HTLV-1 proviral load in cerebrospinal fluid may not be a good marker to differentiate asymptomatic carriers with high proviral load in blood from HAM/TSP patients.

An elevated human T cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is an important risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), although there is a considerable frequency of asymptomatic carriers (AC) with high PVL in blood. Our objective was to evaluate whether PVL quantified in cerebrospinal fluid (CSF) is helpful to distinguish AC from HAM when AC have high PVL in blood (ACH). ACH (n = 7) were characterized to have high PVL in blood by quantification of samples collected over time (mean 7 years). HAM patients (n = 14) also had analyzed blood samples collected at different times (mean 9 years). Comparing paired CSF and blood samples of each individual, CSF PVL mean was 4.7-fold higher than blood PVL in the ACH group and 10.8-fold in the HAM group. CSF PVL was significantly greater than blood PVL in the HAM group (p = 0.004), but not in the ACH group. Important to highlight, CSF PVL was not significantly different between the ACH and the HAM groups. These results suggested that significantly higher PVL in CSF than in blood is a hallmark of HAM/TSP patients, but this is also true for asymptomatic carriers with high PVL in blood, thus reducing its usefulness as a marker for HAM/TSP. A greater number of ACH should be analyzed, but whether they will eventually develop HAM/TSP or why they have not developed the disease are still questions to be clarified. Longitudinal studies are necessary to answer these questions.

Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage.

The degree of phosphorylation and phosphoethanolaminylation of lipid A on neisserial lipooligosaccharide (LOS), a major cell-surface antigen, can be correlated with inflammatory potential and the ability to induce immune tolerance in vitro. On the oligosaccharide of the LOS, the presence of phosphoethanolamine and sialic acid substituents can be correlated with in vitro serum resistance. In this study, we analyzed the structure of the LOS from 40 invasive isolates and 25 isolates from carriers of Neisseria meningitidis without disease. Invasive strains were classified as groups 1-3 that caused meningitis, septicemia without meningitis, and septicemia with meningitis, respectively. Intact LOS was analyzed by high resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Prominent peaks for lipid A fragment ions with three phosphates and one phosphoethanolamine were detected in all LOS analyzed. LOS from groups 2 and 3 had less abundant ions for highly phosphorylated lipid A forms and induced less TNF-α in THP-1 monocytic cells compared with LOS from group 1. Lipid A from all invasive strains was hexaacylated, whereas lipid A of 6/25 carrier strains was pentaacylated. There were fewer O-acetyl groups and more phosphoethanolamine and sialic acid substitutions on the oligosaccharide from invasive compared with carrier isolates. Bioinformatic and genomic analysis of LOS biosynthetic genes indicated significant skewing to specific alleles, dependent on the disease outcome. Our results suggest that variable LOS structures have multifaceted effects on homeostatic innate immune responses that have critical impact on the pathophysiology of meningococcal infections.

Detection of 14-3-3 protein in the CSF of genetic Creutzfeldt-Jakob disease.

The 14-3-3 protein, a protein involved in signal transduction, is present in the CSF of patients with Creutzfeldt-Jakob disease (CJD) and not in patients with other dementing diseases. We show here that this is also true for patients with E200K CJD, but not for healthy carriers of the mutation.

Active production of anti-human T-lymphotropic virus type I (HTLV-I) IgM antibody in HTLV-I-associated myelopathy.

We investigated the presence of anti-human T-lymphotropic virus type I (HTLV-I) IgM in sera and cerebrospinal fluid from patients with HTLV-I-associated myelopathy (HAM) by Western blot analysis. Analyses of 36 serum samples revealed that most patients (31/36; 86.1%) had anti-HTLV-I IgM, whereas only four of 23 (17.4%) HTLV-I carriers had it. In studies of cerebrospinal fluid, anti-HTLV-I IgM was detected in 24 of 36 (66.7%) HAM patients, whereas none was detected in nine HTLV-I carriers. The differences were statistically significant (p less than 0.01). These results suggest that persistent active replication of HTLV-I occurs in the central nervous system as well as in the peripheral blood of HAM patients, and may contribute to the development of HAM.

Tissue inhibitor of metalloproteinase 3, matrix metalloproteinase 9, and neopterin in the cerebrospinal fluid: preferential presence in HTLV type I-infected neurologic patients versus healthy virus carriers.

The human retrovirus HTLV-I is responsible for the chronic progressive myelopathy, TSP/HAM, characterized by the presence of infiltrated T lymphocytes, cytokines, and matrix metalloproteinases (MMPs) within spinal cord lesions. MMPs have been associated with several neurological diseases, and we previously reported the specific presence of the extracellular matrix-degrading protease, MMP-9, in the cerebrospinal fluid of TSP/HAM patients. Nevertheless, previous studies have not yet shown whether the expression of MMP-9 is associated with HTLV-I infection per se, or with neurological symptoms following infection. In the present work, the presence of tissue inhibitors of metalloproteinases 1 and 3 (TIMP-1 and TIMP-3) and of MMP-9 in the CSF of HTLV-I-infected individuals was compared in TSP/HAM patients versus HTLV-I carriers without neurological symptoms. TIMP-3, a regulator of MMP activity and cell survival, was detected with a significantly higher frequency in the TSP/HAM group and paralleled the increased levels of MMP-9 and neopterin, a sensitive indicator of cellular immune activation. These data may reflect the intense cell remodeling that occurs intrathecally in inflamed tissue. Changes in MMP, TIMP, and neopterin expression were not related to age at onset of disease, grade of motor disability, progressor status, or duration of disease, presumably indicating that TSP/HAM patients are continuously subjected to viral and immunological pressure. All these observations suggest that TIMPs and MMPs may contribute to the pathogenesis of TSP/HAM, and hence a new therapeutic strategy targeting the MMP/TIMP balance is needed. These observations also suggest that MMP-9 and TIMP-3 in CSF may be useful markers in the follow-up of the efficacy of therapeutic trials in TSP/HAM patients.

Aberrant immunity in the central nervous system in relation to disease progression in HAM/TSP.

The immunological status of the central nervous systems of 19 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was distinct from that of 6 asymptomatic HTLV-I carriers. Cross-sectional analysis of the time course of disease-related abnormalities in the cerebrospinal fluid (CSF) showed that activated B cell function was a feature in relatively early HAM/TSP patients in whom duration of the disease was less than 5 to 6 years. During this period many patients experienced notable neurological deterioration. By contrast, an increase in CD8+CD11a+ cytotoxic T lymphocytes along with elevated beta 2-microglobulin levels in the CSF was a consistent finding in early as well as late patients with more than a 10-year history of the illness. In light of the generally progressive course of this disorder, the mode of immunity related to the pathogenesis of HAM/TSP may be different according to the stages of the disease.

The central nervous system as a reservoir for simian immunodeficiency virus (SIV): steady-state levels of SIV DNA in brain from acute through asymptomatic infection.

Latent reservoirs of human immunodeficiency virus (HIV) present significant challenges for eradicating HIV from infected persons, particularly reservoirs in the brain established during acute infection. A simian immunodeficiency virus (SIV)/macaque model of HIV dementia was used to show that viral DNA levels in the brain remained at constant levels from acute through asymptomatic infection, despite significant down-regulation of viral RNA in the brain after the acute phase of infection. Viral replication in the brain coincided with activation of macrophages and microglia in the central nervous system; down-regulation of viral replication coincided with increased infiltration of cytotoxic lymphocytes and reduced activation of macrophages and microglia in the brain. Comparison of viral genotypes in the central nervous system and peripheral blood mononuclear cells suggests that recrudescence of viral replication in brain occurs by reactivation of latent viral DNA. Latent virus in the brain must be considered in therapeutic strategies to eliminate HIV from infected persons.