title: Depletion of dendritic cells enhances susceptibility to cell-free infection of human T cell leukemia virus type 1 in CD11c-diphtheria toxin receptor transgenic mice.
abstract: Human T cell leukemia virus type 1 (HTLV-1) is associated with two immunologically distinct diseases: HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T cell leukemia. The genesis of these diseases is believed to be associated with the route (mucosa versus blood) and mode (cell-free versus cell-associated) of primary infection as well as the modulation of dendritic cell (DC) functions. To explore the role of DCs during early HTLV-1 infection in vivo, we used a chimeric HTLV-1 with a replaced envelope gene from Moloney murine leukemia virus to allow HTLV-1 to fuse with murine cells, which are generally not susceptible to infection with human retroviruses. We also used a CD11c-diphtheria toxin receptor transgenic mouse model system that permits conditional transient depletion of CD11c(+) DCs. We infected these transgenic mice with HTLV-1 using both cell-free and cell-associated infection routes in the absence and presence of DCs. The ablation of DCs led to an enhanced susceptibility to infection with cell-free but not cell-associated HTLV-1 in both CD4 and non-CD4 fractions, as measured by the proviral load. Infection with cell-free virus in the absence of DCs was also found to have increased levels of Tax mRNA in the non-CD4 fraction. Moreover, depletion of DCs significantly dampened the cellular immune response (IFN-gamma(+)CD8(+) T cells) against both cell-free and cell-associated virus. These results uniquely differentiate the involvement of DCs in early cell-free versus late cell-associated infection of HTLV-1 and highlight a significant aspect of viral immunopathogenesis related to the progression of adult T cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis after the initial infection.
authors.affiliation: Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, PA 19127, USA.
authors.forename: Saifur
authors.initials: S
authors.lastname: Rahman
authors.forename: Sharrón L
authors.initials: SL
authors.lastname: Manuel
authors.forename: Zafar K
authors.initials: ZK
authors.lastname: Khan
authors.forename: Brian
authors.initials: B
authors.lastname: Wigdahl
authors.forename: Edward
authors.initials: E
authors.lastname: Acheampong
authors.forename: Frederic
authors.initials: F
authors.lastname: Tangy
authors.forename: Pooja
authors.initials: P
authors.lastname: Jain
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000235:genetics*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002474:Cell-Free System / Q000276:immunology / Q000473:pathology / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004167:Diphtheria Toxin / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility / Q000276:immunology / Q000821:virology; D066257:Heparin-binding EGF-like Growth Factor; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007937:Leukapheresis / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015493:Paraparesis, Tropical Spastic / Q000276:immunology* / Q000378:metabolism / Q000821:virology
chemical_list: D039521:CD11c Antigen; D004167:Diphtheria Toxin; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins
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