The major findings of our HTLV-I studies have been: 1) Increased HTLV-I specific CD8+ cells have been shown to be elevated in the peripheral blood and CSF of HAM/TSP patients and directly proportional to the amount of HTLV-I proviral DNA and RNA. These antigen-specific T cells are considered to be immunopathogenic and may be directly involved in virus-host interactions in the CNS. 2) Direct observations of these antigen-specific CD8+ T cells in spinal cord sections of HAM/TSP together with HTLV-I infected CD4+ cells have been demonstrated and support a role for these cyotoxic effector cells in the pathogenesis of this disorder. 3) As another marker of cytoxicity, we demonstrated that spontaneous degranulation and IFN-gamma production (defined by CD107+ IFN-gamma+ cells) was correlated with proviral DNA load in CD14+ macrophages from HTLV-I-infected patients, and that enhanced IL-15 expression on CD14+ cells mediated the dysregulation of CD8+ T cells in HAM/TSP patients. The observation of HTLV-I infected macrophages is novel and suggests a wider tropism for this virus than previously reported. The effect of HTLV-I on CD14+ macrophages is also being investigated. 4) CD4+CD25+ regulatory T cells are important in the maintenance of immunological self-tolerance and in the prevention of autoimmune diseases. We have demonstrated that in HTLV-I infected CD4+CD25+ T cells of patients with HAM/TSP the expression of the forkhead transcription factor Foxp3, a specific marker of regulatory T cells, was lower than that of healthy individuals. We have shown reduced protein expression of Fox-P3 positive T regulatory cells in patients with HAM/TSP. We also have demonstrated that HTLV-I tax had a direct inhibitory effect for the Foxp3 expression and inhibited the regulatory function of these cells. 5) Basic laboratory investigations have demonstrated the importance of the cytokine IL-15 in the life and death of lymphocytes and for its role in autoimmune disorders such as HAM/TSP. IL-15 is pivotally involved in the survival of CD8+ memory T-cells including self-directed cells and we have shown that in HAM/TSP, IL-15 is essential for the survival of HLA class I restricted virus antigen-specific effector and memory CD8+ T-cells. These CD8+ antigen-specific CTL are thought to play a major role in the immunopathogenesis of HAM/TSP since they have been localized in brain and spinal cord sections of patients. As IL-15 is a pro-inflammatory cytokine that stimulates the production of TNFα, IL-1βand other inflammatory cytokines, the release of IL-15 induced by HTLV-I tax in patients with HAM/TSP may underlie the pathogenesis of this autoimmune disease. The mode of action of IL-15 and its receptor subunits IL-15 and IL-15Ralpha are coordinately stimulated and expressed following HTLV-I tax stimulation. We have shown that this trans-stimulation can be virtually totally inhibited for NK and CD8+ T-cells by the addition of a humanized monoclonal antibody, Hu MiK-β1, that blocks IL-15 binding to the IL-2/IL15Rβreceptor subunit expressed on these cells. Collaborative research by the Viral Immunology Section, NINDS and the Metabolism Branch, NCI have initiated a phase I clinical trial for the treatment of HAM/TSP using Hu MiK-beta-1 that blocks the action of IL-15. 6) The HTLV-I induced activation of nuclear factor kappa B (NFκB ) is considered a key event in the leukemogenesis leading to ATLL, but less has been demonstrated regarding the role of NFκB activation in the pathogenesis of HAM/TSP. Herein we show evidence of both canonical and non-canonical NFκB activation in short-term cultures of PBMC from subjects with HAM/TSP, in the absence of exogenous stimulation. We show that the NFκB activation in HAM/TSP PBMC can be reversed by small molecule inhibitors. Inhibition of NFκB activation in HAM/TSP PBMC resulted in the inhibition of STAT5 activation and spontaneous lymphoproliferation, two ex vivo correlates of the immune activation associated with HAM/TSP. These results indicate that NFκB activation plays a critical upstream role in the immune activation associated with HAM/TSP, and identify the NFκB pathway as a potential target for immune modulation in HAM/TSP. 7) Using a genomic SNP analysis of a unique cohort of clinically and radiologically well-characterized MS patients enrolled in a BioMS biomarker study, we are identifying regions of the human genome that may be specific for MS versus a general, healthy population. In addition, we are identifying SNPs that may define subsets of MS patients with high burden of disease as measured by MRI. Once these SNPs are validated on additional MS patient cohorts, we will begin laboratory investigations to determine if gene products of these genomic regions will be informative biomarkers for this disease. 8) We continue to extend our work on the detection of the human herpesvirus (HHV-6) from brain resections of patients with mesial temporal lobe epilepsy and patients with neurologic complications following allogeneic bone marrow transplants. We have isolated this virus from explanted primary astrocyte cell cultures and have shown a dysregulation of glutamate uptake in HHV-6 infected astrocyte cell lines. As there are a number of antiviral HHV-6 compounds currently available we have shown that these drugs have different sensitivities in HHV-6 infected glial cells compared to virus-infected lymphocytes. These data suggest that different treatment strategies should be considered when trying to clear this virus from the periphery or the CNS. We have utilized quantitative real-time PCR for the detection of HHV-6 sequences and developed a novel electrochemiluminescent ELISA method for the quantitative detection of antibodies to HHV-6 IgG. We have screened large panels of sera from patients with MS, encephalitis and controls. Preliminary results suggest significantly more HHV-6 DNA in patients with encephalitis of unknown origin than previously reported. 9) Since HHV-6 is a neurotropic virus that has been associated with a wide variety of neurologic disorders including encephalitis, mesial temporal lobe sclerosis, and multiple sclerosis we have been interested in the route of central nervous system (CNS) entry this virus takes. Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/tract region was elevated compared to other brain regions examined. Given this, we investigated whether HHV-6 may infect the CNS via the olfactory pathway. The specialized olfactory ensheathing glial cells (OECs) that are located in the nasal cavity were demonstrated to support HHV-6 replication in vitro. Furthermore, HHV-6 DNA was detected in a high frequency (41.3%) of nasal mucous samples, showing the nasal cavity is a possible reservoir for HHV-6. These results support HHV-6 utilization of the olfactory pathway as a route of entry into the CNS. 10)A number of laboratory studies have demonstrated that virus infection can activate a variety of CNS-specific cells including microglia and astrocytes. The VIS has investigated the effects of both a human retrovirus (HTLV-I) and herpesvirus (HHV-6) in these cell populations, in vitro. We are attempting to translate these observations to the patient by imaging studies that can detect activated microglia/macrophage and reactive astrocytes. In collaboration with the Molecular Imaging Branch, NIMH, we have begun to investigate the expression of the peripheral benzodiazepine receptor (PBR) in the CNS that has been show be a marker of activated microglia/macrophage and reactive astrocytes. Collectively, these studies continue to define the role of human viruses that are associated with chronic progressive neurologic disease.

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