This is a proposal for a new Program Project (P01) grant entitled "Mechanisms and Immunological Consequences of Host-Virus Interactions". The common theme in this program is the study of T cell responses that are elicited by acute viral infections. The Program is composed of three Projects and two Cores: Project 1, "Differentiation of Antiviral Effector and Memory T Cell Subsets" (PI: Dr. Ulrich von Andrian);Project 2, "Defining and Visualizing Effects of Costimulation on Antiviral Immunity" (Co- PIs: Drs. Arlene Sharpe, John Wherry and Gordon Freeman);Project 3, "Chemokine-Mediated T Cell Trafficking in HIV Infection and Immune Responses" (Co-PIs: Drs. Andrew Luster, Thorsten Mempel and Andrew Tager);Core A "Administrative Core" (PI: Dr. von Andrian);and Core B "Intravital Microscopy Core" (Co-PIs: Drs. von Andrian and Mempel). Each project will investigate multiple steps in the sequence of events that orchestrate T cell responses to viral infections: a) at the anatomic sites where viruses first enter the body;b) in peripheral lymphatics where free virus, virus-infected target cells and antiviral effector cells travel to draining lymph nodes (LNs);c) in secondary lymphoid organs where naive T cells (Tn), central (Tcm), effector (Tem) and transitional memory cells (Ttm) home and are presented with viral antigens (Ags) by dendritic cells;d) during the initial effector (Teff) response;and e) the subsequent memory phase at steady state and upon rechallenge;and f) in microvessels and the extravascular space of normal and infected tissues where Ag-experienced T cell subsets are selectively recruited (or not) to provide local immune surveillance and a rapid response to reinfections. The PIs were brought together by a common long-standing interest in the function of the immune system and the multi-faceted events that precipitate and regulate T cell responses to viral challenge. A defining feature and centerpiece of this program is the Infectious Imaging facility administered by Core B, which incorporates state-of-the-art multi-photon intravital microscopy (MP-IVM) to image single-cell behavior in intact tissues of living infected mice. Although the individual projects each stand on their own merit, they gain tremendously from synergy with the other Program components. Each Project makes critical scientific contributions to the other two Projects and is, in turn, profoundly impacted by the scientific progress in other Program components. Thus, this PPG provides the means by which we work together to resolve important questions on how viral infections are recognized and remembered. The answers to these questions are of fundamental importance and have the potential to translate into new approaches for the prophylaxis and treatment of a broad spectrum of human diseases.

Public Health Relevance

This program project investigates how T cell responses are elicited when tissues are infected with a virus or exposed to a viral vaccine. The goal of the proposed research is to better understand the multi-faceted events that determine the outcome of viral exposure, including: the generation of effector responses that may (or may not) lead to viral clearance;the differentiation of memory cell subsets that can afford long-term protection against reinfection;and the mechanisms by which some viruses escape or subvert T cell responses to disseminate and establish chronic infections. Results from this work may ultimately lead to new approaches for the prophylaxis and treatment of viral diseases in humans.

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-BDP-I (M1))
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Gondre-Lewis, Timothy A
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Harvard Medical School
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