PATHOGENESIS OF HTLV-1 ASSOCIATED MYELOPATHY

Project: Research project

Description

Human T-cell leukemia virus type I (HTLV-I) has been implicated in both
human T-cell malignancy and in a chronic debilitating neurologic disorder
with similarities to multiple sclerosis, known as HTLV-I-associated
myelopathy (HAM). Although pathogenetic mechanisms are partially
understood in the context of HTLV-I-associated leukemia, the relationship
between HTLV-I infection and development of neurologic disorders is
unclear. We wish to explore possible mechanisms underlying HAM by
determining whether genetic and/or biological differences exist between
HTLV-I isolates obtained from the peripheral blood and cerebrospinal fluid
of HAM patients as compared to isolates obtained form asymptomatic carriers
or patients with leukemia. We will compare HTLV-I isolates in contexts
designed to minimize irrelevant biological variation, such as in a
transfusion recipient who developed HAM, compared to those obtained from
the asymptomatic HTLV-I-infected blood donor; from myelopathy patients and
uninfected patients in a recently identified highly infected, heavily
intermarried ethnic group; and in the cerebrospinal fluid as opposed to the
peripheral blood of a single HAM patient. We will determine whether these
HTLV-I isolates can replicate transiently or stably in cell lines/cultures
derived from tissues of human central nervous system origin. We will
compare levels of HTLV-I replication in HAM patients to those in
symptomatic individuals using a novel adaptation of the polymerase chain
elongation technique for analysis of both DNA and RNA levels. Finally, as
preliminary evidence points to potentially important autoimmune mechanisms
in HAM, we will determine whether antibody production plays a role in
pathogenesis of HAM through assay of antibodies contained within the
cerebrospinal fluid for reactivity to normal brain antigens encoded by a
human brain cDNA library. If autoimmune antibody specificities are
defined, we will immortalize antibody-producing B-cell lines from HAM
patients' cerebrospinal fluid to obtain monoclonal reagents for further
studies. This combined molecular virologic and immunological approach
should markedly increase our understanding of pathogenetic mechanisms in
HAM and other neurological disorders caused by human retroviruses.
StatusFinished
Effective start/end date7/1/906/30/93

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Tropical Spastic Paraparesis
Human T-lymphotropic virus 1
Nervous System Diseases
Cerebrospinal Fluid
Leukemia
Cell Line
Antibody-Producing Cells
Antibody Specificity
Spinal Cord Diseases
Brain
Virus Diseases
Retroviridae
Virus Replication
Blood Donors
Gene Library

ASJC

  • Medicine(all)