T cell immunity to Zika virus targets immunodominant epitopes that show cross-reactivity with other Flaviviruses.

Zika virus (ZIKV) Infection has several outcomes from asymptomatic exposure to rash, conjunctivitis, Guillain-Barré syndrome or congenital Zika syndrome. Analysis of ZIKV immunity is confounded by the fact that several related Flaviviruses infect humans, including Dengue virus 1-4, West Nile virus and Yellow Fever virus. HLA class II restricted T cell cross-reactivity between ZIKV and other Flaviviruses infection(s) or vaccination may contribute to protection or to enhanced immunopathology. We mapped immunodominant, HLA class II restricted, CD4 epitopes from ZIKV Envelope (Env), and Non-structural (NS) NS1, NS3 and NS5 antigens in HLA class II transgenic mice. In several cases, ZIKV primed CD4 cells responded to homologous sequences from other viruses, including DENV1-4, WNV or YFV. However, cross-reactive responses could confer immune deviation - the response to the Env DENV4 p1 epitope in HLA-DR1 resulted in IL-17A immunity, often associated with exacerbated immunopathogenesis. This conservation of recognition across Flaviviruses, may encompass protective and/or pathogenic components and poses challenges to characterization of ZIKV protective immunity.

Calcium antagonists and mortality risk in men and women with hypertension in the Framingham Heart Study.

BACKGROUND: Several recent studies have suggested that calcium antagonist drugs, which are widely used for the treatment of hypertension, are associated with increased risk of cardiovascular disease. These studies have cast doubts on the long-term safety of calcium antagonists. OBJECTIVE: To examine the association of calcium antagonist use with mortality in subjects with hypertension followed up in the Framingham Heart Study. SUBJECTS AND METHODS: We stratified 3539 subjects (mean+/-SD age, 64+/-13 years) from the Framingham Heart Study who had hypertension at routine clinic examinations, according to the use of calcium antagonists and presence of coronary heart disease at the baseline examination. At each follow-up examination (every 2-4 years), subjects were reclassified with regard to the use of calcium antagonists. The end point of the study was all-cause mortality. Hazard ratios and 95% confidence intervals associated with the use of calcium antagonists were obtained using Cox proportional hazards regression models. RESULTS: There were 970 deaths during follow-up. Hazard ratios for mortality associated with the use of calcium antagonists were 0.93 (95% confidence interval, 0.72-1.21; P=.59) for subjects with hypertension without coronary heart disease, and 0.92 (95% confidence interval, 0.69-1.24; P=.58) for those with coronary heart disease at baseline. All models were adjusted for age, sex, current smoking, systolic and diastolic blood pressure, use of beta-blockers, and use of other antihypertensive medications. CONCLUSIONS: In this cohort of 3539 subjects with hypertension there were no differences in mortality among subjects with hypertension using a calcium antagonist compared with those who were not. Results were similar among subjects with hypertension with and without coronary heart disease. The results of ongoing long-term, randomized clinical trials will provide more definitive data on the safety of calcium antagonists.