Applications of DNA vaccine technology towards difficult immune targets

Major improvement in DNA vaccine technology over the past decade has reinvigorated this platform which has conceptual advantages over traditional vaccine platforms. In humans prior generations of DNA vaccines were poorly immunogenic. Through multiple improvements including synthetic optimization, genetic adjuvant technology with enhanced EP delivery this technology exhibits improved performance. These synthetic DNA vaccines drive immune responses similar or superior to live viral vectors. We present data in animal models and in human studies that illuminate their immune potency and clinical efficacy targeting both established infection and in prevention approaches to EID

Neutrino Oscillations as a Probe of Dark Energy

We consider a class of theories in which neutrino masses depend significantly on environment, as a result of interactions with the dark sector. Such theories of mass varying neutrinos (MaVaNs) were recently introduced to explain the origin of the cosmological dark energy density and why its magnitude is apparently coincidental with that of neutrino mass splittings. In this Letter we argue that in such theories neutrinos can exhibit different masses in matter and in vacuum, dramatically affecting neutrino oscillations. Both long and short baseline experiments are essential to test for these interactions. As an example of modifications to the standard picture, we consider simple models which may simultaneously account for the LSND anomaly, KamLAND, K2K and studies of solar and atmospheric neutrinos, while providing motivation to continue to search for neutrino oscillations in short baseline experiments such as BooNE.Comment: 5 pages, 1 figure, refs added, additional data considered, minor change in conclusions about LSN

Immune Modulation through 4-1BB Enhances SIV Vaccine Protection in Non-Human Primates against SIVmac251 Challenge

Costimulatory molecules play a central role in the development of cellular immunity. Understanding how costimulatory pathways can be directed to positively influence the immune response may be critical for the generation of an effective HIV vaccine. Here, we evaluated the ability of intravenous administration of a blocking monoclonal antibody (mAb) directed against the negative costimulatory molecule CTLA-4, and an agonist mAb directed against the positive costimulatory molecule 4-1BB, either alone or in combination, to augment intramuscular SIV DNA immunizations. We then tested the ability these of these responses to impact a high-dose SIVmac251 challenge. Following immunization, the groups infused with the anti-4-1BB mAb exhibited enhanced IFN-γ responses compared to the DNA vaccine only group. Interestingly, although CTLA-4 blockade alone did not enhance IFN-γ responses it did increase the proliferative capacity of the CD4+ and CD8+ T cells. The combination of both mAbs enhanced the magnitude of the polyfunctional CD8+ T cell response. Following challenge, the group that received both mAbs exhibited a significant, ∼2.0 log, decrease in plasma viral load compared to the naïve group the included complete suppression of viral load in some animals. Furthermore, the use of the CTLA-4 blocking antibody resulted in significantly higher viral loads during chronic infection compared to animals that received the 4-1BB mAb, likely due to the higher CD4+ T cell proliferative responses which were driven by this adjuvant following immunization. These novel studies show that these adjuvants induce differential modulation of immune responses, which have dramatically different consequences for control of SIV replication, suggesting important implications for HIV vaccine development

Assignment of the Human and Mouse Prion Protein Genes to Homologous Chromosomes

Purified preparations of scrapie prions contain one major macromolecule, designated prion protein (PrP). Genes encoding PrP are found in normal animals and humans but not within the infectious particles. The PrP gene was assigned to human chromosome 20 and the corresponding mouse chromosome 2 using somatic cell hybrids. In situ hybridization studies mapped the human PrP gene to band 20p12→pter. Our results should lead to studies of genetic loci syntenic with the PrP gene, which may play a role in the pathogenesis of prion diseases or other degenerative neurologic disorders

Host cell killing by the West Nile Virus NS2B–NS3 proteolytic complex: NS3 alone is sufficient to recruit caspase-8-based apoptotic pathway

AbstractThe West Nile Virus (WNV) non-structural proteins 2B and 3 (NS2B–NS3) constitute the proteolytic complex that mediates the cleavage and processing of the viral polyprotein. NS3 recruits NS2B and NS5 proteins to direct protease and replication activities. In an effort to investigate the biology of the viral protease, we cloned cDNA encoding the NS2B–NS3 proteolytic complex from brain tissue of a WNV-infected dead crow, collected from the Lower Merion area (Merion strain). Expression of the NS2B–NS3 gene cassette induced apoptosis within 48 h of transfection. Electron microscopic analysis of NS2B–NS3-transfected cells revealed ultra-structural changes that are typical of apoptotic cells including membrane blebbing, nuclear disintegration and cytoplasmic vacuolations. The role of NS3 or NS2B in contributing to host cell apoptosis was examined. NS3 alone triggers the apoptotic pathways involving caspases-8 and -3. Experimental results from the use of caspase-specific inhibitors and caspase-8 siRNA demonstrated that the activation of caspase-8 was essential to initiate apoptotic signaling in NS3-expressing cells. Downstream of caspase-3 activation, we observed nuclear membrane ruptures and cleavage of the DNA-repair enzyme, PARP in NS3-expressing cells. Nuclear herniations due to NS3 expression were absent in the cells treated with a caspase-3 inhibitor. Expression of protease and helicase domains themselves was sufficient to trigger apoptosis generating insight into the apoptotic pathways triggered by NS3 from WNV

Exposing the human nude phenotype [4]

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