Mutational patterns in the frameshift-regulating site of HIV-1 selected by protease inhibitors
Mutational patterns in the frameshift-regulating site of HIV-1 selected by protease inhibitors
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DOI：
10.1007/s00430-011-0224-z
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发表时间：
2012-05-01
影响因子：
5.4
通讯作者：
Verheyen, Jens
中科院分区：
文献类型：
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作者：
Knops, Elena;Brakier-Gingras, Lea;Verheyen, Jens
HIV-1耐药性的出现尤其阻碍了对HIV-1感染者病毒复制的持续抑制。耐药机制主要涉及突变直接改变病毒酶和抑制剂的相互作用。然而，蛋白水解酶抑制剂不只是针对蛋白水解酶的突变，也是针对前体Gag和Pol蛋白的突变。在这项研究中，我们分析了HIV-1 B亚型分离株的移码调节位点，它也编码Gag和Pol蛋白，被归类为治疗-NA；Ve(TN)或蛋白酶抑制耐药(PI-R)。HIV-1 Gag裂解位点突变(G435E、K436N、I437V、L449F/V)与蛋白酶抑制剂耐药突变特别相关，但POL裂解位点突变(D05G、D05S)也可归因于特定的蛋白酶耐药谱。此外，在携带蛋白酶耐药突变的HIV-1分离株中发现了两个Gag非裂解位点突变(S440F和H441P)。然而，在双重荧光素酶分析中，特定克隆的移码效率并没有显示这些突变的任何影响。然而，两种突变模式在体外略微增加了移码率，但在耐PI的HIV-1分离株中并没有特异性积累。综上所述，HIV-1 Gag裂解位点突变在耐PI的HIV-1分离株中占主导地位，但Pol裂解位点突变也影响了蛋白水解酶的耐药性。此外，Gag非裂解位点突变在耐PI的HIV-1分离株中积累，但与增加的移码效率无关。
Sustained suppression of viral replication in HIV-1 infected patients is especially hampered by the emergence of HIV-1 drug resistance. The mechanisms of drug resistance mainly involve mutations directly altering the interaction of viral enzymes and inhibitors. However, protease inhibitors do not only select for mutations in the protease but also for mutations in the precursor Gag and Pol proteins. In this study, we analysed the frameshift-regulating site of HIV-1 subtype B isolates, which also encodes for Gag and Pol proteins, classified as either treatment-na < ve (TN) or protease inhibitor resistant (PI-R). HIV-1 Gag cleavage site mutations (G435E, K436N, I437V, L449F/V) especially correlated with protease inhibitor resistance mutations, but also Pol cleavage site mutations (D05G, D05S) could be assigned to specific protease resistance profiles. Additionally, two Gag non-cleavage site mutations (S440F, H441P) were observed more often in HIV-1 isolates carrying protease resistance mutations. However, in dual luciferase assays, the frameshift efficiencies of specific clones did not reveal any effect from these mutations. Nevertheless, two patterns of mutations modestly increased the frameshift rates in vitro, but were not specifically accumulating in PI-resistant HIV-1 isolates. In summary, HIV-1 Gag cleavage site mutations were dominantly selected in PI-resistant HIV-1 isolates but also Pol cleavage site mutations influenced resistance profiles in the protease. Additionally, Gag non-cleavage site mutations accumulated in PI-resistant HIV-1 isolates, but were not related to an increased frameshift efficiency.