Bictegravir (GS-9883) is an integrase strand transfer inhibitor (INSTI) used for the treatment of human immunodeficiency virus type 1 (HIV-1) infection[1]. By selectively inhibiting the strand transfer activity of HIV-1 integrase, Bictegravir effectively blocks the integration of viral DNA into the host genome, thereby exerting its antiviral effect[2]. Bictegravir demonstrates a significantly higher inhibitory potency (IC50=7.5nM) against HIV-1 integrase strand transfer activity compared to its inhibition of the integrase's 3'-processing activity, indicating high selectivity, and it exhibits potent antiviral activity across various cell types[3-4].
In vitro, treatment of the human hepatoblastoma cell line Hep3B with Bictegravir (1–20μM) for 48 hours significantly reduced cellular glucose uptake and induced mitochondrial dysfunction, leading to mitochondrial stress[5]. Bictegravir (0.01–1000nM) treatment of NL4.3 recombinant viruses carrying combinations of HIV-1 integrase mutations, cultured in GFP-reporter CD4+ T cells for 3 days, significantly inhibited viral replication activity[6].
In vivo, daily oral self-administration of Bictegravir (0.375mg) in combination with Emtricitabine (1.23mg) and Tenofovir Alafenamide (0.15375mg) to EcoHIV-infected mice for 5 weeks significantly reduced CXCL1/KC expression in the nucleus accumbens and altered peripheral immune factor levels[7]. Oral administration of Bictegravir (5mg/kg/day) via peanut butter pellets to C57BL/6 mice for 14 days significantly decreased the mRNA expression of tight junction proteins Tjp1 and Ocln in brain capillaries and downregulated the gene expression of drug efflux transporters Abcb1a and Abcg2[8].
References:
[1] Spagnuolo V, Castagna A, Lazzarin A. Bictegravir. Curr Opin HIV AIDS. 2018 Jul;13(4):326-333.
[2] Markham A. Bictegravir: First Global Approval. Drugs. 2018 Apr;78(5):601-606.
[3] Tsiang M, Jones GS, Goldsmith J, et al. Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile. Antimicrob Agents Chemother. 2016 Nov 21;60(12):7086-7097.
[4] Smith SJ, Zhao XZ, Passos DO, et al. HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants. Antimicrob Agents Chemother. 2020 Aug 20;64(9):e00611-20.
[5] García-Martínez P, Gisbert-Ferrándiz L, Álvarez Á, et al. Bictegravir alters glucose tolerance in vivo and causes hepatic mitochondrial dysfunction. Antiviral Res. 2024 Nov;231:106020.
[6] Cheung PK, Shahid A, Dong W, et al. Impact of combinations of clinically observed HIV integrase mutations on phenotypic resistance to integrase strand transfer inhibitors (INSTIs): a molecular study. J Antimicrob Chemother. 2022 Mar 31;77(4):979-988.
[7] Xie Q, Namba MD, Buck LA, et al. Effects of Antiretroviral Treatment on Central and Peripheral Immune Response in Mice with EcoHIV Infection. Cells. 2024 May 20;13(10):882.
[8] Huang C, Hoque T, Bendayan R. Antiretroviral drugs efavirenz, dolutegravir and bictegravir dysregulate blood-brain barrier integrity and function. Front Pharmacol. 2023 Mar 8;14:1118580.
Bictegravir (GS-9883) 是一种用于治疗人类免疫缺陷病毒1型（HIV-1）感染的整合酶链转移抑制剂（INSTI）[1]。Bictegravir通过选择性抑制HIV-1整合酶的链转移活性，有效阻断病毒DNA整合入宿主基因组，从而发挥抗病毒作用[2]。Bictegravir对HIV-1整合酶链转移活性的抑制效力（IC50为7.5nM）远高于其对整合酶3’-加工活性的抑制，展现出高度的选择性，且在多种细胞中均表现出强效的抗病毒活性[3-4]。
在体外，Bictegravir (1–20μM) 处理人肝癌细胞系Hep3B细胞48小时，显著降低细胞对葡萄糖的摄取，并引起线粒体功能障碍，诱导线粒体应激[5]。Bictegravir (0.01–1000nM) 处理携带HIV-1整合酶突变组合的NL4.3重组病毒，在GFP报告CD4+ T细胞中培养3天，Bictegravir显著抑制病毒复制活性[6]。
在体内，Bictegravir（0.375mg）联合Emtricitabine（1.23mg）和Tenofovir Alafenamide（0.15375mg）通过口服自给药方式每日处理EcoHIV感染小鼠，持续5周，显著降低了伏隔核中CXCL1/KC的表达并改变了外周免疫因子水平[7]。Bictegravir（5mg/kg/day）通过花生酱丸剂口服给药处理C57BL/6小鼠14天，显著降低了脑毛细血管中紧密连接蛋白Tjp1和Ocln的mRNA表达，并下调了药物外排转运蛋白Abcb1a和Abcg2的基因表达[8]。