Department of Microbiology, Immunology and Physiology, Center for AIDS Health Disparities Research, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA.
Viruses. 2024 Aug 29;16(9):1374. doi: 10.3390/v16091374.
The productive replication of human immunodeficiency virus type 1 (HIV-1) involves intricate interactions between viral proteins and host cell machinery. However, the contributions of the lysosomal pathways for HIV-1 replication are not fully understood. The goal of this study was to determine the impact of lysosome-targeting compounds on HIV-1 replication and identify the cellular changes that are linked to HIV-1 inhibition using cell culture models of HIV-1 infection. Here, we demonstrate that the treatment of cells with various pharmacological agents known to inhibit lysosomal functions interfere with HIV-1 replication. The vacuolar ATPase (V-ATPase) inhibitor bafilomycin A1 exerted a potent inhibition of HIV-1 replication. Bafilomycin A1 inhibition of HIV-1 was independent of coreceptor tropism of HIV-1. Our data suggest that bafilomycin A1 inhibits HIV-1 at the post-integration steps of the virus life cycle, which include viral gene expression, virus assembly, and/or egress. Analysis of the cellular alterations following bafilomycin A1 treatment indicates that bafilomycin A1 causes a disruption in lysosome structure and functions. Treatment of cells with bafilomycin A1 caused an accumulation of unesterified cholesterol in lysosomes along with the expansion of the lysosomal compartments. Interestingly, the overexpression of the lysosomal cholesterol transporter Niemann-Pick type C 1 (NPC1) partially relieved bafilomycin A1 inhibition of HIV-1. Collectively, our data suggest that bafilomycin A1 inhibits HIV-1 replication in part by disrupting the lysosomal cholesterol trafficking pathway.
人类免疫缺陷病毒 1 型（HIV-1）的有效复制涉及病毒蛋白和宿主细胞机制之间的复杂相互作用。然而，溶酶体途径在 HIV-1 复制中的作用尚未完全了解。本研究的目的是确定溶酶体靶向化合物对 HIV-1 复制的影响，并使用 HIV-1 感染的细胞培养模型来识别与 HIV-1 抑制相关的细胞变化。在这里，我们证明了用各种已知抑制溶酶体功能的药理学试剂处理细胞会干扰 HIV-1 的复制。液泡型 ATP 酶（V-ATPase）抑制剂巴弗洛霉素 A1 对 HIV-1 复制具有很强的抑制作用。巴弗洛霉素 A1 对 HIV-1 的抑制作用不依赖于 HIV-1 的共受体嗜性。我们的数据表明，巴弗洛霉素 A1 抑制 HIV-1 在病毒生命周期的整合后步骤，包括病毒基因表达、病毒组装和/或出芽。巴弗洛霉素 A1 处理后细胞的变化分析表明，巴弗洛霉素 A1 抑制 HIV-1 在溶酶体结构和功能发生改变时。用巴弗洛霉素 A1 处理细胞会导致溶酶体中未酯化胆固醇的积累，同时溶酶体腔室扩张。有趣的是，溶酶体胆固醇转运蛋白 Niemann-Pick 型 C1（NPC1）的过表达部分缓解了巴弗洛霉素 A1 对 HIV-1 的抑制作用。总的来说，我们的数据表明，巴弗洛霉素 A1 通过破坏溶酶体胆固醇转运途径部分抑制 HIV-1 的复制。
