A rat model of human T lymphocyte virus type I (HTLV-I) infection. 1. Humoral antibody response, provirus integration, and HTLV-I-associated myelopathy/tropical spastic paraparesis-like myelopathy in seronegative HTLV-I carrier rats.

Abstract

Stlmm~'y Human T lymphocyte virus type I (HTLV-I) can be transmitted into several inbred strains of newborn and adult rats by inoculating newly established HTLV-I-immortalized rat T cell lines or the human T cell line MT-2. The transmission efficiency exceeds 80%, regardless of strain differences or the age at transmission. The production of anti-HTLV-I antibodies significantly differs among the strains and depends on the age at the time of transmission. Rats neonatally inoculated with HTLV-I-positive rat or human cells generally become seronegative HTLV-I carriers throughout their lives, whereas adult rats inoculated with HTLV-I-positive cells at 16 wk of age become seropositive HTLV-I carriers. The HTLV-I provirus genome is present in almost all organs, regardless of whether the carriers are seronegative or seropositive. According to antibody titers to HTLV-I, there are three groups of inbred rat strains: ACI, F344, and SDJ (high responders); WKA, BUF, and LEJ (intermediate responders); and LEW (low responder). Three of three 16-mo-old seronegative HTLV-I cartier rats of the WK strain developed spastic paraparesis of the hind legs. Neuropathological examinations revealed that the lesions were confined primarily to the lateral and anterior funiculi of the spinal cord. Both myelin and axons were extensively damaged in a symmetrical fashion, and infiltration with massive foamy macrophages was evident. The most severe lesions were at levels of the thoracic cord and continued from the cervical to the lumbar area. These histopathological features as well as clinical symptoms largely paralld findings in humans with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). These HTLV-I carrier rats, in particular the WKA rats described above, can serve as a useful animal model for investigating virus-host interactions in the etiopathogenesis of HTLV-I-related immunological diseases, particularly HAM/TSP.

Enhanced Replication of Human T-Cell Leukemia Virus Type 1 in T Cells from Transgenic Rats Expressing Human CRM1 That Is Regulated in a Natural Manner

“…It is especially interesting that most of the Wt rat-derived cells do not express CD3 or CD4, whereas the majority of the Tg rat-derived lines possess both of these molecules. Since we and others have established a number of CD4-positive cell lines from various strains of Wt rats (31,36), the present results may be due to experimental disparities. However, it is possible that enhanced HTLV-1 production by the hCRM1-expressing cells and subsequent dissemination of the virus in the culture may influence the phenotypes of the transformed cells.…”

“…Using these susceptible animals, several models have been developed to study HTLV-1-associated diseases. The HAM/ TSP-like disease model in strain WKA rats is well established and has been used to dissect the pathogenic mechanisms of the disease (31,39). In contrast, only a few ATL model systems have been established using rabbits and rats, and their utility is limited.…”

Development of Human T-Cell Leukemia Virus Type 1-Transformed Tumors in Rats following Suppression of T-Cell Immunity by CD80 and CD86 Blockade

“…However, attempts to induce tumor development in experimental animals by HTLV-1 infection have been unsuccessful (39). Instead, a certain strain of rats developed HAM/TSP-like disease after a long-term HTLV-1 carrier state following inoculation of HTLV-1-producing cells (14). Inoculation of HTLV-1-immortalized cells into immunocompetent syngeneic rats generally fails to cause tumor formation, except for a few cases of fully transformed HTLV-1-infected cells with additional mutations (30,34).…”

Antigenic cross-reactivity between human T lymphotropic virus type I (HTLV-I) and retinal antigens recognized by T cells

“…These observations suggest that HTLV-I may play a role in the generation of autoimmune diseases. Autoimmune diseases, such as myelopathy (HAM/TSP) [7,8], arthropathy (HAAP) [9,10], and bronchoalveolitis (HAB) [11], have been found in HTLV-I carriers, termed 'HTLV-I-associated syndrome' [12]. Recently the seroprevalance in patients having uveitis without defined etiologies was found significantly higher than that in patients with non-uveitic ocular diseases or in patients having uveitis with defined etiologies [13].…”