Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
Antiviral Res. 2018 Jun;154:140-148. doi: 10.1016/j.antiviral.2018.04.002. Epub 2018 Apr 6.
Adequate distribution of antiretroviral drugs to infected cells in HIV patients is critical for viral suppression. In humans and primates, HIV- and SIV-infected CD4 T cells in adipose tissues have recently been identified as reservoirs for infectious virus. To better characterize adipose tissue as a pharmacological sanctuary for HIV-infected cells, in vitro experiments were conducted to assess antiretroviral drug efficacy in the presence of adipocytes, and drug penetration in adipose tissue cells (stromal-vascular-fraction cells and mature adipocytes) was examined in treated humans and monkeys. Co-culture experiments between HIV-1-infected CD4 T cells and primary human adipocytes showed that adipocytes consistently reduced the antiviral efficacy of the nucleotide reverse transcriptase inhibitor tenofovir and its prodrug forms tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). In HIV-infected persons, LC-MS/MS analysis of intracellular lysates derived from adipose tissue stromal-vascular-fraction cells or mature adipocytes suggested that integrase inhibitors penetrate adipose tissue, whereas penetration of nucleoside/nucleotide reverse transcriptase inhibitors such as TDF, emtricitabine, abacavir, and lamivudine is restricted. The limited distribution and functions of key antiretroviral drugs within fat depots may contribute to viral persistence in adipose tissue.
为了实现病毒抑制，将抗逆转录病毒药物充分分配到 HIV 患者受感染的细胞中至关重要。在人类和灵长类动物中，最近在脂肪组织中发现了感染 HIV 和 SIV 的 CD4 T 细胞，它们是感染性病毒的储存库。为了更好地将脂肪组织描述为感染 HIV 的细胞的药理学避难所，进行了体外实验以评估在存在脂肪细胞的情况下抗逆转录病毒药物的疗效，并在接受治疗的人类和猴子中检查了药物在脂肪组织细胞（基质血管部分细胞和成熟脂肪细胞）中的渗透。HIV-1 感染的 CD4 T 细胞与原代人脂肪细胞的共培养实验表明，脂肪细胞始终降低核苷酸逆转录酶抑制剂替诺福韦及其前药形式富马酸替诺福韦二吡呋酯（TDF）和替诺福韦艾拉酚胺（TAF）的抗病毒功效。在 HIV 感染者中，源自脂肪组织基质血管部分细胞或成熟脂肪细胞的细胞内裂解物的 LC-MS/MS 分析表明，整合酶抑制剂可渗透脂肪组织，而核苷/核苷酸逆转录酶抑制剂（如 TDF、恩曲他滨、阿巴卡韦和拉米夫定）的渗透则受到限制。关键抗逆转录病毒药物在脂肪储存库中的有限分布和功能可能导致病毒在脂肪组织中持续存在。
