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Kenta Matsuda Stephen A. Migueles Jinghe Huang Lyuba Bolkhovitinov Sarah Stuccio Trevor Griesman Alyssa A. Pullano Byong H Kang Elise Ishida Matthew Zimmerman Neena Kashyap Kelly M. Martins Daniel Stadlbauer Jessica Pederson Andy Patamawenu Nathaniel Wright Tulley Shofner Sean Evans C. Jason Liang Julin Candia Angelique Biancotto Giovanna Fantoni April Poole Jon Smith Jeff Alexander Marc Gurwith Florian Krammer Mark Connors 《The Journal of clinical investigation》2021,131(5)
BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract–immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov and NCT01443936.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C). NCT01806909相似文献
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Monsurrò V Wang E Yamano Y Migueles SA Panelli MC Smith K Nagorsen D Connors M Jacobson S Marincola FM 《Blood》2004,104(7):1970-1978
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Kinter AL Horak R Sion M Riggin L McNally J Lin Y Jackson R O'shea A Roby G Kovacs C Connors M Migueles SA Fauci AS 《AIDS research and human retroviruses》2007,23(3):438-450
HIV infection is characterized by CD4(+) T cell depletion and progressive immune dysfunction; particularly impacted are HIV-specific T cell responses. An important component of immune-mediated control of HIV replication, killing of infected cells, appears to be impaired, in part due to poor cytolytic activity of HIV-specific cytotoxic T cells (CTL). In vitro, several functions of HIV-specific T cells, such as cytokine production, can be enhanced by the depletion of the immunosuppressive CD25(+) FoxP3(+) CD4(+) regulatory (Treg) cell subset. However, the effect of CD25(+) Treg cells on virus-specific cytolytic activity in the context of HIV or any human viral infection has not been investigated. The present study demonstrates that CD25(+) Treg cells isolated from the peripheral blood of HIV-infected subjects significantly suppress HIV Gag-specific cytolytic activity in vitro. In addition, CD25(+) Treg cells suppress effector function (coexpression of TNF-alpha and IFN-gamma) of HIV-specific CD8(+) T cells that proliferate in response to HIV antigen. Finally, the secretion of HIV-inhibitory CC-chemokines by HIV-specific and nonspecific CD8(+) T cells is significantly reduced in the presence of CD25(+) Treg cells. These data suggest that CD25(+) Treg-mediated suppression of the antiviral activity of HIV-specific CD8(+) T cells could impact the ability of HIV-infected individuals to control HIV replication in vivo. 相似文献
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Flor-Alemany Marta Baena-García Laura Migueles Jairo H. Henriksson Pontus Löf Marie Aparicio Virginia A. 《Quality of life research》2022,31(9):2705-2716
Quality of Life Research - The relation between diet and maternal mental health during pregnancy might be relevant to prevent adverse materno-foetal outcomes. This study examined the association of... 相似文献
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In two experiments recognition of actions of a robbery presented in a video was examined in older and younger adults. In both experiments older adults had more false alarms and showed less accurate recognition than younger adults. In addition, when participants were asked in Experiment 1 to indicate Remember/Know/Guess judgments for actions they considered true, older adults accepted more false actions with Remember judgments. And when participants were asked in Experiment 2 to attribute the source (i.e., perpetrator), the older adults were less able to attribute actions that occurred during the robbery to their correct sources. Furthermore, we found a robust positive correlation between source attribution ability and recognition accuracy. Thus, source-memory deficits may contribute to older adults' false memories in real-life eyewitness situations. 相似文献
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In two experiments recognition of actions of a robbery presented in a video was examined in older and younger adults. In both experiments older adults had more false alarms and showed less accurate recognition than younger adults. In addition, when participants were asked in Experiment 1 to indicate Remember/Know/Guess judgments for actions they considered true, older adults accepted more false actions with Remember judgments. And when participants were asked in Experiment 2 to attribute the source (i.e., perpetrator), the older adults were less able to attribute actions that occurred during the robbery to their correct sources. Furthermore, we found a robust positive correlation between source attribution ability and recognition accuracy. Thus, source-memory deficits may contribute to older adults' false memories in real-life eyewitness situations. 相似文献
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Short-cycle structured intermittent treatment of chronic HIV
infection with highly active antiretroviral therapy: Effects on
virologic, immunologic, and toxicity parameters 总被引:5,自引:0,他引:5 下载免费PDF全文
Mark Dybul Tae-Wook Chun Christian Yoder Bertha Hidalgo Michael Belson Kurt Hertogs Brendan Larder Robin L. Dewar Cecil H. Fox Claire W. Hallahan J. Shawn Justement Stephen A. Migueles Julia A. Metcalf Richard T. Davey Marybeth Daucher Punita Pandya Michael Baseler Douglas J. Ward Anthony S. Fauci 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(26):15161-15166
Although continuous highly active antiretroviral therapy (HAART) is effective for many HIV-infected patients, it can be toxic and prohibitive in cost. By decreasing the total amount of time patients receive medications, intermittent HAART could reduce toxicity and cost. Therefore, we initiated a pilot study in which 10 HIV-infected individuals receiving effective therapy that resulted in levels of HIV RNA <50 copies per ml of plasma and CD4(+) T cell counts >300 cells per mm(3) of whole blood received repeated cycles of 7 days on HAART followed by 7 days off of HAART. Patients maintained suppression of plasma viremia for 32-68 weeks. There was no significant increase in HIV proviral DNA or replication-competent HIV in peripheral CD4(+) T cells or HIV RNA in peripheral blood or lymph node mononuclear cells. There was no significant change in CD4(+) T cell counts, no significant increase in CD4(+) or CD8(+) T cells expressing activation markers or producing IFN-gamma in response to HIV, no increase in CD4(+) T cell proliferation to p24 antigen, and no evidence for the development of resistance to HAART medications. There was a significant decrease in serum cholesterol and triglyceride levels. Thus, in this proof-of-concept study, short-cycle intermittent HAART maintained suppression of plasma viremia as well as HIV replication in reservoir sites while preserving CD4(+) T cell counts. In addition, there was a decrease in serum cholesterol and triglyceride levels. Intermittent therapy may be an important strategy to reduce cost and toxicity for HIV-infected individuals. 相似文献
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M. Rodriguez-Ayllon C. Cadenas-Sanchez I. Esteban-Cornejo J.H. Migueles J. Mora-Gonzalez P. Henriksson M. Martín-Matillas A. Mena-Molina P. Molina-García F. Estévez-López G.M. Enriquez J.C. Perales J.R. Ruiz A. Catena F.B. Ortega 《Journal of Science and Medicine in Sport》2018,21(2):179-184