Increased HTLV‐I proviral load and preferential expansion of HTLV‐I tax‐specific CD8⁺ T cells in cerebrospinal fluid from patients with HAM/TSP

Abstract

To date, high human T-cell lymphotropic virus type I proviral load in patients with human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis has been reported and is thought to be related to the pathogenesis of human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis. However, the proviral load in cerebrospinal fluid has not been well investigated. We measured human T-cell lymphotropic virus type I proviral load in cerebrospinal fluid cells from human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis patients using real-time quantitative polymerase chain reaction (TaqMan). Human T-cell lymphotropic virus type I proviral load in cerebrospinal fluid cells were significantly higher than that of the matched peripheral blood mononuclear cells, and a high ratio of human T-cell lymphotropic virus type I proviral load in cerebrospinal fluid cells to peripheral blood mononuclear cells were observed in patients with short duration of illness. Human T-cell lymphotropic virus type I Tax-specific CD8+ T cells, as detected by peptide-loaded HLA tetramers, accumulated in cerebrospinal fluid compared with that in peripheral blood mononuclear cells, while the frequency of cytomegalovirus-specific CD8+ T cells in cerebrospinal fluid was reduced. These observations suggest that accumulation of both human T-cell lymphotropic virus type I-infected cells and preferential expansion of human T-cell lymphotropic virus type I-specific CD8+ cells in cerebrospinal fluid may play a role in the pathogenesis of human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis.

Severe loss of invariant NKT cells exhibiting anti–HTLV-1 activity in patients with HTLV-1–associated disorders

“…Whereas most infected persons remain asymptomatic carriers (ACs), 3% to 5% develop a T-cell malignancy termed adult T-cell leukemia (ATL), and another 0.25% to 3% develop a chronic progressive inflammatory neurologic disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/ TSP). [1][2][3] One of the most important pathogenic factors in HAM/ TSP is an increased HTLV-1 load in the peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid, [4][5][6] which suggests that in affected persons, virus control is inadequate. A higher HTLV-1 load increases the risk of HAM/TSP and ATL.…”

“…[9][10][11] Despite the high frequency of HTLV-1-specific CTLs, the number of HTLV-1-infected T cells is surprisingly high in HAM/TSP patients. 5,6 We and others have reported that the maturation and functioning of HTLV-1-specific CTLs are inadequate in HAM/TSP patients, although in vitro studies have shown that these CTLs exert cytolytic activity against HTLV-1-expressing target cells. 12,13 Therefore, we hypothesize that there may be another cell population without CTLs that contributes to the control of HTLV-1-infected T cells.…”

Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2

“…The other doubly spliced mRNAs contain exons 1 and 2 linked to a splice acceptor at 6629 or 6491; their protein products are less characterized HTLV-1 and HTLV-2 biology G Feuer and PL Green Investigation of HTLV cell tropism in infected patients has indicated that HTLV-1 has a preferential tropism for CD4 þ T cells in both asymptomatic patients and those with neurological disease (Richardson et al, 1990). More recently, studies demonstrated that CD8 þ T cells are an additional viral reservoir in vivo for HTLV-1 in HAM/TSP patients (Nagai et al, 2001). In vitro, it has been shown that Tax-mediated transcription of HTLV-1 is significantly increased in purified CD4 þ versus CD8 þ T cell subsets (Newbound et al, 1996).…”

Host Immune System Abnormalities Among Patients with Human T-Lymphotropic Virus Type 1 (HTLV-1) - Associated Disorders

“…In addition, the HTLV-1 proviral load of HAM/TSP patients may be 5-to 16-fold higher than that of ACs (Hashimoto et al, 1998;Kubota et al, 1993;Nagai et al, 1998). While some studies have found a positive correlation between the frequency of HTLV-1-specific CD8 + T cells and HTLV-1 proviral load has been detected in PBMCs from HAM/TSP patients (Kubota et al, 2000, Nagai et al, 2001b, Yamano et al, 2002, this result is not ubiquitous (Wodarz et al, 2001). Thus, the cytolytic activity of CTLs, rather than their frequency, might be impaired in HAM/TSP patients.…”