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: 9.81). 04/1999; 96(7):3848-53.
Source: PubMed

ABSTRACT 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, Jul 22, 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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    • "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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    • "For example, in HIV-1 infection, although elite controllers are heavily enriched for HLA-B n 57, the phenomenon of B57þ individuals who progress to AIDS at normal rates is well described (Chen et al., 2012). Similarly, in HTLV-1 infection, although HLA-C n 08 is protective (associated with reduced risk of HAM/TSP and reduced proviral load in asymptomatic carriers) it is not associated with a reduced proviral load amongst HAM/TSP patients (Jeffery et al., 1999). And HLA-B n 54, which is detrimental (associated with increased risk of HAM/TSP and increased proviral load in HAM/TSP patients), is not associated with increased proviral load in asymptomatic carriers (Jeffery et al., 2000). "
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