Establishment of Rev based anti-HIV therapy.

即使采用广泛联合使用逆转录酶和/或蛋白酶抑制剂的高活性抗逆转录病毒疗法，根除人类免疫缺陷病毒（艾滋病毒）仍有待实现。因此，迫切需要开发新的抑制剂来阻断新的靶点以及逆转录酶或蛋白酶。在这个项目中，首席研究员专注于病毒附属蛋白Rev，这是HIV复制所必需的，并开发了基于肽的Rev抑制剂。研究人员发现含有10到63个Rev转导细胞氨基酸的肽对HIV感染具有抗性，这表明该区域含有HIV抑制肽序列。为了鉴定该区域，构建了包含Rev 10 ~ 63不同大小和区域的肽序列的表达载体。其中含有富含34 ~ 50个氨基酸序列精氨酸的肽具有抑制作用。加入稳定α-螺旋结构的四种丙氨酸增强了抑制效果。人t细胞白血病病毒Rex是Rev的同源物，它也具有富含精氨酸的结构域。该区域对HIV感染也有抑制作用。合成肽也通过其与CXCR4的结合而不是通过抑制Rev功能来阻断HIV感染，这表明需要提高肽渗透细胞的效率。需要进一步的研究来开发临床上有用的Rev抑制剂。

Even under highly active anti-retroviral therapy using extensive combination of inhibitors to reverse transcriptase and/or protease, eradication of human immunodeficiency virus (HIV) remains to be achieved. Thus, development of new inhibitors that block new targets as well as reverse transcriptase or protease is urgently required. In this project, the principal investigator focuses on a viral accessory protein, Rev that is essential for HIV replication and has developed peptide based Rev inhibitors.The investigator found that a peptide containing 10 to 63 amino acids of Rev transduced cells were resistant to HIV infection, suggesting that the region contains an HIV inhibitory peptide sequence. To identify the region, expression vectors containing peptide sequences in various size and region of Rev 10 to 63 were constructed. Among them, a peptide containing arginine rich 34 to 50 amino acid sequence showed inhibitory effect. Addition of four alanines that stabilize α-helical structure enhances the inhibitory effect. Human T-cell leukemia virus Rex, a homolog of Rev also has arginine rich domain. This region also showed inhibitory effect to HIV infection. Synthetic peptides also block HIV infections through its binding to CXCR4, not through suppression of Rev function, indicating that enhancement of peptide penetration efficiency into cells is needed. Further study is needed to develop clinically useful Rev inhibitors.