Wang T G, Ye J, Lairmore M D, Green P L
Center for Retrovirus Research and Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio 43210, USA.
AIDS Res Hum Retroviruses. 2000 Nov 1;16(16):1661-8. doi: 10.1089/08892220050193119.
Human T cell leukemia virus type 1 (HTLV-1) and 2 (HTLV-2) are distinct oncogenic retroviruses that infect several cell types, but display their biologic/pathogenic activity only in T lymphocytes. HTLV-1 is associated with adult T cell leukemia, a malignancy of mature CD4(+) T cells, and a chronic neurological disorder termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is less pathogenic and has been associated with a few cases of a variant of hairy cell leukemia and neurological disease. Previous studies have indicated that in vivo HTLV-1 has a preferential tropism for CD4(+) T cells, whereas HTLV-2 in vivo tropism is less clear, but appears to favor CD8(+) T cells. The molecular mechanism that determines the cellular tropism of HTLV-1 and HTLV-2 has not been precisely determined. However, one study by our group has provided evidence that HTLV-1-enhanced viral transcription in CD4(+) T cells may be responsible for its tropism. In an effort to understand HTLV-2 tropism we tested the ability of HTLV-2 to infect, replicate in, and transform purified CD4(+) or CD8(+) T cells in cell culture. After cocultures of purified primary human CD4(+) and CD8(+) T cells with an HTLV-2-producer cell line we measured viral transcription by reverse transcription PCR analysis, virus production by p19(gag) ELISA, proviral integration by DNA slot-blot analysis, surface phenotype by FACS analysis, and cellular transformation. We also measured HTLV-2 long terminal repeat-directed transcription in the presence and absence of Tax in purified CD4(+) and CD8(+) T cells, using transient transfection assays. Our data indicate that CD4(+) and CD8(+) T cells are equally susceptible to HTLV-2 infection. We observed no significant difference in viral transcription based on mRNA and virus production in CD4(+) and CD8(+) T cell cocultures. Although LTR transcription was enhanced 12- to 16-fold in the presence of Tax, there was no significant difference in CD4(+) or CD8(+) T cells. Interestingly, we show that HTLV-2 preferentially transforms CD8(+) T cells in culture. Together, our data indicate that, unlike HTLV-1, HTLV-2 cell tropism is not due to inhibition of viral infection and inefficient gene expression in CD4(+) versus CD8(+) T cells, and likely involves unique interactions with viral and CD8(+) T cell-specific proteins.
人类嗜T淋巴细胞病毒1型（HTLV-1）和2型（HTLV-2）是不同的致癌逆转录病毒，可感染多种细胞类型，但仅在T淋巴细胞中表现出其生物学/致病活性。HTLV-1与成人T细胞白血病（一种成熟CD4(+) T细胞的恶性肿瘤）以及一种称为HTLV-1相关脊髓病/热带痉挛性截瘫（HAM/TSP）的慢性神经疾病有关。HTLV-2的致病性较低，与少数毛细胞白血病变种和神经疾病病例有关。先前的研究表明，体内HTLV-1对CD4(+) T细胞具有优先嗜性，而HTLV-2在体内的嗜性尚不清楚，但似乎更倾向于CD8(+) T细胞。决定HTLV-1和HTLV-2细胞嗜性的分子机制尚未精确确定。然而，我们小组的一项研究提供了证据，表明HTLV-1在CD4(+) T细胞中增强的病毒转录可能是其嗜性的原因。为了了解HTLV-2的嗜性，我们在细胞培养中测试了HTLV-2感染、在纯化的CD4(+)或CD8(+) T细胞中复制以及转化这些细胞的能力。将纯化的原代人CD4(+)和CD8(+) T细胞与HTLV-2产生细胞系共培养后，我们通过逆转录PCR分析测量病毒转录，通过p19(gag) ELISA测量病毒产生，通过DNA斑点杂交分析测量前病毒整合，通过流式细胞术分析测量表面表型，并检测细胞转化情况。我们还使用瞬时转染试验，在有无Tax的情况下，测量纯化的CD4(+)和CD8(+) T细胞中HTLV-2长末端重复序列定向转录。我们的数据表明，CD4(+)和CD8(+) T细胞对HTLV-2感染同样敏感。我们观察到，基于CD4(+)和CD8(+) T细胞共培养中的mRNA和病毒产生情况，病毒转录没有显著差异。尽管在Tax存在的情况下LTR转录增强了12至16倍，但在CD4(+)或CD8(+) T细胞中没有显著差异。有趣的是，我们发现HTLV-2在培养中优先转化CD8(+) T细胞。总之，我们的数据表明，与HTLV-1不同，HTLV-2的细胞嗜性不是由于CD4(+)与CD8(+) T细胞中病毒感染的抑制和基因表达效率低下，而可能涉及与病毒和CD8(+) T细胞特异性蛋白的独特相互作用。
