Selection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistance.
Selection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistance.
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DOI：
10.7554/elife.80328
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发表时间：
2023-03-15
期刊：
影响因子：
7.7
通讯作者：
Swanstrom R
中科院分区：
文献类型：
--
作者：
Spielvogel E;Lee SK;Zhou S;Lockbaum GJ;Henes M;Sondgeroth A;Kosovrasti K;Nalivaika EA;Ali A;Yilmaz NK;Schiffer CA;Swanstrom R
Darunavir （DRV）在体内获得的高药物浓度的有效HIV-1蛋白酶抑制剂（pi）中是例外的。对DRV的从头耐药途径知之甚少。我们选择了对10种pi及其结构前体DRV的高药物浓度抗性。突变通过两种途径积累（由蛋白酶突变I50V或I84V锚定）。抑制剂P1'-等效位置的微小变化导致优先使用一种途径。抑制剂P2'-等效位置的变化决定了在耐药病毒中保留的效力差异，并影响了选定的突变。来自两种途径的病毒变异在Gag切割位点的代偿突变选择上存在差异。这些结果揭示了第五代pi可以达到的高水平的选择压力，以及抑制剂的特性如何影响抗性途径和面对抗性时的剩余效力。
Darunavir (DRV) is exceptional among potent HIV-1 protease inhibitors (PIs) in high drug concentrations that are achieved in vivo. Little is known about the de novo resistance pathway for DRV. We selected for resistance to high drug concentrations against 10 PIs and their structural precursor DRV. Mutations accumulated through two pathways (anchored by protease mutations I50V or I84V). Small changes in the inhibitor P1'-equivalent position led to preferential use of one pathway over the other. Changes in the inhibitor P2'-equivalent position determined differences in potency that were retained in the resistant viruses and that impacted the selected mutations. Viral variants from the two pathways showed differential selection of compensatory mutations in Gag cleavage sites. These results reveal the high level of selective pressure that is attainable with fifth-generation PIs and how features of the inhibitor affect both the resistance pathway and the residual potency in the face of resistance.
影响因子：
5.5
作者：
Oezen, Ayseguel;Haliloglu, Turkan;Schiffer, Celia A.
通讯作者：
Schiffer, Celia A.
影响因子：
5.6
作者：
Ozen A;Haliloğlu T;Schiffer CA
通讯作者：
Schiffer CA