18 research outputs found
Systems Analysis of MVA-C Induced Immune Response Reveals Its Significance as a Vaccine Candidate against HIV/AIDS of Clade C
Based on the partial efficacy of the HIV/AIDS Thai trial (RV144) with a canarypox vector prime and protein boost, attenuated poxvirus recombinants expressing HIV-1 antigens are increasingly sought as vaccine candidates against HIV/AIDS. Here we describe using systems analysis the biological and immunological characteristics of the attenuated vaccinia virus Ankara strain expressing the HIV-1 antigens Env/Gag-Pol-Nef of HIV-1 of clade C (referred as MVA-C). MVA-C infection of human monocyte derived dendritic cells (moDCs) induced the expression of HIV-1 antigens at high levels from 2 to 8 hpi and triggered moDCs maturation as revealed by enhanced expression of HLA-DR, CD86, CD40, HLA-A2, and CD80 molecules. Infection ex vivo of purified mDC and pDC with MVA-C induced the expression of immunoregulatory pathways associated with antiviral responses, antigen presentation, T cell and B cell responses. Similarly, human whole blood or primary macrophages infected with MVA-C express high levels of proinflammatory cytokines and chemokines involved with T cell activation. The vector MVA-C has the ability to cross-present antigens to HIV-specific CD8 T cells in vitro and to increase CD8 T cell proliferation in a dose-dependent manner. The immunogenic profiling in mice after DNA-C prime/MVA-C boost combination revealed activation of HIV-1-specific CD4 and CD8 T cell memory responses that are polyfunctional and with effector memory phenotype. Env-specific IgG binding antibodies were also produced in animals receiving DNA-C prime/MVA-C boost. Our systems analysis of profiling immune response to MVA-C infection highlights the potential benefit of MVA-C as vaccine candidate against HIV/AIDS for clade C, the prevalent subtype virus in the most affected areas of the world
High titer HIV-1 V3-specific antibodies with broad reactivity but low neutralizing potency in acute infection and following vaccination.
Identifying the earliest neutralizing antibody specificities that are elicited following infection or vaccination
by HIV-1 is an important objective of current HIV/AIDS vaccine research. We have shown previously that
transplantation of HIV-1 V3 epitopes into an HIV-2 envelope (Env) scaffold provides a sensitive and specific
means to detect and quantify HIV-1 V3 epitope specific neutralizing antibodies (Nabs) in human sera. Here,
we employ this HIV-2/HIV-1 V3 scaffolding strategy to study the kinetics of development and breadth of V3-
specific Nabs in longitudinal sera from individuals acutely infected with clade C or clade B HIV-1 and in
human subjects immunized with clade B HIV-1 immunogens. HIV-2/HIV-1 chimeras containing V3
sequences matched to virus type (HIV-2 or HIV-1), subtype (clade B or C), or strain (autologous or
heterologous) were used as test reagents. We found that by 3â8 weeks post infection, 12 of 14 clade C
subjects had a median IC50 V3-specific Nab titer of 1:700 against chimeric viruses containing a heterologous
clade C V3. By 5 months post-infection, all 14 subjects were positive for V3-specific Nabs with median titers
of 1:8000 against heterologous clade C V3 and 1:1300 against clade B V3. Two acutely infected clade B
patients developed heterologous clade B V3-specific Nabs at titers of 1:300 and 1:1800 by 13 weeks of
infection and 1:5000 and 1:11000 by 7 months of infection. Titers were not different against chimeras
containing autologous clade B V3 sequences. Each of 10 uninfected normal human volunteers who were
immunized with clade B HIV-1 Env immunogens, but none of five sham immunized control subjects,
developed V3-specific Nabs titers as high as 1:3000 (median 1:1300; range 1:700â1:3000). None of the HIV-
1 infected or vaccinated subjects had antibodies that neutralized primary HIV-1 virus strains. These results
indicate that high-titer, broadly reactive V3-specific antibodies are among the first to be elicited during acute
and early HIV-1 infection and following vaccination but these antibodies lack neutralizing potency against
primary HIV-1 viruses, which effectively shield V3 from antibody binding to the functional Env trimer
Sequence and vector shapes vaccine induced antibody effector functions in HIV vaccine trials
Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA/vector, vector/vector and DNA/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA/rAd5 and rAd35/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies
Image et RĂ©cit
Les trois rubriques introduites dans ce recueil tentent de reflĂ©ter les divers champs d'investigation qui s'entrelacent. Sans doute l'interaction entre "les mots et la peinture" (il y a bien discours sur le tableau et/ou tableau dans le discours) donne lieu Ă un ensemble de communications trĂšs homogĂšne tout en faisant appel Ă un corpus d'Ćuvres trĂšs large. La section "l'image-rĂ©cit" touche, en fait, Ă plusieurs types de discours : le discours photographique y est certainement privilĂ©giĂ©, puis apparaissent le discours filmique et enfin le discours figuratif de la bande dessinĂ©e. Il a paru important de regrouper dans la derniĂšre partie ce que nous avons appelĂ© "l'image-mĂ©taphore". Peinture et Ă©criture, image et parole (que la peinture soit enrichissement du langage ou que le texte soit illusion fĂ©conde) posent le problĂšme de la reprĂ©sentation de l'indicible ou de l'invisible et visent Ă transcender le rĂ©el. Tous ces textes s'interrogent en fin de compte sur la prĂ©sentation de deux modes d'expression diffĂ©rents qui semblent impuissants sĂ©parĂ©ment Ă rendre la perception du rĂ©el dans sa complĂ©tude et sa totalitĂ© mais dont le croisement permet d'atteindre le but impossible, la limite toujours repoussĂ©e qui, dĂ©sormais, n'Ă©chappent plus au crĂ©ateur
Proceedings of the 2018 Advances In Motility and In NeuroGastroenterology: AIMING for the Future Single Topic Symposium
OBJECTIVES: Motility and functional disorders are common in children and often debilitating, yet these disorders remain challenging to treat effectively. At the 2018 Annual North American Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting, the Neurogastroenterology and Motility Committee held a full day symposium entitled, 2018 Advances In Motility and In NeuroGastroenterology - AIMING for the future. The symposium aimed to explore clinical paradigms in pediatric gastrointestinal motility disorders and provided a foundation for advancing new scientific and therapeutic research strategies. METHODS: The symposium brought together leading experts throughout North America to review the state of the art in the diagnosis and management of motility and functional disorders in children. Presentations were divided into esophageal, antral duodenal, and colorectal modules. Each module included oral presentations by experts in the respective fields, leading to thought-provoking discussions. There were 2 breakout sessions with small group discussions on select topics, focusing on defining scientific insights into the diagnosis and management of pediatric functional gastrointestinal and motility disorders in a systematic, segment-based approach. CONCLUSIONS: The field of neurogastroenterology has made remarkable progress in the last decade. The current report summarizes the major learning points from the symposium highlighting the diagnosis and promising therapies on the horizon for pediatric neurogastrointestinal and motility disorders