Dendritic cells (DCs) are the most potent antigen presenting cells and are recognized as key regulators of the immune system, linking both stimulatory and inhibitory components of normal immunity. While DCs are well characterized with respect to primary and secondary immune responses, their unique role in coordinating central and peripheral tolerance is not fully delineated. It is increasingly evident that the failure of DCs'ability to maintain tolerance can lead to autoimmune and/or inflammatory diseases. Consequently, human T cell leukemia virus type 1 (HTLV-1) has been used as a model pathogen to explore the role of DCs in virus- induced neuroinflammation. HTLV-1 is the etiologic agent of two immunologically distinct diseases;adult T cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic demyelinating disease with underlying autoimmune condition in the central nervous system with similarities to multiple sclerosis. The progression of HAM/TSP is characterized by an intense proliferation of chronically activated CD8+ cytotoxic T lymphocytes (CTLs), 90% of which are specific for the HTLV-1 transactivator protein Tax. Several clinical observations suggest that Tax-specific CTL response is at best ineffective and may actually be detrimentally contributing to the neuropathogenesis of HAM/TSP by cross-reacting with neuronal antigens or through bystander cell damage. The genesis (antigen presentation and costimulation), priming (normal or defective), and quality (effector versus exhausted) of this hyperactivated CTL response remain incompletely characterized. DCs are of particular importance with respect to HTLV-1 neuropathogenesis as the development of HAM/TSP is associated with rapid maturation of DCs. HTLV-1 is also known to infect DCs both in vitro and in HAM/TSP patients suggesting that DCs play a critical role in HAM/TSP pathogenesis. The HYPOTHESIS of this proposal is that continuous presentation of Tax peptide by activated DCs to naive T cells and modulation of DC functions by Tax play important role in the induction and regulation of Tax-specific CTL response characteristic of HAM/TSP.
The SPECIFIC AIMS to this hypothesis will 1) define the process involved in Tax presentation during direct DC infection and cross-presentation from HTLV-1-infected T cells with respect to the alterations in the biologic, physiologic, and immunologic function of DCs and induction of Tax-specific CTL response;and 2) utilize ex vivo analyses to validate the central role of DCs in regulating antiviral efficacy of CD8+ T cells in HAM/TSP patients within the context of proviral load and Tax expression, the two major risk factors in disease progression. Collectively, these studies will define the involvement of DCs in a virus-associated autoimmune/neuroinflammatory disease and highlight critical functional interactions among immune cells during acquired immunity to a viral agent. Additional information derived from these studies will facilitate the translational research development of novel vaccine and therapeutic initiatives to prevent and/or treat HTLV-1-induced neuroinflammatory disease as well as similar diseases of other etiologies.

Public Health Relevance

The proposed studies are relevant to public health and will reveal significant information concerning the dendritic cells-regulated T cell responses during complex autoimmune/neuroinflammatory diseases such as HAM/TSP and multiple sclerosis. Additionally the results of these studies will shed light on the dynamics of immune cell interactions during chronic viral infections such as HTLV-1, HIV-1, hepatitis virus and herpes simplex virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077414-04
Application #
8197054
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Esch, Thomas R
Project Start
2008-12-15
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$369,890
Indirect Cost
$106,831
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Jaworski, Elizabeth; Narayanan, Aarthi; Van Duyne, Rachel et al. (2014) Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein. J Biol Chem 289:22284-305
Manuel, Sharron L; Sehgal, Mohit; Connolly, John et al. (2013) Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of human T-cell leukemia virus type 1. J Clin Immunol 33:1223-39
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Manuel, Sharron L; Sehgal, Mohit; Khan, Zafar K et al. (2013) An altered maturation and adhesion phenotype of dendritic cells in diseased individuals compared to asymptomatic carriers of human T cell leukemia virus type 1. AIDS Res Hum Retroviruses 29:1273-85
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Sagar, Divya; Foss, Catherine; El Baz, Rasha et al. (2012) Mechanisms of dendritic cell trafficking across the blood-brain barrier. J Neuroimmune Pharmacol 7:74-94
Shetty, Vivekananda; Jain, Pooja; Nickens, Zacharie et al. (2011) Investigation of plasma biomarkers in HIV-1/HCV mono- and coinfected individuals by multiplex iTRAQ quantitative proteomics. OMICS 15:705-17
Rahman, Saifur; Connolly, John E; Manuel, Sharron L et al. (2011) Unique Cytokine/Chemokine Signatures for HIV-1 and HCV Mono-infection versus Co-infection as Determined by the Luminexýý Analyses. J Clin Exp Ophthalmol 2:
Tran, Thuong H; El Baz, Rasha; Cuconati, Andrea et al. (2011) A Novel High-Throughput Screening Assay to Identify Inhibitors of HIV-1 gp120 Protein Interaction with DC-SIGN. J Antivir Antiretrovir 3:49-54

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