaque score. Methods and results: Prior to percutaneous coronary intervention (PCI), we performed volumetric, intravascular ultrasound-derived virtual histology (IVUS-VH) analysis in acute coronary syndrome (ACS) culprit lesions (AC - n=70) and stable angina culprit lesions (SC - n=35). A direct statistical comparison of IVUS-VH data and multiple logistic regression analysis was undertaken. Four main factors were found to be associated (p<0.05) with an AC lesion phenotype: necrotic core/dense calcium (NC/DC) ratio; minimum lumen area <4 mm(2) (MLA <4); remodelling index @MLA >1.05 and VH-TCFA presence. Calculation of each logistic regression coefficient and the equation produces an active plaque discrimination score with an AUC of 0.96 on receiver operating characteristics (ROC) analysis. Validation of the score in 50 independent plaques from the Thoraxcenter in Rotterdam revealed an AUC of 0.71, confirming continued diagnostic ability. Conclusions: We have found four features on IVUS and VH that can predict and discriminate ACS culprit lesion phenotypes from those that are clinically stable. Subsequently, we have constructed and validated the Liverpool Active Plaque Score based upon these features. It is hoped this score may help diagnose active coronary plaques, in the future, to help prevent major adverse cardiac events

Effect of d-amphetamine on emotion-potentiated startle in healthy humans

RATIONALE: An emerging literature associates increased dopaminergic neurotransmission with altered brain response to aversive stimuli in humans. The direction of the effect of dopamine on aversive motivation, however, remains unclear, with some studies reporting increased and others decreased amygdala activation to aversive stimuli following the administration of dopamine agonists. Potentiation of the startle response by aversive foreground stimuli provides an objective and directional measure of emotional reactivity and is considered useful as an index of the emotional effects of different drugs. OBJECTIVE: We investigated the effects of two doses of D-amphetamine (5 and 10 mg), compared to placebo, for the first time to our knowledge, using the affect-startle paradigm. METHOD: The study employed a between-subjects, double-blind design, with three conditions: 0 mg (placebo), and 5 and 10 mg D-amphetamine (initially n = 20/group; final sample: n = 18, placebo; n = 18, 5 mg; n = 16, 10 mg). After drug/placebo administration, startle responses (eyeblinks) to intermittent noise probes were measured during viewing of pleasant, neutral and unpleasant images. Participants' general and specific impulsivity and fear-related personality traits were also assessed. RESULTS: The three groups were comparable on personality traits. Only the placebo group showed significant startle potentiation by unpleasant, relative to neutral, images; this effect was absent in both 5- and 10-mg D-amphetamine groups (i.e. the same effect of D-amphetamine observed at different doses in different people). CONCLUSIONS: Our findings demonstrate a reduced aversive emotional response under D-amphetamine and may help to account for the known link between the use of psychostimulant drugs and antisocial behaviour