PROJECT 3: ABSTRACT CD4 T cells play a key role orchestrating the immune response and play an important role controlling and eliminating viral infections. Due to HIV-1 tropism for CD4 T cells and especially HIV-1 specific CD4 T cells, the CD4 T cell response to combat HIV-1 infection is compromised. The underlying goal of this project is to develop a strategy that would restore full CD4 T cell activity to fight against HIV-1 infection. Working with Project 2, we will employ the most effective way to protect CD4 T cells from HIV-1 infection. Next, we will examine which CD4 T cell subset and which chimeric antigen receptor best restores durable HIV-1 specific activity to CD4 T cells. We will work closely with Project 4 to define the key factors that control the durably and functionality of CD4 T cells. Then using this information we will further refine our gene engineering strategy to enhance anti-HIV-1 CD4 T cell activity.
In aim 3 we will model adoptive T cell trials using humanized mice to determine which combination of engineered provide the most effective and durable control of HIV-1 replication. These studies will provide the basis and rationale for a clinical trial that will follow the study described in Project 1. SA1: To identify the optimal CD4 CAR costimulatory domain and cell type to give durable control of HIV-1 infection in vitro. SA2: To identify the optimal CD4 CAR costimulatory domain and cell type that provides the most help to HIV-1 specific CD8 T cells. SA3: To investigate whether protected HIV-1 specific T cells can functionally control HIV-1 replication in vivo. .

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI117950-03
Application #
9257292
Study Section
Special Emphasis Panel (ZAI1-BP-A)
Project Start
Project End
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
3
Fiscal Year
2017
Total Cost
$478,900
Indirect Cost
$169,900
Name
University of Pennsylvania
Department
Type
Domestic Higher Education
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Barnett, Burton E; Staupe, Ryan P; Odorizzi, Pamela M et al. (2016) Cutting Edge: B Cell-Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection. J Immunol 197:1017-22
Attanasio, John; Wherry, E John (2016) Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease. Immunity 44:1052-68
Leibman, Rachel S; Riley, James L (2015) Engineering T Cells to Functionally Cure HIV-1 Infection. Mol Ther 23:1149-59