Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, 3000 Leuven, Belgium; Laboratory for Biomolecular Modeling, Department of Chemistry, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
Cell Host Microbe. 2014 Nov 12;16(5):651-62. doi: 10.1016/j.chom.2014.09.016.
Distinct integration patterns of different retroviruses, including HIV-1, have puzzled virologists for over 20 years. A tetramer of the viral integrase (IN) assembles on the two viral cDNA ends, docks onto the target DNA (tDNA), and catalyzes viral genome insertion into the host chromatin. We identified the amino acids in HIV-1 IN that directly contact tDNA bases and affect local integration site sequence selection. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene-dense regions. Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution, but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors.
不同逆转录病毒（包括 HIV-1）的独特整合模式让病毒学家困惑了 20 多年。病毒整合酶（IN）的四聚体在两个病毒 cDNA 末端组装，对接靶 DNA（tDNA），并催化病毒基因组插入宿主染色质。我们确定了 HIV-1 IN 中直接与 tDNA 碱基相互作用并影响局部整合位点序列选择的氨基酸。这些残基还决定了病毒整合到灵活 tDNA 序列的倾向。值得注意的是，天然多态性 INS119G 和 INR231G 将病毒的整合重新定向到基因密集区之外。正是这些变体与慢性 HIV-1 亚型 C 感染队列中的快速疾病进展相关。这些发现将整合位点选择与毒力和病毒进化联系起来，但也与宿主免疫反应和抗逆转录病毒治疗有关，因为 HIV-1 IN119 受到 HLA 等位基因和整合酶抑制剂的选择。
