INVOLVEMENT OF HUMAN RETROVIRUS ASSOCIATED WITH CHRONIC NEUROLOGIC DISEASE

Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

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 type 6 (HHV-6) have also been associated with MS. An understanding of the pathogenesis of a neurologic disease with a known viral etiology will aid 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 to viruses from patients with HAM/TSP and MS and role that cytokines and chemokines may play in these disorders; 2) The role of HHV-6 in the pathogenesis of MS. 3) Immunotherapeutic strategies for the treatment of HAM/TSP. The major findings of these studies are; 1) High frequencies of memory CD8+ HTLV-I tax specific T cells in PBL and CSF of HAM/TSP could be detected ex vivo by use of HLA A2/immunoglobulin chimeras and HLA A201 tetramers. 2) The frequency of these cells correlate with HTLV-I proviral load as assessed by PCR Taqman technology for both DNA and RNA. 3) Spontaneous lymphoproliferation of PBMC from HAM/TSP patients previously thought to be predominantly in CD4+ cells have also been shown to be in CD8+ cells. 4) Elevated levels of cytokines and chemokines, particularly IL-15, have been demonstrated in serum of HAM/TSP patients relative to healthy controls and carriers by a novel HPLC technique termed recycling immunoaffintiy chromatography. 5) HHV-6 DNA sequences can be demonstrated in the serum and urine of MS patients which are predominantly of the neurotropic HHV-6A variant. Correlations with MS clinical activity have been demonstrated. 6) Increased lymphoproliferative responses have been demonstrated in MS PBL compared to normal controls to HHV6 strain A both in bulk cultures and at the precursor frequency level. The fine specificity of HHV-6 specific T cell clones are being investigated; 7) A clinical trial of recombinant interferon b1a has enrolled 5 patients for the treatment of HAM/TSP. A reduction in HTLV-I tax specific CD8+ cells has been observed. Collectively, these results continue to define the role of human viruses that are associated with chronic progressive neurologic disease.