Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Viruses ; 3(6): 794-810, 2011 06.
Article in English | MEDLINE | ID: mdl-21994754

ABSTRACT

The initial step in retroviral infection involves specific interactions between viral envelope proteins (Env) and specific receptors on the surface of target cells. For many years, little was known about the entry receptors for HTLV-1. During this time, however, functional domains of the HTLV-1 Env were identified by analyzing the effects of neutralizing antibodies and specific mutations in Env on HTLV-1 infectivity. More recent studies have revealed that HTLV-1 infectivity involves interactions with three different molecules: heparan sulfate proteoglycans (HSPG), the VEGF-165 receptor Neuropilin 1 (NRP-1) and glucose transporter type 1 (GLUT1). Here, we revisit previously published data on the functional domains of Env in regard to the recent knowledge acquired about this multi-receptor complex. We also discuss the similarities and differences between HTLV-1 and other deltaretroviruses in regards to receptor usage.


Subject(s)
Gene Products, env/chemistry , Gene Products, env/metabolism , HTLV-I Infections/metabolism , Human T-lymphotropic virus 1/physiology , Receptors, Virus/metabolism , Virus Internalization , Animals , Gene Products, env/genetics , HTLV-I Infections/genetics , HTLV-I Infections/virology , Human T-lymphotropic virus 1/chemistry , Human T-lymphotropic virus 1/genetics , Humans , Protein Structure, Tertiary , Receptors, Virus/genetics
2.
Proc Natl Acad Sci U S A ; 107(48): 20738-43, 2010 Nov 30.
Article in English | MEDLINE | ID: mdl-21076035

ABSTRACT

The human T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia/lymphoma as well as tropical spastic paraparesis/HTLV-1-associated myelopathy. HTLV-1 is transmitted to T cells through the virological synapse and by extracellular viral assemblies. Here, we uncovered an additional mechanism of virus transmission that is regulated by the HTLV-1-encoded p8 protein. We found that the p8 protein, known to anergize T cells, is also able to increase T-cell contact through lymphocyte function-associated antigen-1 clustering. In addition, p8 augments the number and length of cellular conduits among T cells and is transferred to neighboring T cells through these conduits. p8, by establishing a T-cell network, enhances the envelope-dependent transmission of HTLV-1. Thus, the ability of p8 to simultaneously anergize and cluster T cells, together with its induction of cellular conduits, secures virus propagation while avoiding the host's immune surveillance. This work identifies p8 as a viral target for the development of therapeutic strategies that may limit the expansion of infected cells in HTLV-1 carriers and decrease HTLV-1-associated morbidity.


Subject(s)
HTLV-I Infections/transmission , HTLV-I Infections/virology , Human T-lymphotropic virus 1/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/virology , Viral Proteins/metabolism , Cell Communication , Human T-lymphotropic virus 1/ultrastructure , Humans , Jurkat Cells , Kinetics , T-Lymphocytes/ultrastructure
3.
Blood ; 116(19): 3809-17, 2010 Nov 11.
Article in English | MEDLINE | ID: mdl-20647569

ABSTRACT

The identification of the genes necessary for human T-cell leukemia virus (HTLV-1) persistence in humans may provide targets for therapeutic approaches. We demonstrate that ablation of the HTLV-1 genes encoding p12, p30, or the HBZ protein, does not affect viral infectivity in rabbits and in this species, only the absence of HBZ is associated with a consistent reduction in virus levels. We observed reversion of the HTLV-1 mutants to the HTLV-1 wild-type genotype in none of the inoculated rabbits. In contrast, in macaques, the absence of HBZ was associated with reversion of the mutant virus to the wild-type genotype in 3 of the 4 animals within weeks from infection. Similarly, reversion to the wild type was observed in 2 of the 4 macaque inoculated with the p30 mutant. The 4 macaques exposed to the p12 knock remained seronegative, and only 2 animals were positive at a single time point for viral DNA in tissues. Interestingly, we found that the p12 and the p30 mutants were also severely impaired in their ability to replicate in human dendritic cells. These data suggest that infection of dendritic cells may be required for the establishment and maintenance of HTLV-1 infection in primate species.


Subject(s)
Dendritic Cells/virology , Human T-lymphotropic virus 1/genetics , Human T-lymphotropic virus 1/pathogenicity , Retroviridae Proteins/genetics , Retroviridae Proteins/physiology , Viral Regulatory and Accessory Proteins/genetics , Viral Regulatory and Accessory Proteins/physiology , Animals , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/physiology , Cell Line , DNA Primers/genetics , DNA, Viral/genetics , Dendritic Cells/immunology , Female , Gene Deletion , Genes, Viral , Genes, pX , Genotype , HTLV-I Infections/immunology , HTLV-I Infections/virology , Human T-lymphotropic virus 1/immunology , Human T-lymphotropic virus 1/physiology , Humans , In Vitro Techniques , Macaca mulatta , Mutagenesis , Mutation , Rabbits , Species Specificity , T-Lymphocytes/immunology , T-Lymphocytes/virology , Viral Proteins/genetics , Viral Proteins/physiology , Virulence/genetics , Virulence/physiology
4.
Diabetes ; 59(8): 2010-9, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20460428

ABSTRACT

OBJECTIVE: Peripheral blood CD34(+) cells from diabetic patients demonstrate reduced vascular reparative function due to decreased proliferation and diminished migratory prowess, largely resulting from decreased nitric oxide (NO) bioavailability. The level of TGF-beta, a key factor that modulates stem cell quiescence, is increased in the serum of type 2 diabetic patients. We asked whether transient TGF-beta1 inhibition in CD34(+) cells would improve their reparative ability. RESEARCH DESIGN AND METHODS: To inhibit TGF-beta1 protein expression, CD34(+) cells were treated ex vivo with antisense phosphorodiamidate morpholino oligomers (TGF-beta1-PMOs) and analyzed for cell surface CXCR4 expression, cell survival in the absence of added growth factors, SDF-1-induced migration, NO release, and in vivo retinal vascular reparative ability. RESULTS: TGF-beta1-PMO treatment of diabetic CD34(+) cells resulted in increased expression of CXCR4, enhanced survival in the absence of growth factors, and increased migration and NO release as compared with cells treated with control PMO. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34(+) cells to injured acellular retinal capillaries was greater after TGF-beta1-PMO treatment compared with control PMO-treated cells. CONCLUSIONS: Transient inhibition of TGF-beta1 may represent a promising therapeutic strategy for restoring the reparative capacity of dysfunctional diabetic CD34(+) cells.


Subject(s)
Diabetes Mellitus/physiopathology , Diabetic Angiopathies/prevention & control , Hematopoietic Stem Cells/physiology , Transforming Growth Factor beta1/antagonists & inhibitors , Transforming Growth Factor beta1/pharmacology , Transforming Growth Factor beta/metabolism , Animals , Antigens, CD34/metabolism , Antigens, CD34/physiology , Capillaries/physiopathology , Cell Survival , Diabetic Retinopathy/physiopathology , Flow Cytometry , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Humans , Mice , Morpholines/pharmacology , Morpholines/therapeutic use , Morpholinos , Nitric Oxide/metabolism , Receptors, CXCR4/genetics , Reperfusion Injury/physiopathology , Transforming Growth Factor beta1/metabolism
5.
Cell Immunol ; 249(1): 8-19, 2007 Sep.
Article in English | MEDLINE | ID: mdl-18039542

ABSTRACT

Analysis of the NK cell developmental pathway suggests that CD2 expression may be important in regulating NK maturation. To test this hypothesis, we developed mice containing only an inhibitory CD2 molecule by linking the extracellular domain of CD2 to an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) motif. Mice containing the CD2 Tg(ITIM) transgene, introduced into a CD2 KO background, have no morphologically detectable lymph nodes, although development of the thymus appears normal. In addition, these mice had major loss of both NK and NKT subsets in peripheral organs, while T and B cell frequencies were intact. Expression of CD2 was low on T cells and lacking on B cells and functional defects were observed in these populations. NKT cells expressing CD4 were absent, while the CD8+ and double negative NKT cells were retained. Small subsets of NK cells were detected but expression of CD2 on these cells was very low or absent, and their maturation was impaired. Based on the phenotype described here, we believe that these mice represent a unique model to study lymphoid organ and lymphocyte development.


Subject(s)
CD2 Antigens/immunology , Killer Cells, Natural/immunology , Lymphocyte Subsets/immunology , Thymus Gland/immunology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD2 Antigens/chemistry , CD2 Antigens/genetics , CD2 Antigens/metabolism , CD4 Antigens/metabolism , CD8 Antigens/metabolism , Cell Differentiation , Humans , Killer Cells, Natural/cytology , Lymphocyte Count , Lymphocyte Subsets/cytology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Structure, Tertiary , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tyrosine
6.
AIDS Res Hum Retroviruses ; 21(1): 43-50, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15665643

ABSTRACT

Cholesterol-rich plasma membrane microdomains are important for entry of many viruses, including retroviruses. Depletion of cholesterol with 2-hydroxypropyl-beta-cyclodextrin inhibits entry of human T cell leukemia virus type I (HTLV-1) and HTLV-I envelope pseudotyped lentivirus particles. Using a soluble fusion protein of the HTLV-I surface envelope protein with the immunoglobulin Fc domain, the HTLV-I receptor was found to colocalize with a raft-associated marker and to cluster in specific plasma membrane microdomains. Depletion of cholesterol did not alter receptor binding activity, suggesting a requirement for cholesterol in a postbinding virus entry step.


Subject(s)
Cholesterol/metabolism , Human T-lymphotropic virus 1/pathogenicity , Membrane Microdomains/metabolism , Virion/pathogenicity , 2-Hydroxypropyl-beta-cyclodextrin , Animals , Cell Line , Cell Membrane/metabolism , Human T-lymphotropic virus 1/genetics , Human T-lymphotropic virus 1/metabolism , Humans , Lentivirus/genetics , Receptors, Virus/metabolism , Transfection , Viral Envelope Proteins , Virion/genetics , Virion/metabolism , beta-Cyclodextrins
SELECTION OF CITATIONS
SEARCH DETAIL
...