Delayed seroconversion to STLV-1 infection is associated with mutations in the pol and rex genes.

BACKGROUND: Simian T-cell lymphoma/leukemia virus-1 (STLV-1) infection of non-human primates can serve as a model for human T-cell lymphoma/leukemia virus infection. METHODS: Two tantalus and 2 patas monkeys were transfused with intraspecies whole blood infected with STLV-1. Infection was determined by ELISA, western blot and DNA PCR analyses. The entire genome of the STLV-1 Tan 90 strain and some of the STVL-1 Pat74 strain were amplified using over-lapping primer-pairs and subsequently sequenced. RESULTS: Followup studies conducted over 2 years indicated that all 4 monkeys remained healthy despite being infected with STLV-1, as determined by PCR, cloning and sequencing analyses. ELISA and Western blot analyses indicated that both patas monkeys seroconverted within 2 months of transfusion, while one tantalus monkey required one year to seroconvert and the other never fully seroconverted. The tantalus monkey which never fully seroconverted, failed to react to HTLV-1 p24 Gag antigen. Sequence analyses indicated that, while unique, the deduced p24 Gag amino acid sequence of the STLV-1 Tan 90 strain used for infection was still highly homologous to the HTLV-1 p24 Gag amino acids present in the ELISA and WB assays. However, a mutation in the pol sequence of STLV-1 Tan 90 encoded a putative stop codon, while a common deletion in the pol/rex regulatory gene causes significant changes in the Pol, and p27 Rex proteins. These same mutations were also observed in the viral DNA of both recipient infected tantalus monkeys and were not present in the STLV-1 Pat 74 strain. CONCLUSION: Our data suggest that seroconversion to STLV-1 infection may be prolonged due to the above mutations, and that compensatory molecular events must have occurred to allow for virus transmission.

Inefficient Tax-Specific T-Cell Responses in Mice after Syngeneic Transplantation with tax-Transgenic Mouse-Derived Adult T-Cell Leukemia Cells.

Adult T-cell leukemia (ATL) is induced by chronic latent infection with human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 Tax is an oncogenic factor that can be targeted by host T-cell responses. However, the expression of Tax in vivo is little in ATL cells and the impact of Tax-specific T-cell responses on ATL progression remains unclear. In the present study, we examined Tax-specific T-cell responses in C57BL/6 mice after syngeneic transplantation with tax-transgenic mouse-derived ATL (mATL) cells. We first confirmed that cellular tax cDNAs are mostly maintained and detectable in the spleen three weeks after mATL cell transplantation. However, mATL cell transplantation did not induce significant Tax-specific T-cell responses. Mice immunized with DNA and adenovirus vectors expressing Tax exhibited Tax-specific CD4+ T-cell responses but showed no enhancement of the responses or reduction in cellular tax cDNA levels after mATL cell transplantation. This study provides an animal model for analyzing the interaction between ATL cells and host immune responses as well as indicates the limited impact of Tax-specific T-cell responses on the proliferation of ATL cells.

Ex vivo analysis of human T lymphotropic virus type 1-specific CD4+ cells by use of a major histocompatibility complex class II tetramer composed of a neurological disease-susceptibility allele and its immunodominant peptide.

HLA-DRB1*0101 is associated with susceptibility to human T lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Here, we used a synthetic tetramer of DRB1*0101 and its epitope peptide to analyze HTLV-1-specific CD4(+) T cells ex vivo. The frequency of tetramer(+)CD4(+) T cells was significantly greater in patients with HAM/TSP than in healthy HTLV-1 carriers (HCs) at a given proviral load and correlated with HTLV-1 tax messenger RNA expression in HCs but not in patients with HAM/TSP. These cells displayed an early to intermediate effector memory phenotype and were preferentially infected by HTLV-1. T cell receptor gene analyses of 2 unrelated DRB1*0101-positive patients with HAM/TSP showed similar Vbeta repertoires and amino acid motifs in complementarity-determining region 3. Our data suggest that efficient clonal expansion of virus-specific CD4(+) T cells in patients with HAM/TSP does not simply reflect higher viral burden but rather reflects a rapid turnover caused by preferential infection and/or in vivo stimulation by major histocompatibility complex-peptide complexes.

Baboon T cell lymphomas expressing the B cell-associated surface proteins CD40 and Bgp95.

Papio hamadryas baboons in the Sukhumi colony develop enzootic outbreaks of malignant lymphomas with an incidence of about 1.5% per year among adults of the high-risk stock. We investigated the surface phenotypes of cells from normal and lymphomatous animals using antibodies against human lymphocyte antigens. We found that more than 80% of the lymphomas that developed during the last 3 years were characterized histologically to be of the peripheral T cell type. Generally, the lymphomatous cells also expressed high levels of MHC class II DR protein, CD18 (LFA-1 beta chain), and CD45RO. Surprisingly, these cells also expressed on their surface two proteins previously characterized as being relatively B cell-restricted: CD40 and Bgp95. These proteins were never found on the peripheral blood T cells from normal animals. The expression of these two gene products was confirmed by RNA blotting and immunoprecipitation. In most cases, the two B cell-associated proteins were expressed on the predominant T cell subsets; we found both B cell proteins on CD4+, CD8+ as well as on the CD4/8 double-positive cells when these subsets were expressed at high levels. About 90% of these animals are seropositive for Herpesvirus papio and human T cell leukemia virus-1 (HTLV-1) before developing outright lymphomas. In all of the lymphoma samples, HTLV-1 tax DNA sequences were detected by PCR amplification. Whether or not HTLV-1 or the Herpesvirus papio gene products influence the surface expression of CD40 and Bgp95 remains to be determined.

A wide spectrum of collagen vascular and autoimmune diseases in transgenic rats carrying the env-pX gene of human T lymphocyte virus type I.

To investigate the pathogenesis of human T lymphocyte virus type I (HTLV-I)- related diseases, the env-pX gene of HTLV-I was introduced into the germline of inbred Wistar-King-Aptekman-Hokudai rats. A wide spectrum of collagen vascular diseases was evident in the transgenic rats, including chronic destructive arthritis similar to rheumatoid arthritis, necrotizing arteritis mimicking polyarteritis nodosa, polymyositis, myocarditis, dermatitis, and chronic sialoadenitis and dacryoadenitis resembling Sjögren's syndrome in humans. Thymic atrophy with the depletion of CD4 and CD8 double-positive thymocytes was also observed. In these animals, a number of autoantibodies, including high titers of rheumatoid factor, were present in the serum. We propose that the HTLV-I env-pX gene region may play a pathogenetic role in the development of collagen vascular and autoimmune diseases associated with autoimmune phenomenon.

The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis.

Rheumatoid arthritis (RA) is a polygenic autoimmune disease. The autoimmunity develops from synergistic actions of genetic and environmental factors. We generated a double-mutant mouse by crossing two murine models of RA, a gp130 mutant knock-in mouse (gp130F759/F759) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130F759/F759 mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130F759/F759 mice, including lymphoadenopathy, splenomegaly, hyper-gamma-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHC(bright) CD11c+ population, were augmented in the double mutants. Marked reductions in incidence, severity and immunological abnormalities were seen in the triple mutant, IL-6-/-/gp130F759/F759/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. gp130F759/F759/pX-Tg is a unique mouse model for RA.