tRNA A58-methyltransferase as a Target for HIV Therapy

tRNA A58-甲基转移酶作为 HIV 治疗的靶点

• 批准号: 6892410
• 负责人: CHARLES S MCHENRY
• 金额: $ 19.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892410
• 关键词: AIDS therapy; HIV infections; cell proliferation; clinical research; enzyme activity; enzyme inhibitors; gene targeting; host organism interaction; human immunodeficiency virus 1; human subject; laboratory rabbit; methyltransferase; tissue /cell culture; transfer RNA; virus infection mechanism; virus replication

DESCRIPTION (provided by applicant): During the first stage of HIV nucleic acid replication, HIV reverse transcriptase catalyzes the extension of host tRNA3lys after the annealing of its 3'-18 nucleotides to a complementary 18-nt viral site, In the late stages of replication, this 18-nt site is recapitulated without replication of the entire tRNA. Evidence suggests that a post-transcriptional modification (N-1 methyl A58 ) found in the 19th nucleotide from the 3'-end of the priming tRNA limits replication to 18 nucleotides. If HIV replication is primed with unmodified tRNA3lys in purified biochemical systems, replication aborts after the tRNA copying step accompanying the second strand transfer reaction. We propose to test the hypothesis that tRNA A58 -methyltransferase is an essential enzyme required for successful HIV infection, and that it can be inhibited without toxic consequences for the host within a therapeutic window. We plan to determine whether diminished levels of tRNA A58- methyltransferase in cultured cells produce non-infectious HIV particles and whether human cells with diminished levels of tRNA A58-methyltransferase retain viability. If these conditions are met, tRNA A58- methyltransferase should provide a host target for anti-HIV intervention.

描述（由申请人提供）：在HIV核酸复制的第一阶段，HIV逆转录酶催化宿主tRNA 3lys在其3 '-18核苷酸退火至互补的18-nt病毒位点后的延伸。在复制的后期阶段，该18-nt位点被重现而没有整个tRNA的复制。有证据表明，在启动tRNA的3 '端的第19个核苷酸中发现的转录后修饰（N-1甲基A58）将复制限制在18个核苷酸。如果在纯化的生化系统中用未修饰的tRNA 3lys引发HIV复制，则在伴随第二链转移反应的tRNA复制步骤之后复制中止。我们建议测试的假设，tRNA A58 -甲基转移酶是成功的HIV感染所需的一种必需的酶，它可以被抑制，而不会对治疗窗口内的主机的毒性后果。我们计划确定培养细胞中tRNA A58-甲基转移酶水平降低是否产生非感染性HIV颗粒，以及tRNA A58-甲基转移酶水平降低的人类细胞是否保持活力。如果满足这些条件，tRNA A58-甲基转移酶将为抗HIV干预提供宿主靶点。