Frequent clonal proliferation of human T-cell leukemia virus type 1 (HTLV-1)-infected T cells in HTLV-1-associated myelopathy (HAM-TSP).

Human T-cell leukemia virus type 1 (HTLV-1) integrates its proviruses into random sites in host chromosomal DNA. Random integration of the proviruses was observed in asymptomatic HTLV-1 carriers and patients with HTLV-1-associated myelopathy (HAM/TSP). However, clonal integration has been reported in patients with adult T-cell leukemia (ATL), including that in the smoldering, chronic, and acute states, indicating clonal expansion of infected cells. In this study, we found that about 20% of HAM/TSP patients and their seropositive family members harbored subpopulation(s) of clonally proliferated cells infected with HTLV-1, although they still maintained randomly infected cells as a major population. These clones were stable during examination periods of 4 months to 3 years. However, these carriers or HAM/TSP patients did not show any significant indication of ATL. This extremely high frequency of clonal expansion of HTLV-1-infected cells indicates that some clones of HTLV-1-infected cells have a tendency to proliferate more efficiently than the other population without malignant transformation.     

Antibodies to cardiolipin and beta2-glycoprotein-1 in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Anticardiolipin and anti-beta2GP1 antibodies were measured in 50 patients with HTLV-1-associated Myelopathy-Tropical Spastic Paraparesis (HAM-TSP) and the results were compared with those obtained for 34 HTLV-1-positive and 35 HTLV-1-negative controls, as well as 128 SLE patients. aCL but not anti-beta2GP1 was associated with HTLV-I infection. aCL was more prevalent than anti-beta2GP1 (32% vs. 8%) and was not associated with anti-beta2GP1 in HAM-TSP. IgA was the dominant isotype of aCL and anti-beta2GP1. The data suggest that tin HAM-TSP, IgA aCL are frequent and are associated with HTLV-1 infection.     

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.     

T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1): high prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM)

INTRODUCTION: HIV positive patients co-infected with HTLV-1 may have an increase in their T CD4+ cell counts, thus rendering this parameter useless as an AIDS-defining event. OBJECTIVE: To study the effects induced by the co-infection of HIV-1 and HTLV-1 upon CD4+ cells. MATERIAL AND METHODS: Since 1997, our group has been following a cohort of HTLV-1-infected patients, in order to study the interaction of HTLV-1 with HIV and/or with hepatitis C virus (HCV), as well as HTLV-1-only infected asymptomatic carriers and those with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). One hundred and fifty HTLV-1-infected subjects have been referred to our clinic at the Institute of Infectious Diseases "Emílio Ribas", S?o Paulo. Twenty-seven of them were also infected with HIV-1 and HTLV-1-infection using two ELISAs and confirmed and typed by Western Blot (WB) or polymerase chain reaction (PCR). All subjects were evaluated by two neurologists, blinded to the patient's HTLV status, and the TSP/HAM diagnostic was based on the World Health Organization (WHO) classification. AIDS-defining events were in accordance with the Centers for Disease Control (CDC) classification of 1988. The first T CD4+ cells count available before starting anti-retroviral therapy are shown compared to the HIV-1-infected subjects at the moment of AIDS defining event. RESULTS: A total of 27 HIV-1/HTLV-1 co-infected subjects were identified in this cohort; 15 already had AIDS and 12 remained free of AIDS. The median of T CD4+ cell counts was 189 (98-688) cells/mm(3) and 89 (53-196) cells/mm(3) for co-infected subjects who had an AIDS-defining event, and HIV-only infected individuals, respectively (p = 0.036). Eight of 27 co-infected subjects (30%) were diagnosed as having a TSP/HAM simile diagnosis, and three of them had opportunistic infections but high T CD4+ cell counts at the time of their AIDS- defining event. DISCUSSION: Our results indicate that higher T CD4+ cells count among HIV-1/HTLV-1-coinfected subjects was found in 12% of the patients who presented an AIDS-defining event. These subjects also showed a TSP/HAM simile picture when it was the first manifestation of disease; this incidence is 20 times higher than that for HTLV-1-only infected subjects in endemic areas.     

High frequencies of Th1-type CD4(+) T cells specific to HTLV-1 Env and Tax proteins in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis

CD4(+) T cells are critical for inducing and maintaining efficient humoral and cellular immune responses to pathogens. The CD4(+) T-cell response in human T-lymphotropic virus 1 (HTLV-1) infection has not been studied in detail. However, CD4(+) T cells have been shown to predominate in early lesions in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We present direct estimates of HTLV-1 Env- and Tax-specific CD4(+) T-cell frequencies in patients infected with HTLV-1. We first showed that there was a strong bias toward the Th1 phenotype in these HTLV-1-specific CD4(+) T cells in patients with HAM/TSP. We then demonstrated significantly higher frequencies of HTLV-1-specific Th1-type CD4(+) T cells in HAM/TSP patients than in asymptomatic HTLV-1 carriers. The majority of these HTLV-1-specific CD4(+) T cells did not express HTLV-1 Tax and were therefore unlikely to be infected by HTLV-1. High frequencies of activated HTLV-1-specific CD4(+) T cells of the Th1 phenotype might contribute to the initiation or pathogenesis of HAM/TSP and other HTLV-1-associated inflammatory diseases.     

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.     

Proviral load and the balance of serum cytocines in HTLV-1-asymptomatic infection and in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)

This study compared the proviral load and the plasma cytokine profiles (interleukin-IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) in 87 HTLV-1-infected individuals, including 28 with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), 32 with possible pHAM/TSP and 27 asymptomatic carriers (AC). The control group was composed by 21 HTLV-1-seronegative individuals. Our finding demonstrated that HAM/TSP group presented higher proviral load as compared to all other HTLV-1 groups (p < 0.0001). The HAM/TSP group showed higher serum concentration of IL-6 (p = 0.0009) as compared to all other groups. Moreover, higher serum concentration of IFN-γ (p = 0.0118) and IL-4 (p = 0.0166) were observed in HAM/TSP group as compared to the healthy controls. Additionally, the HAM/TSP group also showed higher serum concentration of TNF-α (p = 0.0239) and IFN-γ (p = 0.0118) as compared to AC. No differences in the serum concentration of IL-2 and IL-10 were observed among the groups. The analysis of cytokine balance demonstrated that HAM/TSP presented higher pro-inflammatory profile with enhanced IFN-γ/IL-10 and IFN-γ/IL-4 ratio as compared to AC and pHAM/TSP. Further analysis pointed out to a positive correlation between the IFN-γ response and the proviral load in AC. Conversely, a negative association between TNF-α and IL-2 with the proviral load was the hallmark of HAM/TSP group. These findings suggested that the proviral load and the pro-inflammatory cytokine profile may be independent events in the peripheral blood of HAM/TSP individuals. The knowledge about the existence of individual virological/immunological behavior upon HTLV-1 infection, may guide to the establishment of more effective therapeutic interventions.     

A refractory human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis patient with lymphoma-type adult T-cell leukemia/lymphoma: A case report and review of the literature

Rationale:Adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are caused by HTLV-1, but the coexistence of both disorders is rare. The estimated incidence is approximately 3%.Patient concerns:A 54-year-old man was unable to stand up because of spastic paraparesis 1 month after the onset. He developed lymphadenopathy in the left supraclavicular fossa 5 months after the onset. The spastic paraplegia and sensory symptoms below the thoracic spinal cord level worsened.Diagnoses:Both blood and cerebrospinal fluid (CSF) tests were positive for anti-HTLV-1 antibodies. The patient was diagnosed with rapidly progressive HAM/TSP. He was also diagnosed with lymphoma-type ATL by the biopsy specimen of the lymph node. CSF examination at the time of symptom exacerbation showed abnormal lymphocytes, suggesting central infiltration of the ATL in the central nervous system.Interventions:Methylprednisolone pulse therapy and oral prednisolone maintenance therapy were administered for rapidly progressive HAM/TSP. Intrathecal injection of methotrexate was administered for the suggested central infiltration of the ATL.Outcomes:Methylprednisolone pulse therapy and intrathecal injection of methotrexate did not improve the patient''s exacerbated symptoms. Five months later, clumsiness and mild muscle weakness of the fingers appeared, and magnetic resonance imaging showed swelling of the cervical spinal cord. Clonality analysis showed monoclonal proliferation only in the DNA of a lymph node lesion, but not in the CSF and peripheral blood cells.Lessons:This was a case of rapidly progressive HAM/TSP associated with lymphoma-type ATL that was refractory to steroids and chemotherapy. The pathogenesis was presumed to involve ATL cells in the brain and spinal cord because of the presence of abnormal lymphocytes in the CSF, but DNA analysis could not prove direct invasion. This case suggests that when we encounter cases with refractory HAM/TSP, it should be needed to suspect the presence of ATL in the background.     

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.     

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 cell leukemia virus Type I (HTLV-I) infection induces greater expansions of CD8 T lymphocytes in persons with HTLV-I-associated myelopathy/tropical spastic paraparesis than in asymptomatic carriers

A quantitative study of the T cell receptor repertoire was performed ex vivo on CD4 and CD8 T cell subsets of human T cell leukemia virus type I (HTLV-I)-infected asymptomatic carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Indexes of oligoclonality that compiled all repertoire modifications were calculated for peripheral blood mononuclear cells and for CD4 and CD8 T cell subsets. Both patients with HAM/TSP and asymptomatic carriers had greater T lymphocyte expansions than did uninfected donors, which was independent of age and at least twice higher in the CD8 than in the CD4 cell compartment. Some expanded CD8 T cells corresponded to cytotoxic T lymphocytes directed against various epitopes of the immunodominant Tax protein. Patients with HAM/TSP had significantly higher CD8 cell expansions than did asymptomatic carriers. These results highlight the prognostic value of measuring CD8 T cell expansions during follow-up of HTLV-I infection.     

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.     

Intrathecal synthesis of antibodies to human T lymphotropic virus type I and the presence of IgG oligoclonal bands in the cerebrospinal fluid of patients with endemic tropical spastic paraparesis

Tropical spastic paraparesis (TSP), a neuromyelopathy predominantly involving the pyramidal tract and commonly observed in tropical and equatorial areas, was recently found to be associated with human T lymphotropic virus type I (HTLV-I). We investigated sera and cerebrospinal fluid (CSF) from 19 patients with TSP who were from the Caribbean area, French Guiana, and Africa. Our results showed an elevated intra-blood-brain barrier IgG synthesis rate and an elevated IgG index, with an increased HTLV-I antibody-to-albumin ratio and the presence of CSF oligoclonal bands in the majority of the patients. These data, in association with similar HTLV-I antibody patterns between patients with TSP who were from these three regions, strengthen the probable etiologic role of HTLV-I in the pathogenesis of such chronic neuromyelopathies.     

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.