T-cell Transformation by Oncoviruses

我实验室的一个研究方向是了解人类T细胞白血病/淋巴瘤病毒1型（HTLV-1）的发病机制。HTLV-1是唯一已知的导致人类癌症的逆转录病毒。流行病学、分子和生化证据表明，HTLV-1在宿主体内的持续存在与T细胞克隆扩增和随后的遗传病变积累有关，从而导致白血病。因此，了解病毒持久性的机制对于预防白血病的发生至关重要。我们继续研究病毒基因组3端编码的p12I和p30II蛋白的功能。我们推测它们可能在病毒的持久性和发病机制中发挥重要作用。我们发现p12I影响近端T细胞受体（TCR）信号，以及PLC-gamma1、Vav和T细胞激活连接子（LAT）的磷酸化。因此，钙释放和活化T细胞核因子（NFAT）转录减少。与LAT一样，p12I位于脂筏中，并在TCR结扎后几分钟内被募集到免疫突触。p12I还降低了细胞毒性T细胞对MHC i类限制性靶细胞的识别。这些发现可能与HTLV-1感染中观察到的免疫抑制和免疫逃避有关。另一个令人兴奋的新发现是，病毒基因组3端的ORF II编码的p30II蛋白通过一种新的转录后机制减少了前病毒的表达。我们发现p30II与双剪接的Tax/Rex mRNA结合并将其保留在细胞核中。正如预期的那样，在htlv -1感染的T细胞系中，p30II的表达也通过降低Tax水平来减少病毒复制。在HTLV-2（一种与HTLV-1基因相关的病毒）中也发现了具有类似功能的蛋白（p28II）。我实验室的一个研究方向是了解人类T细胞白血病/淋巴瘤病毒1型（HTLV-1）的发病机制。HTLV-1是唯一已知的导致人类癌症的逆转录病毒。流行病学、分子和生化证据表明，HTLV-1在宿主体内的持续存在与T细胞克隆扩增和随后的遗传病变积累有关，从而导致白血病。因此，了解病毒持久性的机制对于预防白血病的发生至关重要。我们继续研究病毒基因组3端编码的p12I和p30II蛋白的功能。我们推测它们可能在病毒的持久性和发病机制中发挥重要作用。我们发现p12I影响近端T细胞受体（TCR）信号，以及PLC-gamma1、Vav和T细胞激活连接子（LAT）的磷酸化。因此，钙释放和活化T细胞核因子（NFAT）转录减少。与LAT一样，p12I位于脂筏中，并在TCR结扎后几分钟内被募集到免疫突触。p12I还降低了细胞毒性T细胞对MHC i类限制性靶细胞的识别。这些发现可能与HTLV-1感染中观察到的免疫抑制和免疫逃避有关。另一个令人兴奋的新发现是，病毒基因组3端的ORF II编码的p30II蛋白通过一种新的转录后机制减少了前病毒的表达。我们发现p30II与双剪接的Tax/Rex mRNA结合并将其保留在细胞核中。正如预期的那样，在htlv -1感染的T细胞系中，p30II的表达也通过降低Tax水平来减少病毒复制。在HTLV-2（一种与HTLV-1基因相关的病毒）中也发现了具有类似功能的蛋白（p28II）。

One line of research in my laboratory is related to understanding human T cell leukemia/lymphoma virus type 1 (HTLV-1) pathogenesis. HTLV-1 is the only known retrovirus that causes human cancer. Epidemiological, molecular, and biochemical evidence suggests that HTLV-1 persistence in the host is associated with T cell clonal expansion and consequent accumulation of genetic lesions, resulting in leukemia. Thus, the understanding of mechanisms of viral persistence is essential to prevent the occurrence of leukemia. We continued to study the function of the p12I and p30II proteins encoded by the 3 end of the viral genome. We hypothesized that they may play an essential role in viral persistence and pathogenesis. We found that p12I affects proximal T cell receptor (TCR) signaling, and phosphorylation of PLC-gamma1, Vav, and linker for activation of T cells (LAT). Consequently, calcium release and nuclear factor of activated T cells (NFAT) transcription are decreased. p12I, like LAT, is located in the lipid rafts and is recruited to the immunological synapse within minutes from TCR ligation. p12I also decreased MHC class I-restricted recognition of targeted cells by cytotoxic T cells. These findings may relate to the immunosuppression and immune evasion observed in HTLV-1 infection. Another exciting new development has been the finding that the p30II protein encoded by the ORF II at the 3 end of the viral genome decreases proviral expression by a novel post-transcriptional mechanism. We found that p30II binds to the doubly spliced Tax/Rex mRNA and retains it in the nucleus. As expected, expression of p30II in HTLV-1-infected T cell lines also decreases viral replication by decreasing the level of Tax. A protein (p28II) with similar function is also found in HTLV-2, a virus genetically related to HTLV-1. One line of research in my laboratory is related to understanding human T cell leukemia/lymphoma virus type 1 (HTLV-1) pathogenesis. HTLV-1 is the only known retrovirus that causes human cancer. Epidemiological, molecular, and biochemical evidence suggests that HTLV-1 persistence in the host is associated with T cell clonal expansion and consequent accumulation of genetic lesions, resulting in leukemia. Thus, the understanding of mechanisms of viral persistence is essential to prevent the occurrence of leukemia. We continued to study the function of the p12I and p30II proteins encoded by the 3 end of the viral genome. We hypothesized that they may play an essential role in viral persistence and pathogenesis. We found that p12I affects proximal T cell receptor (TCR) signaling, and phosphorylation of PLC-gamma1, Vav, and linker for activation of T cells (LAT). Consequently, calcium release and nuclear factor of activated T cells (NFAT) transcription are decreased. p12I, like LAT, is located in the lipid rafts and is recruited to the immunological synapse within minutes from TCR ligation. p12I also decreased MHC class I-restricted recognition of targeted cells by cytotoxic T cells. These findings may relate to the immunosuppression and immune evasion observed in HTLV-1 infection. Another exciting new development has been the finding that the p30II protein encoded by the ORF II at the 3 end of the viral genome decreases proviral expression by a novel post-transcriptional mechanism. We found that p30II binds to the doubly spliced Tax/Rex mRNA and retains it in the nucleus. As expected, expression of p30II in HTLV-1-infected T cell lines also decreases viral replication by decreasing the level of Tax. A protein (p28II) with similar function is also found in HTLV-2, a virus genetically related to HTLV-1.