To investigate the pathogenetic role of human T lymphocyte virus type I (HTLV-I) in central nervous system disease, a rat model for HTLV-I-associated myelopathy/tropical spastic paraparesis, designated as HAM rat disease, has been established. Wistar-King-Aptekman-Hokudai strain rats with induced HTLV-I infection develop a chronic progressive myeloneuropathy with paraparesis of hind limbs after an incubation period of 15 months. In the affected spinal cord in these rats, white matter degeneration, demyelination and vacuolar change with microglia/macrophage infiltration are present as are the provirus DNA and the virus mRNA. To identify infected cells in the affected lesions, we carried out in situ hybridization of amplified fragments of the provirus DNA by polymerase chain reaction on thin sections, plus immunohistochemistry on the same sections. The provirus DNA was localized in some microglia/macrophages in the spinal cord lesion. In addition, the HTLV-I provirus was clearly evident not only in ED-1-negative lymphoid cells but also in ED-1-positive macrophages from lymph nodes. These observations suggest that cells of microglia/macrophage lineage may be one of dominant viral reservoirs in the spinal cords and lymph nodes in HAM rat disease. These infected microglia/macrophages may relate to cause the myeloneuropathy through neurotoxic cytokine synthesis.

The pathogenetic roles of human T lymphocyte virus type I (HTLV-I) and cytokines were investigated in HTLV-I-induced myeloneuropathy in Wistar-King-Aptekman-Hokudai rats. In the nervous system, pX messenger RNAs of HTLV-I were selectively expressed in the diseased spinal cord and peripheral nerves but not in the unaffected cerebrum and cerebellum, even though proviral DNAs were consistently identified in these tissues. Among several cytokines examined, mRNA expression and production of tumor necrosis factor (TNF)-alpha in the spinal cord and cerebrospinal fluid correlated positively with the development of spinal cord lesions. The collective evidence strongly suggests that selective activation of HTLV-I, in particular Tax expression and production of TNF-alpha induced by HTLV-I infection in target spinal cord and peripheral nerves, is causally related to apoptotic death of oligodendrocytes and Schwann cells, a major pathogenetic pathway of the HTLV-I-induced myeloneuropathy.

To investigate the pathogenetic role of human T-lymphocyte virus type I (HTLV-I) in central nervous system disease, a rat model for HTLV-I-associated myelopathy/tropical spastic paraparesis, designated as HAM rat disease, was examined with regard to chronological neuropathology, from early asymptomatic phase to late disease. In the thoracic spinal cord of rats with HTLV-I infection, the first event was the appearance of apoptosis of oligodendrocytes beginning at 7 months after induced infection, thereafter followed by the appearance of white matter degeneration, increase of macrophages/activated microglia and of gemistocytic astrocytes at 12, 15 and 20 months, respectively. In the spinal cord, HTLV-I provirus DNA was evident as early as 4 months after the infection, and HTLV-I pX and the tumor necrosis factor (TNF)-alpha messages began to be expressed at age 7 months, just before or at the same time as the appearance of apoptotic cells. Collective evidence suggests that the apoptotic death of oligodendrocytes, which may be induced either directly by the local expression of HTLV-I or indirectly by TNF-alpha, through the transactive function of p40Tax, is the major cause of chronic progressive myeloneuropathy in Wistar-King-Aptekman-Hokudai rats with HTLV-I infection.

Apoptosis of the spinal oligodendrocytes is the main factor linked to the pathogenesis of human T-lymphocyte virus type I (HTLV-I)-induced myeloneuropathy in rats (HAM rat). To clarify apoptosis-related mechanisms, expression of apoptosis-related genes in the spinal cord of these rats was chronologically examined by means of a semiquantitative reverse transcriptase-polymerase chain reaction. Provirus expansion and increment of HTLV-I pX mRNA were evident at 7 months after the induced infection. Tumor necrosis factor-alpha increased gradually soon after pX expression. The expression of a major apoptosis-resistant gene, bcl-2, was markedly suppressed at a period of the provirus expansion and bax was also down-regulated. p53 was consistently expressed at high levels. These findings were never observed in spinal cords of HAM-resistant strains with HTLV-I infection even throughout their entire life. Collective evidence suggests that the local provirus expansion and deregulation of apoptosis-related genes, especially down-regulation of bcl-2, may lead to apoptosis of oligodendrocytes, thus being a major pathogenetic pathway in the HTLV-I-induced myeloneuropathy.