Polymorphisms in HTLV-1 Tax-responsive elements in HTLV-1-associated myelopathy/tropical spastic paraparesis patients are associated with reduced proviral load but not with disease progression

2021 ◽  
Vol 102 (9) ◽  
Author(s):  
Yago Côrtes Pinheiro Gomes ◽  
Marcus Tulius Teixeira Silva ◽  
Ana Claudia Celestino Bezerra Leite ◽  
Marco Antonio Sales Dantas Lima ◽  
Abelardo Queiroz Campos Araújo ◽  
...  
Keyword(s):  
Disease Progression ◽  
Latin American ◽  
Proviral Load ◽  
Spastic Paraparesis ◽  
Tropical Spastic Paraparesis ◽  
Clinical Severity ◽  
Long Terminal Repeats ◽  
T Lymphotropic Virus ◽  
High Proviral Load

Human T-lymphotropic virus type 1 (HTLV-1) provirus expression is mainly directed by Tax-responsive elements (TRE) within the long terminal repeats (LTR). Mutations in TRE can reduce provirus expression and since a high proviral load (PVL) is a risk factor for the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), we evaluated polymorphisms in the 5′ LTR and the association with PVL and disease progression. HTLV-1 LTR and tax sequences derived from asymptomatic carriers (AC) and HAM/TSP patients followed in a longitudinal study were analysed according to PVL and clinical severity. Individuals infected with HTLV-1 presenting the canonical TRE, considering strain ATK-1 as the consensus, displayed sustained higher PVL. By contrast, an LTR A125G mutation in TRE was associated with slightly reduced PVL only in HAM/TSP patients, although it did not influence the speed of disease progression. Moreover, this polymorphism was frequent in Latin American strains of the HTLV-1 Cosmopolitan Transcontinental subtype. Therefore, polymorphisms in the 5′ TRE of HTLV-1 may represent one of the factors influencing PVL in HAM/TSP patients, especially in the Latin American population. Indeed, higher PVL in the peripheral blood has been associated with an increased inflammatory activity in the spinal cord and to a poorer prognosis in HAM/TSP. However, this event was not associated with TRE polymorphisms.

scholarly journals HLA-B*35 as a new marker for susceptibility to Human T-cell Lymphotropic Virus type 1 (HTLV-1) Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in patients living in Argentina

2020 ◽  
Author(s):  
Paula Benencio ◽  
Sindy A. Fraile Gonzalez ◽  
Nicolás Ducasa ◽  
Kimberly Page ◽  
Carolina A. Berini ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Viral Infections ◽  
Spastic Paraparesis ◽  
Tropical Spastic Paraparesis ◽  
T Lymphotropic Virus ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
High Proviral Load

Abstract Background: Human T lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV associated myelopathy/ Tropical Spastic Paraparesis (HAM/TSP) and Adult T cell leukemia/lymphoma (ATLL), in around 2-5% of the infected individuals. Host genetic background might play a role in disease progression. Several previous studies across many countries report HLA haplotype to be one such factor. Here, we sequenced HLA-A, -B and -C of 72 individuals by Sequence-Based Typing (SBT), and compared the frequency of different alleles among ATLL patients, HAM/TSP patients, asymptomatic carriers and non-infected individuals living in Argentina.Results: The frequency of HLA-A, -B and -C alleles largely matched that of the general population in Argentina. We identified HLA-A*02 and HLA-B*35 as associated to protection from ATLL (p=0.037) and susceptibility to HAM/TSP (p<0.001), respectively. We also found a strong correlation between high proviral load (PVL) and disease (p=0.003), but were unable to identify any particular allele associated with high or low PVL.Conclusions: Our results match several previous reports that link HLA-A*02 and protection from disease. However, this is the first study associating HLA-B*35 to susceptibility to disease in HTLV-1, an allele that has been largely associated to different severity factors related to other viral infections, such as Human Immunodeficiency Virus (HIV-1) and Hepatitis B Virus (HBV).

scholarly journals HLA-B*35 as a new marker for susceptibility to Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in patients with Human T-cell Lymphotropic Virus type 1 (HTLV-1) in Argentina

2020 ◽  
Author(s):  
Paula Benencio ◽  
Sindy A. Fraile Gonzalez ◽  
Nicolás Ducasa ◽  
Kimberly Page ◽  
Carolina A. Berini ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Viral Infections ◽  
Spastic Paraparesis ◽  
Tropical Spastic Paraparesis ◽  
T Lymphotropic Virus ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
High Proviral Load

Abstract Background Human T lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV associated myelopathy/ Tropical Spastic Paraparesis (HAM/TSP) and Adult T cell leukemia/lymphoma (ATLL), in around 2–5% of the infected individuals. Host genetic background might play a role in disease progression. Several previous studies across many countries report HLA haplotype to be one such factor. Here, we sequenced HLA-A, -B and -C of 73 individuals by Sequence-Based Typing (SBT), and compared the frequency of different alleles among ATLL patients, HAM/TSP patients, asymptomatic carriers and non-infected individuals in Argentina. Results The frequency of HLA-A, -B and -C alleles largely matched that of the general population in Argentina. We identified HLA-A*02 and HLA-B*35 as associated to protection from ATLL (p = 0.042) and susceptibility to HAM/TSP (p = 0.006), respectively. We also found a strong correlation between high proviral load (PVL) and disease (p = 0.0177), but were unable to identify any particular allele associated with high or low PVL. Conclusions Our results match several previous reports that link HLA-A*02 and protection from disease. However, this is the first study associating HLA-B*35 to susceptibility to disease in HTLV-1, an allele that has been largely associated to different severity factors related to other viral infections, such as Human Immunodeficiency Virus (HIV-1) and Hepatitis B Virus (HBV).

The Role of Human T-Lymphotropic Virus Type 1 (HTLV-1)-Infected Dendritic Cells in the Development of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

1999 ◽  
Vol 73 (6) ◽  
pp. 4575-4581 ◽  
Author(s):  
Masahiko Makino ◽  
Satoshi Shimokubo ◽  
Shin-Ichi Wakamatsu ◽  
Shuji Izumo ◽  
Masanori Baba
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Virus Type ◽  
Spastic Paraparesis ◽  
Tropical Spastic Paraparesis ◽  
Normal Donor ◽  
Dependent Manner ◽  
T Lymphotropic Virus

ABSTRACT The development of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is closely associated with the activation of T cells which are HTLV-1 specific but may cross-react with neural antigens (Ags). Immature dendritic cells (DCs), differentiated from normal donor monocytes by using recombinant granulocyte-macrophage colony-stimulating factor and recombinant interleukin-4, were pulsed with HTLV-1 in vitro. The pulsed DCs contained HTLV-1 proviral DNA and expressed HTLV-1 Gag Ag on their surface 6 days after infection. The DCs matured by lipopolysaccharides stimulated autologous CD4+ T cells and CD8+ T cells in a viral dose-dependent manner. However, the proliferation level of CD4+ T cells was five- to sixfold higher than that of CD8+ T cells. In contrast to virus-infected DCs, DCs pulsed with heat-inactivated virions activated only CD4+ T cells. To clarify the role of DCs in HAM/TSP development, monocytes from patients were cultured for 4 days in the presence of the cytokines. The expression of CD86 Ag on DCs was higher and that of CD1a Ag was more down-regulated than in DCs generated from normal monocytes. DCs from two of five patients expressed HTLV-1 Gag Ag. Furthermore, both CD4+ and CD8+ T cells from the patients were greatly stimulated by contact with autologous DCs pulsed with inactivated viral Ag as well as HTLV-1-infected DCs. These results suggest that DCs are susceptible to HTLV-1 infection and that their cognate interaction with T cells may contribute to the development of HAM/TSP.

Human T-Lymphotropic Virus Type-1-Associated Myelopathy/Tropical Spastic Paraparesis: The First Case Report in Southeast Asia

2017 ◽  
Vol 33 (7) ◽  
pp. 629-631
Author(s):  
Sekh Thanprasertsuk ◽  
Suwapan Pleumkanitkul ◽  
Supaporn Wacharapluesadee ◽  
Teerada Ponpinit ◽  
Thiravat Hemachudha ◽  
...  
Keyword(s):  
Case Report ◽  
Southeast Asia ◽  
Virus Type ◽  
Spastic Paraparesis ◽  
Tropical Spastic Paraparesis ◽  
T Lymphotropic Virus ◽  
First Case

Impaired function of human T-lymphotropic virus type 1 (HTLV-1)–specific CD8+ T cells in HTLV-1–associated neurologic disease

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2411-2420 ◽  
Author(s):  
Amir H. Sabouri ◽  
Koichiro Usuku ◽  
Daisuke Hayashi ◽  
Shuji Izumo ◽  
Yoshiro Ohara ◽  
...  
Keyword(s):  
T Cells ◽  
Virus Type ◽  
Cd8 T Cells ◽  
Proviral Load ◽  
Spastic Paraparesis ◽  
Inverse Correlation ◽  
T Lymphotropic Virus ◽  
Impaired Function ◽  
Protective Allele

Abstract Despite abundant activated virus-specific cytotoxic T lymphocytes (CTLs), patients with human T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) showed a significantly higher frequency of infected T cells than did healthy virus carriers (HVCs). Here, we demonstrate that at a given proviral load, the frequency of CD8+ T cells that are negative for specific costimulatory molecules was significantly higher in HAM/TSP than in age-matched HVCs and uninfected healthy controls (HCs), whereas the frequency of intracellular perforin-positive CD8+ T cells was significantly lower in both HAM/TSP and HVCs than in HCs. An inverse correlation between HTLV-1 proviral load (PVL) and percent perforin-positive CD8+ T cells were observed only in disease-protective allele HLA-A*02–positive HVCs, but not in HAM/TSP patients, whether HLA-A*02 positive or negative, nor in HLA-A*02–negative HVCs. Significantly lower perforin expression was observed in HTLV-1–specific than in cytomegalovirus-specific CD8+ T cells. Majority of HTLV-1–specific CD8+ T cells in HVCs showed a CD28−CD27+ phenotype, whereas HAM/TSP showed a CD28−CD27− phenotype. HTLV-1–specific CD8+ T cells from HAM/TSP patients showed significantly lower degranulation than HVCs by CD107a mobilization assay. These findings suggest that an impaired function of HTLV-1–specific CTLs is associated with failing antiviral control and disease HAM/TSP.

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