Worldwide, 20 million people are infected with HTLV-1, a majority of which remain asymptomatic carriers (ACs), while a few develop ATL or HAM/TSP with no effective treatment or vaccine for either disease state. The exact mechanism(s) of disease pathophysiology remain unresolved with a big question of high proviral load in HAM/TSP patients despite vigorous cellular immune response (primarily directed towards viral transactivator protein Tax)? Our initial studies implicated programmed death (PD)-1 receptor and its ligand, PD-L1 as potential underlying factors for observed immune cells'dysfunctions leading to viral persistence and disease progression, primarily in HAM/TSP patients. PD-1:PD-L1/PD-L2 are the members of immunoglobulin superfamily (IgSF) co-signaling molecules and have been linked with CD8 T-cell exhaustion during chronic viral infections. Several members of this family including CTL-4:B7-1(CD80)/B7-2(CD86), LAG-3:HLA-DR, Tim- 3:Galectin-9, 2B4:CD48, and BTLA CD160:HVEM play critical role in regulating antigen-specific immune responses. Thus far, PD-1 and CTLA-4 pathways have been extensively studied;and blocking antibodies against these have shown clinical benefit in the setting of cancer. Further recent data suggest that blocking multiple inhibitory receptors simultaneously may improve T-cell based therapies, but further studies are required to clarify the role of each receptor-ligand pair. Moreover, the clinical applicability of PD-1 and CTLA-4 remains to be tested with respect to human chronic viral infections as well as neuroinflammatory diseases, such as HAM/TSP, NeuroAIDS, etc. Interestingly, HTLV-1 provides a good model for both and thus, we find it significant to investigate the role of key inhibitory receptors/ligands in HTLV-1 infection and tes their combined blockade as potential immunotherapeutic strategy to restore immune cell functions in HAM/TSP patients. While this approach should help in restoring functions of pre-existing antiviral immunity in patients, activating new CTLs to mimic polyclonal CD8 T-cell response found in ACs will be the key for a successful immunotherapeutic intervention of HTLV-associated diseases. Therefore, we propose to systematically identify T-cell epitopes presented by HTLV-1-infected cells that define protective immunity in silent carriers alongside blocking inhibitory pathways in order to fully restore T-cell functions in chronically infected patients.
Th Specific Aims to achieve these goals are to 1) Investigate co-expression patterns of IgSF negative regulators and devise a blockade strategy to restore polyfunctionality and cytolytic potential of antigen-specific T-cells in HTLV-1 patient cohorts;2) Perform extensive immunoproteomics analyses of MHC Class I:peptide complexes on the infected cells, and identify best candidate(s) for anti-HTLV-1 polyclonal T-cell response by comparative immunogenicity testing in carriers versus diseased individuals;and 3) Evaluate the combined strategy of restoring immune cell functions along with the expansion of cellular immune response using neo-epitopes in the context of HTLV-1-infected humanized mice. .

Public Health Relevance

These studies will investigate approaches to restore immune cell functions and enhance protective anti-viral immunity during human T-cell leukemia virus type 1 (HTLV-1)-associated diseases. Additional information derived from these studies will facilitate the development of novel immunotherapeutic initiatives to prevent and/or treat HTLV-induced neuroinflammatory disease as well as those of other etiologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI077414-06A1
Application #
8870005
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Esch, Thomas R
Project Start
2007-12-01
Project End
2015-06-30
Budget Start
2014-07-15
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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