Llano Manuel, Saenz Dyana T, Meehan Anne, Wongthida Phonphimon, Peretz Mary, Walker William H, Teo Wulin, Poeschla Eric M
Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Science. 2006 Oct 20;314(5798):461-4. doi: 10.1126/science.1132319. Epub 2006 Sep 7.
Chromosomal integration enables human immunodeficiency virus (HIV) to establish a permanent reservoir that can be therapeutically suppressed but not eradicated. Participation of cellular proteins in this obligate replication step is poorly understood. We used intensified RNA interference and dominant-negative protein approaches to show that the cellular transcriptional coactivator lens epithelium-derived growth factor (LEDGF)/p75 (p75) is an essential HIV integration cofactor. The mechanism requires both linkages of a molecular tether that p75 forms between integrase and chromatin. Fractionally minute levels of endogenous p75 are sufficient to enable integration, showing that cellular factors that engage HIV after entry may elude identification in less intensive knockdowns. Perturbing the p75-integrase interaction may have therapeutic potential.
染色体整合使人类免疫缺陷病毒（HIV）能够建立一个永久性储存库，该储存库可以通过治疗得到抑制，但无法根除。细胞蛋白在这一必需的复制步骤中的参与情况尚不清楚。我们使用强化RNA干扰和显性负性蛋白方法来表明，细胞转录共激活因子晶状体上皮衍生生长因子（LEDGF）/p75（p75）是HIV整合的一种必需辅助因子。该机制需要p75在整合酶和染色质之间形成的分子系链的两个连接。内源性p75的微小水平就足以实现整合，这表明在进入后与HIV相互作用的细胞因子可能在强度较低的敲低实验中难以鉴定。干扰p75与整合酶的相互作用可能具有治疗潜力。
