Department of Virology, Medical Microbiology, University Medical Center Utrecht, The Netherlands.
Retrovirology. 2011 Aug 24;8:70. doi: 10.1186/1742-4690-8-70.
Maturation inhibitors are an experimental class of antiretrovirals that inhibit Human Immunodeficiency Virus (HIV) particle maturation, the structural rearrangement required to form infectious virus particles. This rearrangement is triggered by the ordered cleavage of the precursor Gag polyproteins into their functional counterparts by the viral enzyme protease. In contrast to protease inhibitors, maturation inhibitors impede particle maturation by targeting the substrate of protease (Gag) instead of the protease enzyme itself. Direct cross-resistance between protease and maturation inhibitors may seem unlikely, but the co-evolution of protease and its substrate, Gag, during protease inhibitor therapy, could potentially affect future maturation inhibitor therapy. Previous studies showed that there might also be an effect of protease inhibitor resistance mutations on the development of maturation inhibitor resistance, but the exact mechanism remains unclear. We used wild-type and protease inhibitor resistant viruses to determine the impact of protease inhibitor resistance mutations on the development of maturation inhibitor resistance.
Our resistance selection studies demonstrated that the resistance profiles for the maturation inhibitor bevirimat are more diverse for viruses with a mutated protease compared to viruses with a wild-type protease. Viral replication did not appear to be a major factor during emergence of bevirimat resistance. In all in vitro selections, one of four mutations was selected: Gag V362I, A364V, S368N or V370A. The impact of these mutations on maturation inhibitor resistance and viral replication was analyzed in different protease backgrounds. The data suggest that the protease background affects development of HIV-1 resistance to bevirimat and the replication profiles of bevirimat-selected HIV-1. The protease-dependent bevirimat resistance and replication levels can be explained by differences in CA/p2 cleavage processing by the different proteases.
These findings highlight the complicated interactions between the viral protease and its substrate. By providing a better understanding of these interactions, we aim to help guide the development of second generation maturation inhibitors.
成熟抑制剂是一种实验性的抗逆转录病毒药物，可抑制人类免疫缺陷病毒（HIV）颗粒成熟，这是形成感染性病毒颗粒所需的结构重排。这种重排是由病毒蛋白酶有序切割前体 Gag 多聚蛋白为其功能对应物触发的。与蛋白酶抑制剂不同，成熟抑制剂通过靶向蛋白酶（Gag）的底物而不是蛋白酶本身来阻碍颗粒成熟。蛋白酶和成熟抑制剂之间的直接交叉耐药性似乎不太可能，但蛋白酶抑制剂治疗期间蛋白酶和其底物 Gag 的共同进化可能会影响未来的成熟抑制剂治疗。以前的研究表明，蛋白酶抑制剂耐药突变也可能对成熟抑制剂耐药的发展产生影响，但确切的机制尚不清楚。我们使用野生型和蛋白酶抑制剂耐药病毒来确定蛋白酶抑制剂耐药突变对成熟抑制剂耐药发展的影响。
我们的耐药选择研究表明，与野生型蛋白酶相比，突变型蛋白酶的病毒对成熟抑制剂比伐洛宾的耐药谱更为多样化。病毒复制在比伐洛宾耐药出现过程中似乎不是一个主要因素。在所有体外选择中，选择了四个突变中的一个：Gag V362I、A364V、S368N 或 V370A。在不同的蛋白酶背景下分析了这些突变对成熟抑制剂耐药性和病毒复制的影响。数据表明，蛋白酶背景影响 HIV-1 对比伐洛宾的耐药性发展和比伐洛宾选择的 HIV-1 的复制谱。不同蛋白酶的 CA/p2 切割处理差异可以解释蛋白酶依赖性比伐洛宾耐药性和复制水平的差异。
这些发现强调了病毒蛋白酶与其底物之间复杂的相互作用。通过更好地了解这些相互作用，我们旨在帮助指导第二代成熟抑制剂的开发。
