Human Retrovirus Associated With Chronic Neurologic Dis

Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

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: I) The host immune response to viruses from patients with HAM/TSP and MS with particular focus on virus-specific CD8+ cells and the definition of new viral epitopes recognized by these cells; II) The role of HHV-6 in the pathogenesis of MS and other chronic neurological disorders of the central nervous system; III) Immunotherapeutic strategies for the treatment of HAM/TSP. The major findings of these studies are: 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. Novel immunological methods for the detection of antigen-specific CD8+ cells have been developed based on the capacity of T cells to acquire MHC/peptide complexes. In this manner, new regions within the HTLV-I envelope gene have been defined that can serve as targets for HTLV-I specific T cells. In addition, the stage of maturation of these T cells has been analyzed with respect to phenotypic markers and function. Unlike CMV specific CTL which have a predominantly effector T cell phenotype, HTLV-I CD8+ T cells are memory cells which upon activation rapidly mature into effector cells. 2) We have completed recruitment of HAMTSP patients for a clinical trial of recombinant interferon b1a in HAM/TSP. We have demonstrated a reduction in both HTLV-I tax11-19 specific and CMV peptide specific CD8+ T cells and HTLV-I induced spontaneous lymphoproliferation during and after treatment in the absence of a reduction in HTLV-I proviral load. These results suggest a more global affect of interferon ?b1a in patients with neurologic disease. We continue to actively pursue a detailed analysis of patients and controls with an HTLV-I seroindeterminate Western blot and can demonstrate that such reactivities represent exposure to prototype HTLV-I. This is confirmed at both the molecular level and reactivity of patients PBMC with HTLV-I specific tetramers. We have intitated a serum proteomic profiling analysis of patients with HAM/TSP, adult T cell leukemia, and controls and can demonstrate unique signatures that discriminate patients from controls. In addition, specific protein peaks have been identified and characterized. The application of this technology will be expanded to other neurologic diseases including MS. 3) Using novel TCR-like antibodies, we have detected MHC-viral peptide complexes on PBMC from HAM/TSP patients. Moreover, we have shown that a subset of CD4+ T cells (CD4+CD25+) express such complexes and also contain the highest HTLV-I viral load. As this subset has been shown to have T cell regulatory capabilities, we will investigate if infection of such cells leads to disregulation of the immune response in patients with HAM/TSP. 4) We have shown that cells from brain resections of patients with mesial temporal lobe epilepsy that are phenotypically defined as astrocytes react with HHV-6 specific antibodies. No such reactivity was seen in patients with neocortical epilepsy. We have successfully infected human progenitor derived astrocytes with both variants of HHV-6 with vastly different outcomes. Studies are currently underway to infect primary human glial cells with HHV-6. Collectively, these results continue to define the role of human viruses that are associated with chronic progressive neurologic disease.