Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Translational Research Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
mBio. 2021 Jan 12;12(1):e03134-20. doi: 10.1128/mBio.03134-20.
Despite the effectiveness of antiretroviral (ARV) therapy, virological failure can occur in some HIV-1-infected patients in the absence of mutations in drug target genes. We previously reported that, , the lab-adapted HIV-1 NL4-3 strain can acquire resistance to the integrase inhibitor dolutegravir (DTG) by acquiring mutations in the envelope glycoprotein (Env) that enhance viral cell-cell transmission. In this study, we investigated whether Env-mediated drug resistance extends to ARVs other than DTG and whether it occurs in other HIV-1 isolates. We demonstrate that Env mutations can reduce susceptibility to multiple classes of ARVs and also increase resistance to ARVs when coupled with target-gene mutations. We observe that the NL4-3 Env mutants display a more stable and closed Env conformation and lower rates of gp120 shedding than the WT virus. We also selected for Env mutations in clinically relevant HIV-1 isolates in the presence of ARVs. These Env mutants exhibit reduced susceptibility to DTG, with effects on replication and Env structure that are HIV-1 strain dependent. Finally, to examine a possible relevance of Env-mediated drug resistance, we performed single-genome sequencing of plasma-derived virus from five patients failing an integrase inhibitor-containing regimen. This analysis revealed the presence of several mutations in the highly conserved gp120-gp41 interface despite low frequency of resistance mutations in integrase. These results suggest that mutations in Env that enhance the ability of HIV-1 to spread via a cell-cell route may increase the opportunity for the virus to acquire high-level drug resistance mutations in ARV target genes. Although combination antiretroviral (ARV) therapy is highly effective in controlling the progression of HIV disease, drug resistance can be a major obstacle. Recent findings suggest that resistance can develop without ARV target gene mutations. We previously reported that mutations in the HIV-1 envelope glycoprotein (Env) confer resistance to an integrase inhibitor. Here, we investigated the mechanism of Env-mediated drug resistance and the possible contribution of Env to virological failure We demonstrate that Env mutations can reduce sensitivity to major classes of ARVs in multiple viral isolates and define the effect of the Env mutations on Env subunit interactions. We observed that many Env mutations accumulated in individuals failing integrase inhibitor therapy despite a low frequency of resistance mutations in integrase. Our findings suggest that broad-based Env-mediated drug resistance may impact therapeutic strategies and provide clues toward understanding how ARV-treated individuals fail therapy without acquiring mutations in drug target genes.
尽管抗逆转录病毒 (ARV) 疗法有效，但在没有药物靶基因突变的情况下，一些 HIV-1 感染患者仍可能发生病毒学失败。我们之前报道过，实验室适应的 HIV-1 NL4-3 株可以通过在增强病毒细胞间传播的包膜糖蛋白 (Env) 中获得突变来获得对整合酶抑制剂多替拉韦 (DTG) 的耐药性。在这项研究中，我们研究了 Env 介导的耐药性是否扩展到 DTG 以外的其他 ARV 以及是否发生在其他 HIV-1 分离株中。我们证明，Env 突变可以降低对多种 ARV 的敏感性，并且当与靶基因突变结合时，还可以增加对 ARV 的耐药性。我们观察到 NL4-3 Env 突变体显示出更稳定和封闭的 Env 构象，以及比 WT 病毒更低的 gp120 脱落率。我们还在 ARV 存在的情况下选择了临床相关的 HIV-1 分离株中的 Env 突变。这些 Env 突变体对 DTG 的敏感性降低，对复制和 Env 结构的影响因 HIV-1 株而异。最后，为了研究 Env 介导的耐药性的可能相关性，我们对五名正在接受整合酶抑制剂治疗方案的患者的血浆衍生病毒进行了单基因组测序。这项分析显示，尽管整合酶中的耐药突变频率较低，但在高度保守的 gp120-gp41 界面中存在多种突变。这些结果表明，增强 HIV-1 通过细胞间途径传播能力的 Env 突变可能会增加病毒获得 ARV 靶基因高水平耐药突变的机会。尽管联合抗逆转录病毒 (ARV) 疗法在控制 HIV 疾病进展方面非常有效，但耐药性可能是一个主要障碍。最近的研究结果表明，耐药性可以在没有 ARV 靶基因突变的情况下发展。我们之前报道过，HIV-1 包膜糖蛋白 (Env) 的突变赋予了对整合酶抑制剂的耐药性。在这里，我们研究了 Env 介导的耐药性机制以及 Env 对病毒学失败的可能贡献。我们证明，Env 突变可以降低多种病毒分离株中主要 ARV 类别的敏感性，并定义了 Env 突变对 Env 亚基相互作用的影响。我们观察到，尽管整合酶中的耐药突变频率较低，但许多 Env 突变在接受整合酶抑制剂治疗的个体中积累。我们的研究结果表明，广泛的 Env 介导的耐药性可能会影响治疗策略，并提供线索，了解为什么 ARV 治疗的个体在没有获得药物靶基因突变的情况下会失败治疗。
