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

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.

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

Background: Human T-cell 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 66 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, HLA-B*35 and HLA-C*07 as associated to protection from ATLL (p=0.031), susceptibility to HAM/TSP (p<0.001) and susceptibility to ATLL (p=0.017), respectively. We also found a strong correlation between high proviral load (PVL) and disease (p=0.008), but were unable to identify any particular allele associated with high or low PVL.Conclusions: We have found HLA-A*02, HLA-B*35 and HLA-C*07 to be associated to protection from ATLL (HLA-A*02) and susceptibility to HAM/TSP (HLA-B*35) or to ATLL (HLA-C*07), respectively. Whereas HLA-A*02 protection from ATLL has already been extensively described in other regions of the world, this is the first report that links HLA-B*35 and an increased susceptibility to HAM/TSP. As for HLA-C*07 it has previously been associated to susceptibility to HAM/TSP in other countries but in our population it has been linked to ATLL.

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

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).

PRMT5 Is Required for Bovine Leukemia Virus Infection In Vivo and Regulates BLV Gene Expression, Syncytium Formation, and Glycosylation In Vitro

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis, which is the most common neoplastic disease of cattle and is closely related to human T-cell leukemia viruses. We investigated the role of a new host protein, PRMT5, in BLV infection. We found that PRMT5 is overexpressed only in BLV-infected cattle with a high proviral load, but not in those with a low proviral load. Furthermore, this upregulation continued to the lymphoma stage. PRMT5 expression was upregulated in response to experimental BLV infection; moreover, PRMT5 upregulation began in an early stage of BLV infection rather than after a long period of proviral latency. Second, siRNA-mediated PRMT5 knockdown enhanced BLV gene expression at the transcript and protein levels. Additionally, a selective small-molecule inhibitor of PRMT5 (CMP5) enhanced BLV gene expression. Interestingly, CMP5 treatment, but not siRNA knockdown, altered the gp51 glycosylation pattern and increased the molecular weight of gp51, thereby decreasing BLV-induced syncytium formation. This was supported by the observation that CMP5 treatment enhanced the formation of the complex type of N-glycan more than the high mannose type. In conclusion, PRMT5 overexpression is related to the development of BLV infection with a high proviral load and lymphoma stage and PRMT5 inhibition enhances BLV gene expression. This is the first study to investigate the role of PRMT5 in BLV infection in vivo and in vitro and to reveal a novel function for a small-molecule compound in BLV-gp51 glycosylation processing.

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

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).