To date, the lack of a suitable small animal model has hindered our quest to understand the immuno- and neuropathogenesis of HTLV-1 in an in vivo system. This is due to the inefficient fusion of HTLV-1 envelope with murine cells. Recently, a chimeric HTLV-1 virus has been developed that utilizes the envelope gene of the Moloney-murine leukemia virus thereby allowing fusion of the chimeric virus with murine cells. Utilizing this chimeric virus we have recently demonstrated that depletion of DCs enhances susceptibility to cell-free infection of HTLV-1 in CD11c-DTR-transgenic mice (Rahman et al., J. Immunol, in press). These mice are uniquely designed to selectively deplete DCs in vivo. Murine cells, unlike simian and human cells, are generally refractive to diphtheria toxin (DT). The fusion of DTR transgene to the CD11c promoter (largely expressed in murine splenic DCs) in CD11c-DTR-Tg mice allows for the complete ablation of DCs in the presence of DT without affecting other APCs such as B cells and macrophages. This system has been used to study role of DCs in the pathogenesis of several viruses including LCMV, HSV-1, and recently HTLV-1 (Rahman et al., J. Immunol., in press). However, these mice still pose problem in studying human MHC class I-associated immune responses (such as those observed in HAM/TSP patients) due to the mouse MHC background. This issue has been addressed in a separate strain of mice, known as line HHD II, which express human HLA-A2.1 molecule and are knockout for the mouse H-2Db MHC class I molecule and beta2-microglobulin thereby carrying only human HLA class I molecules. We have previously demonstrated the immunization and induction of Tax 11-19-specific CTL response in these mice (Manuel et al., J. Leuk. Biol., 2009). The study proposed herein attempts to generate a new transgenic strain (HHD II/DTR-Tg) of mice to study HTLV-1 infection and subsequent HLA-A2-restrticted cellular immune response in the absence and presence of DCs. The newly generated strain could be further utilized to investigate mechanistic aspects of DC:T cell interaction during HTLV-1-mediated immunopathogenesis. The ability to selectively ablate DCs in vivo offers a powerful tool to explore the role of this unique cell population in various infection and disease models. The development of a new hybrid strain (HHD II/DTR-Tg), as proposed here, will greatly facilitate future studies of HTLV-1 immuno/neuropathogenesis in addition to providing a valuable tool to the scientific community in general.

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
Exploratory/Developmental Grants (R21)
Project #
5R21AI093172-02
Application #
8197542
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Park, Eun-Chung
Project Start
2010-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$231,750
Indirect Cost
$81,750
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Jain, Pooja; Lavorgna, Alfonso; Sehgal, Mohit et al. (2015) Myocyte enhancer factor (MEF)-2 plays essential roles in T-cell transformation associated with HTLV-1 infection by stabilizing complex between Tax and CREB. Retrovirology 12:23
Sagar, Divya; Masih, Shet; Schell, Todd et al. (2014) In vivo immunogenicity of Tax(11-19) epitope in HLA-A2/DTR transgenic mice: implication for dendritic cell-based anti-HTLV-1 vaccine. Vaccine 32:3274-84
Hollenbach, Rebecca; Sagar, Divya; Khan, Zafar K et al. (2014) Effect of morphine and SIV on dendritic cell trafficking into the central nervous system of rhesus macaques. J Neurovirol 20:175-83
Sehgal, Mohit; Khan, Zafar K; Talal, Andrew H et al. (2013) Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle? Virology (Auckl) 4:1-25
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
Manuel, SharrĂ³n 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
Shirazi, Jasmine; Shah, Sonia; Sagar, Divya et al. (2013) Epigenetics, drugs of abuse, and the retroviral promoter. J Neuroimmune Pharmacol 8:1181-96
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
Sagar, Divya; Lamontagne, Anne; Foss, Catherine A et al. (2012) Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation. J Neuroinflammation 9:245
Rahman, Saifur; Quann, Kevin; Pandya, Devanshi et al. (2012) HTLV-1 Tax mediated downregulation of miRNAs associated with chromatin remodeling factors in T cells with stably integrated viral promoter. PLoS One 7:e34490