ASU Statement of Work R01 Proposal Title: Quantifying the balance between vaccine-induced T cell protection and pathology Performance Period: Start: 07/01/2014 End: 6/30/2019 Sponsor: NIH PI: Dr. Rustom Antia, Ph.D. Emory University Subaward: Dr. Joseph Blattman, Ph.D. Arizona State University Purpose of the project: CD8 T cells play an integral role in both protection from infection and in mediating disease during infection. Understanding this balance requires moving from a qualitative to quantitative description of virus infection and immune responses; this approach has the potential to improve both the safety and efficacy of vaccine design as wells to result in improved therapy strategies for persistent viral infections. Mathematical models are immensely powerful tools for understanding the complex non-linear interactions between infectious pathogens and the immune system. The proposed studies will develop quantitative mathematical models of persistent virus infection and the CD8 T cells response, including parameters for T cell exhaustion that occurs during persistent infection, parameterize these using the lymphocytic choriomeningitis virus (LCMV) mouse model of persistent viral infection, and use the developed model to make predictions about key viral and immune parameters that affect protection versus pathology. Dr. Blattmans group will be responsible for all experimental measurements of parameters required for model development. This includes measurement of in vivo proliferation rates, death rates, cytokine production, and cytolysis during persistent LCMV infection, as well measurement of pathology (clinical scoring, weight loss, and histological assessment). In this collaboration, Dr. Antia and Dr. Blattman will then identify key virus or immune parameters and make predictions regarding how their manipulation will affect both protection and pathology during virus challenge. Dr. Blattman will then test how experimental manipulation of each of these parameters (virus: infectivity, proliferation, escape from T cell recognition; T cells: numbers, avidity, phenotype, and function) affect the outcome of infection. The data generated will then be used to refine the developed quantitative models of infection and immunity. Finally, Dr. Blattman will experimentally test predictions from the model regarding how targeted suppression of virus load and immune reactivation therapies might be employed to improve protection while avoiding pathology. Milestones: Year 1-2: Parameterization of the initial quantitative models of persistent virus infection and immune responses/exhaustion. This will involve in vivo assessment of virus levels, T cell responses, and disease/pathology. Year 2-4: Tests of the key predictions from the developed quantitative models of persistent virus infection and immune responses/exhaustion. This will involve manipulation of virus infectivity/replication rates, forcible induction of virus escape from T cell recognition, and manipulation of T cell response parameters; primarily this will be done by adoptive transfer of different T cell populations into immune replete mice and challenge with LCMV. Year 4-5: Tests of the key predictions from the refined quantitative models of persistent virus infection and immune responses/exhaustion. This will involve treatment with antiviral agents (ribavirin) or blockade of inhibitory immune receptors (PD-1) to lower viremia and abrogate exhaustion, with assessment of the effect on virus clearance and pathology/disease. At the end of this project, we will have developed and refined quantitative models for persistent virus infection (including T cell responses and exhaustion during infection), used these to test evaluate key virus and immune parameters that might be manipulated to improve virus clearance (protection) while avoiding increased disease (pathology), and evaluated therapeutic strategies for reducing virus load while improving T cell function for their ability to provide protection while minimizing pathology.
|Effective start/end date||2/1/14 → 4/30/19|
- HHS-NIH: National Institute of Allergy & Infectious Diseases (NIAID): $902,280.00