HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy

Department of Immunology, Imperial College School of Medicine, St. Mary's, Norfolk Place, London W2 1PG, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/1999; 96(7):3848-53.
Source: PubMed


The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02(+) healthy HTLV-I carriers have a proviral load one-third that (P = 0.014) of HLA-A*02(-) HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections.

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Available from: Alun Lloyd, Oct 01, 2015
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    • "It was suggested that HLA class I-restricted immune responses influence the HTLV-I PVL. HLA class II alleles such as HLA-DRB1*0101 was associated with high risk for HAM/TSP (Jeffery et al. 1999; Usuku et al. 1988). In another study, Borducchi et al. also reported that HLA- A*02 is associated with a low prevalence of HAM/TSP in white subjects but not Mestizo subjects in Brazil. "
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    • "Increased risk for developing HAM is associated with blood-borne viral transmission, increased proviral DNA loads and anti-HTLV antibodies, polymorphisms in the IL-10 promoter and IL-28B gene, HLA-A*02- and HLA-DRB1*0101 alleles, and impaired anti-HTLV cytotoxic T-cell responses [7,15-19]. There is no indication that either HTLV-1 or HTLV-2 directly infects neuronal tissue. "
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    ABSTRACT: Previously, we had shown that persons infected with human T-cell lymphoma leukemia virus 1 or 2 (HTLV-1 or 2) had an increased prevalence of antibodies to a peptide in the Pol protein of the retrovirus HERV-K10, homologous to a peptide in HTLV gp21 envelope protein. The prevalence rate was higher in those with myelopathy vs. non-myelopathy. We have now extended our observations to a cohort restricted to North America in whom the diagnosis of HTLV myelopathy was rigorously confirmed to also test for reactivity to another HERV-K10 peptide homologous to the HTLV p24 Gag protein. Sera from 100 volunteer blood donors (VBD), 53 patients with large granular lymphocytic leukemia (LGLL), 74 subjects with HTLV-1 or 2 infection (58 non-myelopathy and 16 myelopathy) and 83 patients with multiple sclerosis (MS) were evaluated in ELISA assays using the above peptides. The HTLV myelopathy patients had a statistically significant increased prevalence of antibodies to both HERV-K10 peptides (87.5%) vs. the VBD (0%), LGLL patients (0%), MS patients (4.8%), and the HTLV positive non-myelopathy subjects (5.2%). The data suggest that immuno-cross-reactivity to HERV-K10 peptides and/or transactivation of HERV-K10 expression by the HTLV Tax protein may be involved in the pathogenesis of HTLV-associated myelopathy/tropical spastic paraparesis and spastic ataxia.
    Virology Journal 12/2013; 10(1):360. DOI:10.1186/1743-422X-10-360 · 2.18 Impact Factor
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    • "Evidence has accumulated to support the theory that infected CD4 + T cells (as opposed to infected neuronal cells or non-infected peripheral blood mononuclear cells) are primarily responsible for this transition to the HAM/TSP disease state: HTLV-1 primarily infects CD4 + T cells (Richardson et al., 1990); levels of infected CD4 + T cells circulating in the blood of patients with HAM/TSP are higher than those in the blood of asymptomatic carriers (Nagai et al., 1998; Yamano et al., 2002), the levels in the CSF surrounding the spinal cord are higher still (Nagai et al., 2001a); and these infected CD4 + T cells have also been detected in the spinal cord lesions themselves (Moritoyo et al., 1996; Matsuoka et al., 1998). There are many cell types capable of producing an inflammatory response upon contact with viral antigens, and it is true that the cases where these antigen-specific cells are most abundant are indeed in patients with HAM/TSP, but there is a large range of overlap in which patients with HAM/TSP and asymptomatic carriers have the same amount of antigen-specific cells in their peripheral blood mononuclear cells (Jacobson et al., 1990; Jeffery et al., 1999; Kubota et al., 2000; Yamano et al., 2002). Therefore, we hypothesized that their presence may not be the key factor that determines a patient's fate to experience the disease or not, and that perhaps there might be another cell type responsible for initiating the chronic inflammation in HAM/TSP through a more unique pathway. "
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    ABSTRACT: Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease characterized by chronic inflammation in the spinal cord. We hypothesized that a positive feedback loop driven by chemokines may be responsible for the chronic inflammation in HAM/TSP. We aimed to determine the identity of these chemokines, where they are produced, and how they drive chronic inflammation in HAM/TSP. We found that patients with HAM/TSP have extraordinarily high levels of the chemokine CXCL10 (also known as IP-10) and an abundance of cells expressing the CXCL10-binding receptor CXCR3 in the cerebrospinal fluid. Histological analysis revealed that astrocytes are the main producers of CXCL10 in the spinal cords of patients with HAM/TSP. Co-culture of human astrocytoma cells with CD4(+) T cells from patients with HAM/TSP revealed that astrocytes produce CXCL10 in response to IFN-γ secreted by CD4(+) T cells. Chemotaxis assays results suggest that CXCL10 induces migration of peripheral blood mononuclear cells to the central nervous system and that anti-CXCL10 neutralizing antibody can disrupt this migration. In short, we inferred that human T-lymphotropic virus type 1-infected cells in the central nervous system produce IFN-γ that induces astrocytes to secrete CXCL10, which recruits more infected cells to the area via CXCR3, constituting a T helper type 1-centric positive feedback loop that results in chronic inflammation.
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