This Program entitled """"""""Anti-viral Immune Responses in Lymph Nodes"""""""" seeks to gain a deeper understanding of the induction and regulation of immunological events that are elicited by viral antigens in lymph nodes (LNs). Many viruses and most conventional vaccines enter the body through the skin and travel via lymphatics to draining LNs. These organs are believed to have a critical role in the adaptive immune response to peripheral infections;therefore, understanding the cellular and molecular interactions that occur within LNs will provide insights that may be useful for improved vaccine development. Lymph-borne foreign matter entering LNs is captured and processed by antigen-presenting cells (APCs), which then present this material to B and T cells to elicit effector responses and long-lived immunological memory. The rules that determine how lymph-derived antigenic material is handled in LNs, especially in the context of ongoing infections, and what cells and molecules must interact to elicit a protective immune response (or fail to do so) are poorly understood. Why do some viruses (e.g. VSV in mice) induce a potent, multi-pronged protective immune response that eliminates the pathogen, while others (e.g. influenza) generate only transient protective immunity, and a few (e.g. HIV in humans) establish a chronic presence by continuously subverting and eventually exhausting the host's anti-viral defenses? The mechanisms behind these different outcomes are likely multi-factorial and depend upon differences in the way individual viruses interact with their hosts. To explore the dynamics of these interactions in living animals, all component projects of this Program will employ multi-photon intravital microscopy (MP-IVM) in intact LNs that will be offered in the Intravital Microscopy Core for time-and space-resolved visualization of the innate and adaptive immune response to lymph-borne virions. In Project 1, Dr. von Andrian will explore innate and adaptive immune responses to lymph-borne viral infections using VSV and several other viral pathogens. In Project 2. Drs. Sharpe and Wherry will visualize the effects of the negative costimulatory pathways, PD-1:PD-L1, PD-1:PD-L2 and PDL1 :B7.1 on antiviral immunity to influenza and LCMV. In Project 3. Dr. Carroll will dissect the role of complement and complement receptors in humoral immunity to influenza virus. Finally, in Project 4, Drs. Luster. Mempel and Tager will characterize the cellular dynamics and viral dissemination in HIV-infected lymph nodes of humanized mice. It is hoped that the mechanistic insights gained from these highly interactive and synergistic experiments will lead to new, evidence-based and knowledge-driven development strategies for anti-viral vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-ELB-I (M1))
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Gondre-Lewis, Timothy A
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Harvard University
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Deruaz, Maud; Moldt, Brian; Le, Khoa M et al. (2016) Protection of Humanized Mice From Repeated Intravaginal HIV Challenge by Passive Immunization: A Model for Studying the Efficacy of Neutralizing Antibodies In Vivo. J Infect Dis 214:612-6
Wheeler, Lee Adam; Trifonova, Radiana T; Vrbanac, Vladimir et al. (2016) TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice. Cell Rep 15:1715-27
Gerlach, Carmen; Moseman, E Ashley; Loughhead, Scott M et al. (2016) The Chemokine Receptor CX3CR1 Defines Three Antigen-Experienced CD8 T Cell Subsets with Distinct Roles in Immune Surveillance and Homeostasis. Immunity 45:1270-1284
Pang, Paul; Jin, Xiaohua; Proctor, Brandon M et al. (2015) RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm. Kidney Int 87:771-83
Stary, Georg; Olive, Andrew; Radovic-Moreno, Aleksandar F et al. (2015) VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science 348:aaa8205
Griesbeck, Morgane; Ziegler, Susanne; Laffont, Sophie et al. (2015) Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women. J Immunol 195:5327-36
Sewald, Xaver; Ladinsky, Mark S; Uchil, Pradeep D et al. (2015) Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection. Science 350:563-7
Kumar, Lalit; Chou, Janet; Yee, Christina S K et al. (2014) Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. J Exp Med 211:929-42
Crawford, Alison; Angelosanto, Jill M; Kao, Charlly et al. (2014) Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection. Immunity 40:289-302
Riol-Blanco, Lorena; Ordovas-Montanes, Jose; Perro, Mario et al. (2014) Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510:157-61

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