The human T lymphotropic virus type I (HTLV-I) is the etiologic agent of a chronic progressive myelopathy known as HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease clinically similar to the chronic progressive form of multiple sclerosis (MS). An understanding of the pathogenesis of a neurologic disease with a known viral etiology (HTLV-I and HAM/TSP) will aid in defining similar mechanisms of pathogenesis in MS, a disease of unknown etiology in which viruses have been suspected to play a role. Additionally, other viruses have also been associated with MS and particular attention has recently focused on ubiquitous human herpesvirus (HHV-6). Investigative research on this agent in MS has led to the study of other disorders that may also be associated with viruses including epilepsy, neurological complications following allogeneic bone marrow transplant, and encephalitis. The major findings of these 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. 3) 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. These results suggest that direct human retroviral infection of CD4+CD25+ T cells may be associated with the pathogenesis of HTLV-I associated neurologic disease through the dysregulation of CD4+CD25+ regulatory T cells. 4) We have also demonstrated that the HTLV-I tax gene inhibits expression of Foxp3 by a mechanism that blocks TGF-beta signalling. Since TGF-b signalling has been shown to be critical for both Foxp3 expression and Treg function, we have also shown that this signalling pathway was dysregulated in HAM/TSP patients. We found that levels of Smad7 (a TGF-beta-inducible gene) and TGF-beta receptor II (TGF-bRII) in CD4+ T cells were significantly reduced in patients with HAM/TSP compared to normal donors. Furthermore, expression of TGF-bRII inversely correlated with the proviral load. Importantly, CD4+CD25+ and CD4+CD25- T cells from HAM/TSP patients exhibited reduced TGF-bRII expression compared to normal donors, which was associated with functional deficits in vitro, including loss of Treg suppressor function and escape of effector T cells from Treg-mediated control. This evidence suggests that a virus-induced breakdown of immune tolerance affecting both regulatory and effector T cells contributes to the pathogenesis of HAM/TSP. 5) An understanding of the role of regulatory T cells in HAM/TSP had led to the analysis of this T cell subset in patients with MS. Using assays and approaches developed in the HTLV-I - HAM/TSP system, we cannot demonstrate an alteration in the T regulatory cells (either in number or in function) in the peripheral blood of MS patients compared to healthy controls. However, in a clinical trial with humanized anti-IL2 receptor (daclizumab) in MS, we have observed a significant reduction in this important regulatory population in all patients treated. In addition, a surprising number of daclizumab-treated MS patients have manifested skins lesions and attempts are currently underway to determine if this clinical observation is related to the disregulation of T regulatory cells. 6) 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. 7) 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. 8)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 ben 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. Collectively, these studies continue to define the role of human viruses that are associated with chronic progressive neurologic disease.
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