HIV-1 Integrase Variants Retarget Viral Integration and Are Associated with Disease Progression in a Chronic Infection Cohort
HIV-1 Integrase Variants Retarget Viral Integration and Are Associated with Disease Progression in a Chronic Infection Cohort
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DOI：
10.1016/j.chom.2014.09.016
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发表时间：
2014-11-12
影响因子：
30.3
通讯作者：
Gijsbers, Rik
中科院分区：
文献类型：
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作者：
Demeulemeester, Jonas;Vets, Sofie;Gijsbers, Rik
不同逆转录病毒（包括HIV-1）的独特整合模式困扰了病毒学家20多年。病毒整合酶（IN）的四聚体在两个病毒cDNA末端组装，对接到靶DNA（tDNA）上，并催化病毒基因组插入宿主染色质。我们鉴定了HIV-1 IN中直接接触tDNA碱基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柔性tDNA序列中的倾向。值得注意的是，天然多态性INS 119 G和INR 231 G将病毒整合重新定位在基因安全区域之外。确切地说，这些变异与慢性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，而且还与宿主免疫应答和抗逆转录病毒治疗联系起来，因为HIV-1 IN 119受到HLA等位基因和整合酶抑制剂的选择。
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 genedense 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.