Person: Seung, Edward N.
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Seung
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Edward N.
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Seung, Edward N.
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Publication PD-1 Blockade in Chronically HIV-1-Infected Humanized Mice Suppresses Viral Loads(Public Library of Science, 2013) Seung, Edward N.; Dudek, Timothy E; Allen, Todd M.; Freeman, Gordon; Luster, Andrew; Tager, Andrew MartinAn estimated 34 million people are living with HIV worldwide (UNAIDS, 2012), with the number of infected persons rising every year. Increases in HIV prevalence have resulted not only from new infections, but also from increases in the survival of HIV-infected persons produced by effective anti-retroviral therapies. Augmentation of anti-viral immune responses may be able to further increase the survival of HIV-infected persons. One strategy to augment these responses is to reinvigorate exhausted anti-HIV immune cells present in chronically infected persons. The PD-1-PD-L1 pathway has been implicated in the exhaustion of virus-specific T cells during chronic HIV infection. Inhibition of PD-1 signaling using blocking anti-PD-1 antibodies has been shown to reduce simian immunodeficiency virus (SIV) loads in monkeys. We now show that PD-1 blockade can improve control of HIV replication in vivo in an animal model. BLT (Bone marrow-Liver-Thymus) humanized mice chronically infected with HIV-1 were treated with an anti-PD-1 antibody over a 10-day period. The PD-1 blockade resulted in a very significant 45-fold reduction in HIV viral loads in humanized mice with high CD8+ T cell expression of PD-1, compared to controls at 4 weeks post-treatment. The anti-PD-1 antibody treatment also resulted in a significant increase in CD8+ T cells. PD-1 blockade did not affect T cell expression of other inhibitory receptors co-expressed with PD-1, including CD244, CD160 and LAG-3, and did not appear to affect virus-specific humoral immune responses. These data demonstrate that inhibiting PD-1 signaling can reduce HIV viral loads in vivo in the humanized BLT mouse model, suggesting that blockade of the PD-1-PD-L1 pathway may have therapeutic potential in the treatment of patients already infected with the AIDS virus.Publication HIV-infected T cells are migratory vehicles for viral dissemination(2012) Murooka, Thomas; Deruaz, Maud; Marangoni, Francesco; Vrbanac, Vladimir; Seung, Edward N.; von Andrian-Werburg, Ulrich; Tager, Andrew Martin; Luster, Andrew; Mempel, ThorstenAfter host entry through mucosal surfaces, HIV-1 disseminates to lymphoid tissues to establish a generalized infection of the immune system. The mechanisms by which this virus spreads among permissive target cells locally during early stages of transmission, and systemically during subsequent dissemination are not known1. In vitro studies suggest that formation of virological synapses (VSs) during stable contacts between infected and uninfected T cells greatly increases the efficiency of viral transfer2. It is unclear, however, if T cell contacts are sufficiently stable in vivo to allow for functional synapse formation under the conditions of perpetual cell motility in epithelial3 and lymphoid tissues4. Here, using multiphoton intravital microscopy (MP-IVM), we examined the dynamic behavior of HIV-infected T cells in lymph nodes (LNs) of humanized mice. We found that most productively infected T cells migrated robustly, resulting in their even distribution throughout the LN cortex. A subset of infected cells formed multinucleated syncytia through HIV envelope (Env)-dependent cell fusion. Both uncoordinated motility of syncytia as well as adhesion to CD4+ LN cells led to the formation of long membrane tethers, increasing cell lengths to up to 10 times that of migrating uninfected T cells. Blocking the egress of migratory T cells from LNs into efferent lymph, and thus interrupting T cell recirculation, limited HIV dissemination and strongly reduced plasma viremia. Thus, we have found that HIV-infected T cells are motile, form syncytia, and establish tethering interactions that may facilitate cell-to-cell transmission through VSs. While their migration in LNs spreads infection locally, T cell recirculation through tissues is important for efficient systemic viral spread, suggesting new molecular targets to antagonize HIV infection.Publication Detection of JC Virus-Specific Immune Responses in a Novel Humanized Mouse Model(Public Library of Science, 2013) Tan, Chen; Broge, Thomas A.; Seung, Edward N.; Vrbanac, Vladimir; Viscidi, Raphael; Gordon, Jennifer; Tager, Andrew Martin; Koralnik, Igor J.Progressive Multifocal Leukoencephalopathy (PML) is an often fatal disease caused by the reactivation of the JC virus (JCV). Better understanding of viral-host interactions has been hampered by the lack of an animal model. Engrafting NOD/SCID/IL-2-Rg (null) mice with human lymphocytes and thymus, we generated a novel animal model for JCV infection. Mice were inoculated with either a PML isolate, JCV Mad-4, or with JCV CY, found in the kidney and urine of healthy individuals. While mice remained asymptomatic following inoculation, JCV DNA was occasionally detected in both the blood and the urine compartments. Mice generated both humoral and cellular immune responses against JCV. Expressions of immune exhaustion marker, PD-1, on lymphocytes were consistent with response to infection. Using this model we present the first in vivo demonstration of virological and immunological differences between JCV Mad-4 and CY. This model may prove valuable for studying JCV host immune responses.Publication TLR7/9 Antagonist Reduces HIV-1-Induced Immune Activation(BioMed Central, 2012) Chang, Ju-Hui; Lindsay, RJ; Doyle, EH; Vrbanac, Vladimir; Seung, Edward N.; Dudek, Timothy E; Bosch, Ronald; Precopio, M; Kandimalla, E; Tager, Andrew Martin; Altfeld, MarcusPublication Rapid Evolution of HIV-1 to Functional CD8+ T-cell rResponses in Humanized BLT Mice(BioMed Central, 2012) Dudek, TE; No, DC; Vrbanac, Vladimir; Fadda, L; Bryant, KF; Luster, AD; Knipe, DM; Tager, AM; Allen, TM; Seung, Edward N.; Altfeld, MarcusPublication Neutralizing Anti-HIV Antibodies Develop in a Humanized Mouse Model of HIV-1 Infection(BioMed Central, 2012) Vrbanac, Vladimir; Tivey, T; Cariappa, A; Seung, Edward N.; Dugast, Anne-Sophie; Dudek, Timothy E; Mattoo, Hamid; Murooka, Thomas; Pillai, Shiv; Tager, Andrew Martin; Luster, AndrewPublication Evolutionarily Conserved Recognition and Innate Immunity to Fungal Pathogens by the Scavenger Receptors SCARF1 and CD36(Rockefeller University Press, 2009) Tampakakis, Emmanouil; Puckett, Lindsay; Tai, Melissa F.; Stewart, Cameron R.; Hickman, Suzanne E.; Moore, Kathryn J.; El Khoury, Joseph; Means, Terry K.; Mylonakis, E; Colvin, Richard Anthony; Seung, Edward N.; Pukkila-Worley, Read; Calderwood, Stephen; Hacohen, Nir; Luster, AndrewReceptors involved in innate immunity to fungal pathogens have not been fully elucidated. We show that the Caenorhabditis elegans receptors CED-1 and C03F11.3, and their mammalian orthologues, the scavenger receptors SCARF1 and CD36, mediate host defense against two prototypic fungal pathogens, Cryptococcus neoformans and Candida albicans. CED-1 and C03F11.1 mediated antimicrobial peptide production and were necessary for nematode survival after C. neoformans infection. SCARF1 and CD36 mediated cytokine production and were required for macrophage binding to C. neoformans, and control of the infection in mice. Binding of these pathogens to SCARF1 and CD36 was β-glucan dependent. Thus, CED-1/SCARF1 and C03F11.3/CD36 are β-glucan binding receptors and define an evolutionarily conserved pathway for the innate sensing of fungal pathogens.