Different cytokine production in tax-expressing cells between patients with human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis and asymptomatic HTLV-I carriers

Human T cell lymphotropic virus type I (HTLV-I) provirus load has been reported to be generally higher in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) than in asymptomatic HTLV-I carriers (ACs). However, some ACs have a high HTLV-I provirus load comparable with that in patients with HAM/TSP. To examine whether other factors influence the outcome of HTLV-I infection in patients with HAM/TSP and ACs, we analyzed spontaneous Tax expression and cytokine production in peripheral blood mononuclear cells using flow cytometry. The Tax expression in HTLV-I-infected cells (percentage of Tax expressing cells/HTLV-I provirus load when assumed 1 copy/cell) and the intensity of Tax expression did not differ between these 2 groups. However, the production of interferon-gamma and tumor necrosis factor-alpha in Tax-expressing cells was significantly lower in ACs with high HTLV-I provirus load than in patients with HAM/TSP. This result suggests that the production of inflammatory cytokines in Tax-expressing cells is one of the factors that contribute to the development of HAM/TSP.     

Decreased human T lymphotropic virus type I (HTLV-I) provirus load and alteration in T cell phenotype after interferon-alpha therapy for HTLV-I-associated myelopathy/tropical spastic paraparesis

To analyze the mechanism by which interferon (IFN)-alpha is effective against human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), we investigated the T cell phenotype and HTLV-I provirus load in peripheral blood mononuclear cells from 25 patients with HAM/TSP that were obtained before and after administration of IFN-alpha. The frequency of memory (CD45RA(-)CD27(+)) T cells that were CD8(high+), CXCR3(+) cell populations, and HTLV-I provirus loads were significantly decreased after treatment. The proportion of memory T cells in the CD8(high+) cell population correlated well with HTLV-I provirus load, whereas the proportion of effector (CD45RA(+)CD27(-)) cells in the CD8(high+) cell population was inversely correlated with provirus load. Interestingly, the frequency of perforin expression in CD8(high+) cells was significantly decreased after treatment in patients who experienced clinical improvement, whereas patients who did not experience clinical improvement showed an increased frequency of perforin expression. Our data suggest that fluctuations in these cell subsets are associated with both the immunomodulatory effect of IFN-alpha and the observed clinical benefit of IFN-alpha treatment in patients with HAM/TSP.     

Polygenic control of human T lymphotropic virus type I (HTLV-I) provirus load and the risk of HTLV-I-associated myelopathy/tropical spastic paraparesis

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of infection with HTLV-I. A population association study of 229 patients with HAM/TSP and 202 healthy carriers of HTLV-I in southern Japan showed that this outcome of HTLV-I infection and the HTLV-I provirus load are under polygenic control. Of 58 polymorphic sites studied in 39 non-HLA candidate gene loci, 3 new host genetic factors that influenced the risk of HAM/TSP or the provirus load of HTLV-I were identified. The promoter TNF -863A allele predisposed to HAM/TSP, whereas SDF-1 +801A 3'UTR, and IL-15 191C alleles conferred protection. Knowledge of HTLV-I-infected individuals' ages, sex, provirus load, HTLV-I subgroup, and genotypes at the loci HLA-A, HLA-C, SDF-1, and TNF-alpha allowed for the correct identification of 88% of cases of HAM/TSP in this Japanese cohort.     

Increased activated human T cell lymphotropic virus type I (HTLV-I) Tax11-19-specific memory and effector CD8+ cells in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis: correlation with HTLV-I provirus load

To discern the T cell subtype associated with T cell differentiation, the expression of CD45RA and CD27 was measured from total CD8(high) cells and from human T cell lymphotropic virus type I (HTLV-I) Tax11-19 peptide-specific CD8(+) cells in peripheral blood lymphocytes of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Phenotypically defined memory and/or effector cells (CD45RA(-)CD27(+), CD45RA(+)CD27(-), and CD45RA(-)CD27(-)) were increased in HAM/TSP CD8(+) cells, compared with those of HTLV-I-seronegative healthy control subjects. The percentage of human leukocyte antigen (HLA)-DR-positive cells was also increased in CD8(+) cells of HAM/TSP, compared with those in HLA-DR(+)CD8(+) cells of healthy control subjects. HTLV-I provirus load correlated with the frequency of Tax11-19-specific CD8(+) cells. The high frequency of memory and/or effector type HTLV-I Tax11-19-specific CD8(+) cells suggests that continuous restimulation driven by HTLV-I antigens in vivo may be associated with the pathogenesis of HAM/TSP.     

Phylogenetic subgroups of human T cell lymphotropic virus (HTLV) type I in the tax gene and their association with different risks for HTLV-I-associated myelopathy/tropical spastic paraparesis

The association between human T cell lymphotropic virus (HTLV) type I tax variation and disease outcome was studied. The tax gene was sequenced in 61 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), 55 patients with adult T cell leukemia, and 62 healthy carriers (HCs). Phylogenetic analysis revealed 2 tax gene subgroups that are related on the basis of the long terminal repeat sequence. Further analysis using restriction fragment length polymorphism in 192 patients with HAM/TSP and 200 HCs revealed a higher incidence of 1 tax subgroup (taxA) in HAM/TSP. taxA was present in 30 (15.5%) of 192 patients with HAM/TSP and in 14 (7%) of 200 HCs. The difference was significant (chi2=6.47; P=.014; odds ratio, 2.46; 95% confidence interval, 1.26-4.80). This effect was independent of HLA-A*02, which has been reported to prevent HAM/TSP development. These findings suggest that both host genetic factors and HTLV-I subgroup are associated with different risks for development of HAM/TSP.     

Helminthic infection down-regulates type 1 immune responses in human T cell lymphotropic virus type 1 (HTLV-1) carriers and is more prevalent in HTLV-1 carriers than in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis

Human T cell lymphotropic virus type 1 (HTLV-1) infection is associated with an exacerbated type 1 immune response and secretion of high levels of proinflammatory cytokines. In contrast, helminthic infection induces a type 2 immune response. In the present study, the cytokine profile in HTLV-1 carriers coinfected with helminths (Strongyloides stercoralis and/or Schistosoma mansoni) was compared with that in HTLV-1 carriers not coinfected with helminths. Levels of interferon (IFN)- gamma were higher in HTLV-1 carriers not coinfected with helminths than in HTLV-1 carriers coinfected with helminths (P<.05). The overall frequency of IFN- gamma -expressing CD8+ and CD4+ cells was decreased in HTLV-1 carriers coinfected with helminths (P<.05). The percentage of interleukin (IL)-5- and IL-10-expressing T cells in HTLV-1 carriers coinfected with helminths was higher than that in HTLV-1 carriers not coinfected with helminths (P<.05). Moreover, we found that the prevalence of helminthic infection was 7-fold higher in HTLV-1 carriers than in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (P<.05). These data show that helminthic infection decreases activation of type 1 cells, which may influence the clinical outcome of HTLV-1 infection.     

Central nervous system activation of the indoleamine-2,3-dioxygenase pathway in human T cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis

Human T cell lymphotropic virus type I (HTLV-I) is associated with a chronic neurologic disease called HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The potential mechanisms of HAM/TSP pathogenesis were assessed by examination of 2 pathways initiated by interferon-gamma, a predominant cytokine in HAM/TSP. Jamaican HAM/TSP patients (n=17) were compared with patients with other neurologic diseases (ONDs; n=13) with respect to cerebrospinal fluid levels of the following: neopterin; nitrite plus nitrate, a stable indicator of nitric oxide; and tryptophan and kynurenine, metabolites of the indoleamine-2,3-dioxygenase (IDO) pathway. HAM/TSP patients had significantly elevated levels of neopterin (P=.003) and kynurenine (P=.05) and a significantly decreased level of tryptophan (P=.003), compared with patients with ONDs. These results support immune activation within the central nervous system and activation of the IDO pathway. Thus, activation of the IDO pathway may play a role in HAM/TSP.     

Human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis in an HIV-positive patient coinfected with human T lymphotropic virus type 2 following initiation of antiretroviral therapy.

We describe a patient coinfected with human immunodeficiency virus (HIV) and human T lymphotropic virus type 2 in Spain who developed paraparesis resembling human T lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis shortly after initiation of highly active antiretroviral therapy, hypothetically as the result of an immune reconstitution inflammatory syndrome.     

Human T cell lymphotropic virus type I (HTLV-I) p12I is dispensable for HTLV-I transmission and maintenance of infection in vivo

The function of the p12(I) protein of human T cell lymphotropic virus type I (HTLV-I) has been under debate. p12K (lysine) and p12R (arginine) variants of this protein at amino acid 88 and a shorter life of p12K had been reported by another group. Because HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients usually have a higher provirus load than asymptomatic HTLV-I carriers (ACs), and p12(I) had been suggested to confer a proliferative effect on HTLV-I-infected cells in vitro, it is possible that the relatively unstable p12K is less frequent in HAM/TSP patients than in ACs. To elucidate whether p12K and other alterations in the p12 gene were related to the outcome of HTLV-I infection, we sequenced the p12 gene in 144 HAM/TSP patients, 41 adult T cell leukemia (ATL) patients, and in 46 ACs. p12K was observed in only two HAM/TSP patients, but was not present in either ATL patients or ACs. Interestingly, a premature termination codon in the p12 was observed in 5.6% of HAM/TSP patients and in 4.9% of ATL patients but none was found in ACs. The p12 initiation codon was destroyed in one HAM/TSP patient. These HTLV-I variants with truncated p12 protein or with a destroyed initiation codon in the p12 gene appeared to have been transmitted in the subjects' families. These findings suggest that p12 is dispensable for the transmission and maintenance of HTLV-I infection, although it is premature to conclude that sequence varitation in the p12 gene is associated with differences in the outcome of HTLV-I infection.     

Reduced Tim-3 expression on human T-lymphotropic virus type I (HTLV-I) Tax-specific cytotoxic T lymphocytes in HTLV-I infection

T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) and programmed cell death-1 (PD-1) are T cell exhaustion molecules. We investigated the expression of Tim-3 and PD-1 in human T-lymphotropic virus type I (HTLV-I) infection. Tim-3 expression, but not PD-1 expression, was reduced on CD4(+) and CD8(+) T cells of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and HTLV-I carriers as compared with healthy controls. Tim-3 expression was also reduced in HTLV-I Tax-specific cytotoxic T lymphocytes (CTLs) as compared with cytomegalovirus-specific CTLs. Tim-3(+), but not PD-1(+), Tax-specific CTLs produced less interferon-γ and exhibited low cytolytic activity. However, we observed no difference in the expression of Tim-3 or cytolytic activity between Tax-specific CTLs of HAM/TSP patients or carriers. Moreover, HTLV-I-infected CD4(+) T cells showed decreased Tim-3 expression. These data suggest that Tim-3 expression is reduced in HTLV-I infection and that a high number of Tim-3(-) HTLV-I-specific CTLs preserves their cytolytic activity, thereby controlling viral replication.     

Remarkable increase in CD26-positive T cells in patients with human T lymphotropic virus type I (HTLV-I) associated myelopathy.

We used two-color flow cytometric analysis to investigate CD26+ (Ta1+) cells in peripheral blood T lymphocytes from patients with human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy (HAM). The percentage of CD26+ cells among CD3+ cells was markedly increased in patients with HAM, compared with anti-HTLV-I seropositive carriers (p < 0.001) and seronegative controls (p < 0.01). Within the subpopulation of T cells, a significantly high percentage of CD26+ cells was detected in both CD4+ and CD8+ cell populations. Furthermore, analysis of HLA-DR+ T cells revealed similar results. In contrast CD4+CD45RA+ cells were significantly decreased in comparison with controls. These results suggest that immunologically activated or memory T cells found in peripheral blood may be etiologically relevant to HAM.     

Human T cell leukemia virus type I-associated myelopathy in a patient with systemic lupus erythematosus.

A case of human T cell leukemia virus type I (HTLV-1) associated myelopathy (HAM)/tropical spastic paraparesis (TSP) with 14-year history of systemic lupus erythematosus (SLE) is reported. For 9 years, the numbness of the feet and sacral region progressed with occasional urinary incontinence and constipation. She was admitted to hospital due to gait disturbance and aggravation of SLE and the diagnosis of HAM/TSP was confirmed, indicating that HTLV-1 infection is associated with the development of not only HAM/TSP but also SLE.