The HIV-1 specific T cell response is initially effective but in the face of HIV-1's phenomenal ability to alter its sequence and escape from immune pressure, loss of CD4 T cell help and chronic antigen, the response becomes "exhausted" and no longer can longer control HIV-1 replication. Overcoming or reversing T cell exhaustion is likely going to be an important part of any successful HIV-1 immunotherapy, but how to do this is currently not clear. We propose to develop and combine two exciting approaches to restore HIV-1 specific immunity. The first involves using high affinity HIV-1 specific TCRs to redirect the immune response toward HIV-1. This approach has the potential to reset the HIV-1 specific exhaustion clock and to re-establish control of HIV-1 replication. Our preliminary data indicates the high affinity TCRs confer a more pronounced polyfunctional T cell response, the ability to control HIV-1 replication at low effector to target ratios and the ability to recognize common SL9-escape mutants. Here, we propose to extend these to studies to in vivo models and mechanistic studies. The second approach is to render these HIV-1 specific T cells resistant to the exhaustion differentiation pathway by targeting PD-1 expression. To do this we will use zinc finger nucleases to permanently disrupt PD-1 expression. The advantage of this approach over the systematic delivery of blocking Abs is that loss of PD-1 expression is restricted to the HIV-1 specific T cells that are being infused. Thus, the potential for autoimmunity is reduced. We propose to achieve our goal of reinvigorating the HIV-1 specific immune response through three related and coordinated specific aims: 1) Develop and characterize a lead PD-1 specific ZFN;2 Determine how PD-1 deficiency affects the HIV-1 specific T cell response;3) Perform in vivo, pre-clinical experiments to determine whether PD-1 deficient HIV-1 specific T cells are superior at controlling HIV-1 replication. These studies will provide the basis and rationale to test this approach in humans and hopefully lead to clinical tools that successfully control of HIV-1 replication in the absence of HAART.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA147795-05S1
Application #
8786618
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Ogunbiyi, Peter
Project Start
2010-04-15
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$24,257
Indirect Cost
$9,096
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Moon, Edmund K; Wang, Liang-Chuan; Dolfi, Douglas V et al. (2014) Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res 20:4262-73
Thakral, Deepshi; Coman, Maria M; Bandyopadhyay, Arunima et al. (2013) The human CD8* M-4 isoform dominant in effector memory T cells has distinct cytoplasmic motifs that confer unique properties. PLoS One 8:e59374