Human T Cell Lymphotropic Virus Type I (HTLV-I)-Specific CD4+T Cells: Immunodominance Hierarchy and Preferential Infection with HTLV-I

Abstract It is thought that human T-cell lymphotropic virus type I (HTLV-I) preferentially infects CD4+ T cells in vivo. However, observations of high HTLV-I proviral load in patients with HTLV-I–associated myelopathy/tropical spastic paraparesis suggest that HTLV-I may infect other cell types in addition to CD4+ T cells. To identify in vivo T-cell tropisms of HTLV-I, real-time quantitative polymerase chain reaction (PCR) and intracellular protein staining were used. A high amount of HTLV-I proviral DNA was detected from purified CD8+ T cells by quantitative PCR (between 1.64 and 62.83 copies of HTLV-I provirus per 100 isolated CD8+ T cells). CD8+ T cells expressed HTLV-I–related antigens (HTLV-I Tax and p19 protein) after a short time in cultivation. These results demonstrate that CD8+ T cells are also infected with HTLV-I and express HTLV-I antigens at levels that are comparable to HTLV-I–infected CD4+ cells. Therefore, CD8+ cells are an additional viral reservoir in vivo for HTLV-I and may contribute to the pathogenesis of HTLV-I–mediated disorders.

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Abundant Tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes

Blood ◽

10.1182/blood.v95.4.1386.004k22_1386_1392 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1386-1392 ◽

Cited By ~ 185

Author(s):

Emmanuel Hanon ◽

Sarah Hall ◽

Graham P. Taylor ◽

Mineki Saito ◽

Ricardo Davis ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Type I ◽

Ctl Response ◽

Specific Ctls ◽

Human T Cell

The role of the cellular immune response in human T-cell leukemia virus type I (HTLV-I) infection is not fully understood. A persistently activated cytotoxic T lymphocyte (CTL) response to HTLV-I is found in the majority of infected individuals. However, it remains unclear whether this CTL response is protective or causes tissue damage. In addition, several observations paradoxically suggest that HTLV-I is transcriptionally silent in most infected cells and, therefore, not detectable by virus-specific CTLs. With the use of a new flow cytometric procedure, we show here that a high proportion of naturally infected CD4+ peripheral blood mononuclear cells (PBMC) (between 10% and 80%) are capable of expressing Tax, the immunodominant target antigen recognized by virus-specific CTLs. Furthermore, we provide direct evidence that autologous CD8+ T cells rapidly kill CD4+ cells naturally infected with HTLV-I and expressing Tax in vitro by a perforin-dependent mechanism. Consistent with these observations, we observed a significant negative correlation between the frequency of Tax11-19-specific CD8+ T cells and the percentage of CD4+ T cells in peripheral blood of patients infected with HTLV-I. Those results are in accordance with the view that virus-specific CTLs participate in a highly efficient immune surveillance mechanism that persistently destroys Tax-expressing HTLV-I-infected CD4+ T cells in vivo.

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Activation of T cell-derived lymphokine genes in T cells and fibroblasts: effects of human T cell leukemia virus type I p40xprotein and bovine papilloma virus encoded E2 protein

Nucleic Acids Research ◽

10.1093/nar/16.14.6547 ◽

1988 ◽

Vol 16 (14) ◽

pp. 6547-6566 ◽

Cited By ~ 50

Author(s):

Shoichiro Miyatake ◽

Motoharu Seiki ◽

Rene DeWaal Malefijt ◽

Toshio Heike ◽

Jun-ichi Fujisawa ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Leukemia Virus ◽

Type I ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Papilloma Virus ◽

Human T Cell ◽

T Cell Leukemia Virus

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Protective effect of interferon ? on human T cell leukaemia virus type I infection of CD4+ T cells isolated from human cord blood

Cancer Immunology Immunotherapy ◽

10.1007/bf01517041 ◽

1993 ◽

Vol 37 (2) ◽

pp. 97-104 ◽

Cited By ~ 3

Author(s):

Beatrice Macchi ◽

Isabella Faraoni ◽

Antonio Mastino ◽

Chiara D'Onofrio ◽

Gianna Romeo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Protective Effect ◽

Cord Blood ◽

Virus Type ◽

Cell Leukaemia ◽

Type I ◽

Human Cord Blood ◽

Leukaemia Virus ◽

Human T Cell

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Human T-cell lymphotropic virus type I-transformed T-cells have a partial defect in ceramide synthesis in response to N-(4-hydroxyphenyl)retinamide

Biochemical Journal ◽

10.1042/bj20050578 ◽

2005 ◽

Vol 392 (1) ◽

pp. 231-239 ◽

Cited By ~ 6

Author(s):

Nadine Darwiche ◽

Ghada Abou-Lteif ◽

Tarek Najdi ◽

Lina Kozhaya ◽

Ahmad Abou Tayyoun ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Growth Inhibition ◽

Virus Type ◽

De Novo ◽

Type I ◽

De Novo Synthesis ◽

Human T Cell ◽

Ceramide Synthesis ◽

Malignant T Cells

Treatment with the synthetic retinoid HPR [N-(4-hydroxyphenyl)-retinamide] causes growth arrest and apoptosis in HTLV-I (human T-cell lymphotropic virus type-I)-positive and HTLV-I-negative malignant T-cells [8]. It was observed that HPR-mediated growth inhibition was associated with ceramide accumulation only in HTLV-I-negative cells. The aim of the present study was to investigate the mechanism by which HPR differentially regulates ceramide metabolism in HTLV-I-negative and HTLV-I-positive malignant T-cells. Clinically achievable concentrations of HPR caused early dose-dependent increases in ceramide levels only in HTLV-I-negative cells and preceded HPR-induced growth suppression. HPR induced de novo synthesis of ceramide in HTLV-I-negative, but not in HTLV-I-positive, cells. Blocking ceramide glucosylation in HTLV-I-positive cells, which leads to accumulation of endogenous ceramide, rendered these cells more sensitive to HPR. Exogenous cell-permeant ceramides that function partially by generating endogenous ceramide induced growth suppression in all tested malignant lymphocytes, were consistently found to be less effective in HTLV-I-positive cells confirming their defect in de novo ceramide synthesis. Owing to its multipotent activities, the HTLV-I-encoded Tax protein was suspected to inhibit ceramide synthesis. Tax-transfected Molt-4 and HELA cells were less sensitive to HPR and C6-ceramide mediated growth inhibition respectively and produced lower levels of endogenous ceramide. Together, these results indicate that HTLV-I-positive cells are defective in de novo synthesis of ceramide and that therapeutic modalities that bypass this defect are more likely to be successful.

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Human T-cell lymphotropic virus type I-transformed T-cells have a partial defect in ceramide synthesis in response to N-(4-hydroxyphenyl)retinamide

Biochemical Journal ◽

10.1042/bj4440619u ◽

2012 ◽

Vol 444 (3) ◽

pp. 619-619

Author(s):

N. Darwiche ◽

G. Abou-Lteif ◽

T. Najdi ◽

L. Kozhaya ◽

A. Abou Tayoun ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Type I ◽

Human T Cell ◽

Ceramide Synthesis

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Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I–associated neurologic disease

Blood ◽

10.1182/blood-2008-02-138529 ◽

2008 ◽

Vol 112 (6) ◽

pp. 2400-2410 ◽

Cited By ~ 25

Author(s):

Yoshimi Enose-Akahata ◽

Unsong Oh ◽

Christian Grant ◽

Steven Jacobson

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Spastic Paraparesis ◽

Cd8 T Cell ◽

Mononuclear Phagocytes ◽

Type I ◽

Human T Cell ◽

Ifn Γ

AbstractCD8+ T cells contribute to central nervous system inflammation in human T-cell lymphotropic virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP). We analyzed CD8+ T-cell dysfunction (degranulation and IFN-γ production) and have demonstrated that CD8+ T cells of patients with HAM/TSP (HAM/TSP patients) spontaneously degranulate and express IFN-γ in ex vivo unstimulated culture. CD8+ T cells of HTLV-I asymptomatic carriers and healthy donors did not. Spontaneous degranulation was detected in Tax11-19/HLA-A*201 tetramer+ cells, but not in CMV pp65 tetramer+ cells. Interestingly, degranulation and IFN-γ production in CD8+ T cells was induced by coculture with autologous CD14+ cells, but not CD4+ T cells, of HAM/TSP patients, which correlated with proviral DNA load in CD14+ cells of infected patients. Moreover, the expression of IL-15, which induced degranulation and IFN-γ production in infected patients, was enhanced on surface of CD14+ cells in HAM/TSP patients. Blockade of MHC class I and IL-15 confirmed these results. Thus, CD8+ T-cell dysregulation was mediated by both virus infection and enhanced IL-15 on CD14+ cells in HAM/TSP patients. Despite lower viral expression than in CD4+ T cells, HTLV-I–infected or –activated CD14+ cells may be a heretofore important but under recognized reservoir particularly in HAM/TSP patients.

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p53 functional impairment and high p21waf1/cip1 expression in human T- cell lymphotropic/leukemia virus type I-transformed T cells

Blood ◽

10.1182/blood.v88.5.1551.1551 ◽

1996 ◽

Vol 88 (5) ◽

pp. 1551-1560 ◽

Cited By ~ 90

Author(s):

A Cereseto ◽

F Diella ◽

JC Mulloy ◽

A Cara ◽

P Michieli ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Cell Transformation ◽

Leukemia Virus ◽

Type I ◽

Wild Type ◽

Human T Cell ◽

Wild Type P53

Abstract Human T-cell lymphotropic/leukemia virus type I (HTLV-I) is associated with T-cell transformation both in vivo and in vitro. Although some of the mechanisms responsible for transformation remain unknown, increasing evidence supports a direct role of viral as well as dysregulated cellular proteins in transformation. We investigated the potential role of the tumor suppressor gene p53 and of the p53- regulated gene, p21waf1/cip1 (wild-type p53 activated fragment 1/cycling dependent kinases [cdks] interacting protein 1), in HTLV-I- infected T cells. We have found that the majority of HTLV-I-infected T cells have the wild-type p53 gene. However, its function in HTLV-I- transformed cells appears to be impaired, as shown by the lack of appropriate p53-mediated responses to ionizing radiation (IR). Interestingly, the expression of the p53 inducible gene, p21waf1/cip1, is elevated at the messenger ribonucleic acid and protein levels in all HTLV-I-infected T-cell lines examined as well as in Taxl-1, a human T- cell line stably expressing Tax. Additionally, Tax induces upregulation of a p21waf1/cip1 promoter-driven luciferase gene in p53 null cells, and increases p21waf1/cip1 expression in Jurkat T cells. These findings suggest that the Tax protein is at least partially responsible for the p53-independent expression of p21waf1/cip1 in HTLV-I-infected cells. Dysregulation of p53 and p21waf1/cip1 proteins regulating cell-cycle progression, may represent an important step in HTLV-I-induced T-cell transformation.

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p53 functional impairment and high p21waf1/cip1 expression in human T- cell lymphotropic/leukemia virus type I-transformed T cells

Blood ◽

10.1182/blood.v88.5.1551.bloodjournal8851551 ◽

1996 ◽

Vol 88 (5) ◽

pp. 1551-1560 ◽

Cited By ~ 16

Author(s):

A Cereseto ◽

F Diella ◽

JC Mulloy ◽

A Cara ◽

P Michieli ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Cell Transformation ◽

Leukemia Virus ◽

Type I ◽

Wild Type ◽

Human T Cell ◽

Wild Type P53

Human T-cell lymphotropic/leukemia virus type I (HTLV-I) is associated with T-cell transformation both in vivo and in vitro. Although some of the mechanisms responsible for transformation remain unknown, increasing evidence supports a direct role of viral as well as dysregulated cellular proteins in transformation. We investigated the potential role of the tumor suppressor gene p53 and of the p53- regulated gene, p21waf1/cip1 (wild-type p53 activated fragment 1/cycling dependent kinases [cdks] interacting protein 1), in HTLV-I- infected T cells. We have found that the majority of HTLV-I-infected T cells have the wild-type p53 gene. However, its function in HTLV-I- transformed cells appears to be impaired, as shown by the lack of appropriate p53-mediated responses to ionizing radiation (IR). Interestingly, the expression of the p53 inducible gene, p21waf1/cip1, is elevated at the messenger ribonucleic acid and protein levels in all HTLV-I-infected T-cell lines examined as well as in Taxl-1, a human T- cell line stably expressing Tax. Additionally, Tax induces upregulation of a p21waf1/cip1 promoter-driven luciferase gene in p53 null cells, and increases p21waf1/cip1 expression in Jurkat T cells. These findings suggest that the Tax protein is at least partially responsible for the p53-independent expression of p21waf1/cip1 in HTLV-I-infected cells. Dysregulation of p53 and p21waf1/cip1 proteins regulating cell-cycle progression, may represent an important step in HTLV-I-induced T-cell transformation.

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