High frequencies of functionally competent circulating Tax-specific CD8+ T cells in human T lymphotropic virus type 2 infection.

Human T lymphotropic virus type 2 (HTLV-2) is characterized by a clinically asymptomatic persistent infection in the vast majority of infected individuals. In this study, we have characterized for the first time ex vivo specific CTL responses against the HTLV-2 Tax protein. We could detect CTL responses only against a single HLA-A*0201-restricted Tax2 epitope, comprising residues 11-19 (LLYGYPVYV), among three alleles screened. Virus-specific CTLs could be detected in most evaluated subjects, with frequencies as high as 24% of circulating CD8(+) T cells. The frequency of specific CTLs had a statistically significant positive correlation with proviral load levels. The majority of virus-specific CD8(+) T cells exhibited an effector memory/terminally differentiated phenotype, expressed high levels of cytotoxicity mediators, including perforin and granzyme B, and lysed in vitro target cells pulsed with Tax2((11-19)) synthetic peptide in a dose-dependent manner. Our findings suggest that a strong, effective CTL response may control HTLV-2 viral burden and that this may be a significant factor in maintaining persistent infection and in the prevention of disease in infected individuals.

Reduced expression of excitatory amino acid transporter 2 and diffuse microglial activation in the cerebral cortex in AIDS cases with or without HIV encephalitis.

To determine the relationship between the human immunodeficiency virus type 1 (HIV-1) encephalitis (HIVE) and diffuse poliodystrophy in the acquired immunodeficiency syndrome dementia complex, we examined the neuropathologic features in brain autopsy tissue specimens of HIV-1-infected patients with (n = 11) or without HIVE (n = 9). The brains were free of opportunistic diseases and major cerebrovascular lesions. In both groups, there was diffuse microglial activation, astrocytic gliosis, and decreased excitatory amino acid transporter 2 (EAAT-2) immunoreactivity. These changes did not correlate either with the severity of encephalitis or local HIV-1 infection as detected by p24 immunostaining. Some activated microglia expressed EAAT-2; interleukin-1beta and tumor necrosis factor were detected only in microglial nodules of HIVE cases but not in areas with diffusely activated microglia. There was a significant negative correlation between the areas of EAAT-2 expression and numbers of activated microglia (p < 0.01) in cases with decreased EAAT-2. These data indicate that diffuse cortical changes may occur independently of HIVE in acquired immunodeficiency syndrome patients. The expression of EAAT-2 by activated microglia suggests that they might exert a compensatory effect that protects neurons from glutamate neurotoxicity.

In vivo expression of proinflammatory cytokines in HIV encephalitis: an analysis of 11 autopsy cases.

As the pathogenesis of AIDS dementia complex (ADC), cytokines such as TNF-alpha and IL-1beta have been thought to have toxic effects on CNS cells and induce neuronal cell death. However, many of the discussions have been based on the studies done by in vitro experiments. There are only a few reports which demonstrate proinflammatory cytokines directly in vivo in HIV encephalitis (HIVE) brains, and roles of these cytokines with relation to HIV-1 infection are not yet clarified. In the present study, we examined 11 autopsy cases of HIVE using immunohistochemistry, and explored which cell types expressed these cytokines and whether expression of cytokines was related to viral infection. IL-1beta was detected in the frontal white matter of all 11 cases where microglial nodules were observed to varying degrees, whereas TNF-alpha was detected in seven cases. IL-1beta- or TNF-alpha-positive cells were almost restricted to CD68-positive macrophages/microglia and mild expression of these cytokines by astrocytes was observed in two cases with severe HIVE. IL-1beta was detected in some HIVp24-positive multinucleated giant cells. However, we could not detect TNF-alpha expression in the HIVp24-positive cells, which indicates that IL-1beta is induced by HIV-1 infection. In conclusion, a macrophage/microglia lineage is the main cell type to release cytokines in HIVE, and IL-1beta expression by HIV-1-infected cells may be one of the important factors for induction of HIVE. In addition, many non-infected macrophages/microglia as well as some astrocytes express IL-1beta and TNF-alpha, which might contribute to pathogenesis of ADC.

Reusable and environmentally friendly ionic trinuclear iron complex catalyst for atom transfer radical polymerization.

Ionic iron complex [(Me(3)tacn)(2)Fe(2)Cl(3)](+)[(Me(3)tacn)FeCl(3)](-) (1), which is readily soluble in methanol, acted as a powerful catalyst in controlled radical polymerization of styrene and MMA, and showed promising features of removal from the resulting polymers and was reusable after recovery from the crude products.

A clinical study of adult human parvovirus B19 infection.

OBJECTIVE: We investigated the clinical aspects of adult human parvovirus (HPV) B19 infection. PATIENTS AND METHODS: We retrospectively reviewed the charts of 21 consecutive patients [4 males, aged 32 to 43 years (average 38.0 years), and 17 females, aged 15 to 43 (average 34.2)] with adult HPV B19 infection who visited our outpatient department between July 1997 and June 1998. All diagnoses of adult HPV B19 infection were based on positive anti-HPV B19 IgM antibody in serum and/or positive HPV B19 DNA in peripheral blood. RESULTS: The predominant signs and symptoms of the patients were: fever (81.0%), arthralgia/myalgia (61.9%), skin rash (47.6%), general fatigue (42.9%), lymph node swelling (38.1%) and edema (38.1%). Six patients had the following underlying diseases or complications: pregnancy, myoma uteri, cervical cancer of the uterus, lupus diathesis/ endometriosis, hereditary spherocytosis, and multiple sclerosis. The following abnormal laboratory findings (more or less than normal limits) were observed: anemia (81.0%), leukopenia (33.3%), elevated transaminases (28.6%), and elevated lactate dehydrogenase (LDH) (57.1%). Six patients were considered to have persistent infection. CONCLUSION: HPV B19 can infect healthy adults and causes more predominant signs and symptoms (arthralgia, myalgia and fever) than in children, and adult HPV B19 infection can be suspected from the familial history and clinical findings. Accordingly, more attention must be paid to adult HPV B19 infection, particularly when erythema infectiosum is prevalent in children.

[Intradural recurrence of multiple myeloma during the hematological complete remission].

In December 1997, a 55-year-old man presented with left-sided back and arm pain. Pretreatment examination revealed IgG-lambda type M-protein, Bence-Jones protein and the posterior mediastinum tumor. Bone marrow examination revealed hypercellular marrow with 73.6% plasma cells. He was diagnosed as having multiple myeloma with extramedullary lesion. As a result of VAD, MP, interferon and radiation therapy, he had a hematological complete remission. After 21 months, he developed intradural relapse at cauda equina and cerebrum. Many plasma cells and IgG-lambda type M-protein were detected in the cerebrospinal fluid. Laboratory examinations showed a complete remission except for cerebral and meningeal involvement. The myeloma cells might have infiltrated the intradural space at diagnosis and expanded in the central nervous system despite chemotherapy. Because reported cases with cerebral and meningeal myeloma are increasing according to the recent advance of treatment, we must pay attention to the meningeal myeloma.

The nuclear import of the human T lymphotropic virus type I (HTLV-1) tax protein is carrier- and energy-independent.

HTLV-1 is the etiologic agent of the adult T cell leukemialymphoma (ATLL). The viral regulatory protein Tax plays a central role in leukemogenesis as a transcriptional transactivator of both viral and cellular gene expression, and this requires Tax activity in both the cytoplasm and the nucleus. In the present study, we have investigated the mechanisms involved in the nuclear localization of Tax. Employing a GFP fusion expression system and a range of Tax mutants, we could confirm that the N-terminal 60 amino acids, and specifically residues within the zinc finger motif in this region, are important for nuclear localization. Using an in vitro nuclear import assay, it could be demonstrated that the transportation of Tax to the nucleus required neither energy nor carrier proteins. Specific and direct binding between Tax and p62, a nucleoporin with which the importin beta family of proteins have been known to interact was also observed. The nuclear import activity of wild type Tax and its mutants and their binding affinity for p62 were also clearly correlated, suggesting that the entry of Tax into the nucleus involves a direct interaction with nucleoporins within the nuclear pore complex (NPC). The nuclear export of Tax was also shown to be carrier independent. It could be also demonstrated that Tax it self may have a carrier function and that the NF-kappaB subunit p65 could be imported into the nucleus by Tax. These studies suggest that Tax could alter the nucleocytoplasmic distribution of cellular proteins, and this could contribute to the deregulation of cellular processes observed in HTLV-1 infection.

Simian immunodeficiency virus encephalitis in the white matter and degeneration of the cerebral cortex occur independently in simian immunodeficiency virus-infected monkey.

Highly active antiretroviral therapy (HAART) has been successful to reduce progression of acquired immunodeficiency syndrome (AIDS). Nevertheless, recent autopsy analysis of the brain from patients with human immunodeficiency virus (HIV)-1 infection reported same or even increasing numbers of AIDS encephalopathy. This insufficient effect of HAART for central nervous system (CNS) complication might be explained by independent pathogenetic processes in lymph node and CNS. We inoculated macaques with three Simian immunodeficiency virus (SIV) strains and investigated relationship between degree of the lymph node pathology and that of AIDS-related brain pathology. Animals infected with T-cell-tropic viruses SIVmac239 and SHIV-RT developed typical AIDS pathology in the lymph node 46 to 156 weeks after infection. The cerebral cortex of these animals showed focal or diffuse gliosis, and electron microscopic analysis demonstrated degenerative changes, such as accumulation of dense lamellar bodies in the dendrites and swelling of astrocytic processes. However, there was no evidence of microglial nodules or multinucleated giant cells in the white mater. The animals infected with macrophage-tropic SIV239env/MERT did not develop lymph node pathology of AIDS in the same or longer period of infection. The white mater of the animal, however, showed microglial nodules with multinucleated giant cells, a pathological hallmark of AIDS encephalopathy. SIV immunoreactivity was demonstrated in these giant cells as well as macrophage/microglia cells. On the other hand, there was no abnormality in the cerebral cortex. These findings suggest that there are two independent pathogenetic processes in AIDS encephalopathy: immune response against virus infected macrophage/microglial cells in the white mater without immunodeficiency and cortical degeneration caused in the late stage of AIDS.