DataSheet_1_Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques.docx

Introduction and methodsTo understand the relationship between immunovirological factors and antiretroviral (ARV) drug levels in lymph nodes (LN) in HIV therapy, we analyzed drug levels in twenty-one SIV-infected rhesus macaques subcutaneously treated with daily tenofovir (TFV) and emtricitabine (FTC) for three months.
ResultsThe intracellular active drug-metabolite (IADM) levels (TFV-dp and FTC-tp) in lymph node mononuclear cells (LNMC) were significantly lower than in peripheral blood mononuclear cells (PBMC) (P≤0.005). Between Month 1 and Month 3, IADM levels increased in both LNMC (P≤0.001) and PBMC (P≤0.01), with a steeper increase in LNMC (P≤0.01). The viral dissemination in plasma, LN, and rectal tissue at ART initiation correlated negatively with IADM levels at Month 1. Physiologically-based pharmacokinetic model simulations suggest that, following subcutaneous ARV administration, ART-induced reduction of immune activation improves the formation of active drug-metabolites through modulation of kinase activity and/or through improved parent drug accessibility to LN cellular compartments.
ConclusionThese observations have broad implications for drugs that need to phosphorylate to exert their pharmacological activity, especially in the settings of the pre-/post-exposure prophylaxis and efficacy of antiviral therapies targeting pathogenic viruses such as HIV or SARS-CoV-2 replicating in highly inflammatory anatomic compartments.

引言与方法
为明确HIV治疗中免疫病毒学因素与淋巴结（lymph nodes, LN）内抗逆转录病毒（antiretroviral, ARV）药物水平的关联，我们对21只每日皮下注射替诺福韦（tenofovir, TFV）与恩曲他滨（emtricitabine, FTC）、持续治疗3个月的猴免疫缺陷病毒（Simian Immunodeficiency Virus, SIV）感染恒河猴的药物水平进行了分析。
结果
淋巴结单个核细胞（lymph node mononuclear cells, LNMC）内的细胞内活性药物代谢物（intracellular active drug-metabolite, IADM）水平（替诺福韦二磷酸TFV-dp与恩曲他滨三磷酸FTC-tp）显著低于外周血单个核细胞（peripheral blood mononuclear cells, PBMC）（P≤0.005）。在第1个月至第3个月期间，LNMC与PBMC内的IADM水平均有所升高（P≤0.001、P≤0.01），且LNMC内的升高幅度更为显著（P≤0.01）。抗逆转录病毒治疗启动时，血浆、淋巴结及直肠组织内的病毒播散情况与第1个月的IADM水平呈负相关。基于生理的药代动力学模型（physiologically-based pharmacokinetic model）模拟结果显示，皮下给予ARV药物后，抗逆转录病毒治疗诱导的免疫激活可通过调控激酶活性、或改善原形药物向LN细胞区室的递送效率，促进活性药物代谢物的生成。
结论
上述发现对需经磷酸化发挥药理活性的药物具有广泛的应用价值，尤其适用于以在高炎症性解剖部位复制的HIV或新型冠状病毒（Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2）等致病性病毒为靶点的抗病毒治疗，以及暴露前/暴露后预防的相关场景。