The human T lymphotropic virus type I (HTLV-I) is associated with 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). Other viruses such as human herpes virus 6 (HHV-6) and a recently described human endogenous retrovirus has also been associated with MS. An understanding of the pathogenesis of a neurologic disease with a known viral etiology will aide in defining similar mechanisms of pathogenesis in MS, a disease of unknown etiology. Areas of research addressing these neurovirological and neuroimmunological issues include: 1) the host immune response in HAM/TSP; in particular, the role of CD8+, HTLV- I-specific, HLA class I-restricted cytotoxic T lymphocytes (CTL) and the role that cytokines and chemokines play in this disorder; 2) the in situ detection of these immunopathogenic CTL, as well as, the localization of human retroviral sequences in the central nervous system and lymphoid organs of HAM/TSP patients; 3) the generation of transgenic mice expressing HTLV-I gene products under an astrocyte-specific promoter; 4) the detection of HHV-6 and an MS-associated retrovirus in patients with MS; 5) immunotherapeutic strategies for the treatment of HAM /TSP. The major findings of these studies are; 1) the demonstration of a high frequency of CD8+, CTL directly isolated from PBL and the capacity for these cells to produce high levels of TNF-alpha and IFN- gamma by the in situ expression of cytokines using intracellular staining techniques; 2) the detection of HLA A2-restricted, HTLV-I tax peptide-specific T cells in PBL and CSF of HAM/TSP patients by T cell receptor-specific oligonucleotide PCR amplification; 3) identification of altered peptide ligands which have been shown to specifically interfere with antigen-specific CTL clones; 4) the HTLV-I tax-specific induction of cytokines and co-stimulatory molecules in astroglioma-HTLV- I tax transfectants; 5) the generation of a transgenic mouse colony in which the HTLV-I tax gene is expressed under control of an astrocyte- specific promoter (GFAP). HTLV-I tax has been demonstrated in the CNS of these mice; 6) HHV-6 has been demonstrated in the serum of MS patients by a specific increase in HHV-6 IgM and the detection of HHV-6 DNA by nested PCR. A correlation between HHV-6 serum DNA and gadolinium-enhancing lesions by MRI has been shown in one patient; 7) the demonstration of a recently described human retrovirus MSRV in MS PBL and serum has begun; 8) a phase I/II clinical trial of humanized anti-IL2 receptor antibody in the treatment of HAM/TSP has enrolled 10 of 15 HAM/TSP patients. Inhibition of some immune functions have been observed with a clear decrease in HTLV-I viral load as determined by Southern blot analysis and quantitative PCR. Collectively, these results continue to define the role of human viruses that are associated with chronic-progressive neurological disease.
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