Transforming Potential of Emerging Human Retroviruses

新兴人类逆转录病毒的转化潜力

• 批准号: 7690756
• 负责人: SUSAN J MARRIOTT
• 金额: $ 19.19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690756
• 关键词: Address; Adult; Africa; African; Agar; Amino Acid Sequence; Animals; Binding; Cancer Etiology; DNA Microarray Chip; Disease; Family; Gene Expression; Genome; Growth; Homologous Gene; Human; Human T-Cell Leukemia Viruses; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; Link; Malignant Neoplasms; Oncogene Proteins; Oncogenic; Outcome; Pattern; Play; Primates; Property; Protein Family; Proteins; Proteomics; Regulation; Reporting; Retroviridae; Role; STLV-3; Simian Retroviruses; Simian T-lymphotropic virus 1; Specificity; T-Cell Leukemia; Taxes; Time; Transactivation; Transgenic Mice; Viral; Virus; base; density; human disease; insight; leukemia; leukemia virus; member; metaplastic cell transformation; mouse model; public health relevance; tax Gene Products; tax Genes; tumor

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.

描述（由申请人提供）：人类T细胞白血病病毒1型（HTLV-1）是首次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）的病原体，编码一种病毒癌蛋白Tax，它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，该家族还包括HTLV-2，其尚未明确与任何人类疾病相关。HTLV-1和-2分别与猴T细胞白血病病毒STLV-1和-2密切相关。2005年，第三个猿猴逆转录病毒群STLV-3的人类同源物（HTLV-3）从中非灵长类动物猎人中独立分离了两次，最近报道了第三次从人类中独立分离HTLV-3。HTLV-3（2026 ND）分离株的基因组，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重要的结构域中。STLV-3在非洲灵长类动物中的广泛分布和HTLV-3多次从人类中独立分离，表明HTLV-3在非洲流行。另一种人类逆转录病毒HTLV-4也于2005年从非洲灵长类动物猎人中分离出来，与所有已知的HTLV和STLV不同。与HTLV-3相反，HTLV-4基因组，特别是Tax基因，与HTLV-2比与HTLV-1更密切相关。本申请基于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，重点是确定转化潜力，转录活性，蛋白质相互作用的合作伙伴的HTLV-3和HTLV-4税务蛋白进行调查。由于HTLV-3和HTLV-4似乎是作为新的人类逆转录病毒出现的，因此我们确定这些病毒在人类中引起疾病的潜力至关重要。公共卫生相关性：病毒是动物和人类癌症的重要原因。一种叫做HTLV-1的特殊病毒已知会导致人类的一种白血病。最近在人类中发现了两种新病毒，这些新病毒与HTLV-1非常密切相关。因此，我们认为至少有一种新病毒可能导致人类癌症。HTLV-1产生一种名为Tax的蛋白质，这种蛋白质是病毒致癌所必需的。我们计划将HTLV-1产生的Tax蛋白与两种新病毒产生的Tax蛋白进行比较，以便确定新病毒是否可能导致人类癌症。