Transforming Potential of Emerging Human Retroviruses

描述（由申请人提供）：人类T细胞白血病病毒1型（HTLV-1）是第一个发现的致病性人类逆转录病毒。HTLV-1是成人T细胞白血病（ATL）的病原，它编码一种病毒癌蛋白Tax，这是病毒转化所必需和充分的。HTLV-1是人类逆转录病毒家族的原型成员，它还包括HTLV-2，它与任何人类疾病没有明确的联系。HTLV-1和-2分别与类人猿T细胞白血病病毒STLV-1和-2亲缘关系密切。2005年，第三个类人猿逆转录病毒群STLV-3的人类同源物（HTLV-3）两次从中非灵长类动物猎人中独立分离出来，最近报道了第三个HTLV-3从人类中独立分离出来。HTLV-3 （2026ND）分离物的基因组，特别是Tax基因，与HTLV-1的关系比与HTLV-2的关系更密切，特别是在被认为对转化很重要的区域。STLV-3在非洲灵长类动物中的广泛分布以及HTLV-3多次从人类中独立分离，表明HTLV-3在非洲普遍存在。另外一种人类逆转录病毒HTLV-4也于2005年从一种非洲灵长类动物猎人身上分离出来，它与所有已知的htlv和stlv不同。与HTLV-3相比，HTLV-4基因组，尤其是Tax基因，与HTLV-2的关系比与HTLV-1的关系更密切。这一应用是基于HTLV-3 Tax蛋白具有致癌特性而HTLV- 4 Tax蛋白不具有的假设。这一假设将在两个特定的目标中进行研究，重点是确定HTLV-3和HTLV-4 Tax蛋白的转化潜力、转录活性和蛋白质相互作用伙伴。由于HTLV-3和HTLV-4似乎正在作为新的人类逆转录病毒出现，因此我们必须确定这些病毒在人类中引起疾病的可能性。公共卫生相关性：病毒是动物和人类癌症的重要原因。一种名为HTLV-1的特殊病毒已知会导致一种人类白血病。最近在人类身上发现了两种新病毒，这些新病毒与HTLV-1密切相关。因此，我们认为至少有一种新病毒可能会导致人类癌症。HTLV-1产生一种叫做Tax的蛋白质，这种蛋白质是病毒导致癌症所必需的。我们计划将HTLV-1制造的Tax蛋白与两种新病毒制造的Tax蛋白进行比较，以确定新病毒是否可能导致人类癌症。

DESCRIPTION (provided by applicant): Human T cell leukemia virus type 1 (HTLV-1) was the first discovered pathogenic human retrovirus. HTLV-1, the etiologic agent of adult T cell leukemia (ATL), encodes a viral oncoprotein, Tax that is necessary and sufficient for viral transformation. HTLV-1 is the prototypic member of a human retrovirus family that also includes HTLV-2, which has not been definitively linked to any human disease. HTLV-1 and -2 are closely related to the simian T cell leukemia viruses, STLV-1 and -2, respectively. In 2005, the human homologue (HTLV-3) of a third simian retrovirus group, STLV-3, was independently isolated twice from Central African primate hunters, and a third independent isolation of HTLV-3 from humans was recently reported. The genome of the HTLV-3 (2026ND) isolate, in particular the Tax gene, is more closely related to HTLV-1 than to HTLV-2, especially in domains that are thought to be important for transformation. The broad distribution of STLV-3 in African primates and independent isolation of HTLV-3 multiple times from humans, suggest that HTLV-3 is prevalent in Africa. An additional human retrovirus, HTLV-4, was also isolated from an African primate hunter in 2005 and is distinct from all known HTLVs and STLVs. In contrast to HTLV-3, the HTLV-4 genome, in particular the Tax gene, is more closely related to HTLV-2 than to HTLV-1. This application is based on the hypothesis that the HTLV-3 Tax protein possesses oncogenic properties while the HTLV- 4 Tax protein does not. This hypothesis will be investigated in two specific aims that focus on determining the transforming potential, transcriptional activity, and protein interacting partners of the HTLV-3 and HTLV-4 Tax proteins. Since HTLV-3 and HTLV-4 appear to be emerging as new human retroviruses, it is critical that we determine the potential of these viruses to cause disease in humans. PUBLIC HEALTH RELEVANCE: Viruses are important causes of cancer in animals and in humans. One particular virus called HTLV-1 is known to cause a type of leukemia in humans. Two new viruses were recently found in humans and these new viruses are very closely related to HTLV-1. Therefore, we think that at least one of the new viruses may cause cancer in humans. HTLV-1 makes a protein called Tax that is necessary for the virus to cause cancer. We plan to compare the Tax protein made by HTLV-1, with the Tax protein made by each of the two new viruses so that we can determine whether the new viruses are likely to cause human cancer.