美国FDA批准的长效皮下利纳卡帕韦（LEN）作为第一类HIV壳体抑制剂被用于治疗多药耐药性HIV-1，采用每年两次的剂量给药，目前正在进行HIV-1预暴露预防（PrEP）的研究。我们之前构建了一个编码HIV-1壳体并在猪尾巴猴（PTM）中高效复制的类猴HIV-1克隆体（stHIV-A19），从而得到一个非人类灵长类动物模型，非常适合评估在体内的LEN PrEP效果。我们通过体外实验确定了LEN对PTM体外外周血单个核细胞中stHIV-A19的抗病毒活性，并在体内评估了天然PTM中皮下LEN的药代动力学。为了评估LEN PrEP的保护效果，天然PTM分别在stHIV-A19高剂量静脉挑战前30天接受了单次皮下LEN注射（剂量为25 mg/kg，N=3）或溶剂（N=4），或在stHIV-A19挑战前3天开始连续7天皮下注射3种药物的对照PrEP方案（N=3）。体外实验结果显示，LEN对stHIV-A19表现出与对HIV-1相当的强效抗病毒活性。在体内，皮下LEN在PTM中显示出持续的血浆药物暴露。在stHIV-A19挑战后，所有溶剂对照组动物均被感染，而所有LEN和对照PrEP组动物均被保护免受感染。这些发现凸显了stHIV-A19/PTM模型的实用性，并支持了长效LEN在人类PrEP方面的临床开发。Gilead Sciences作为Gilead Sciences和Frederick National Lab之间的合作研究与开发协议的一部分；来自国家癌症研究所、国立卫生研究院的联邦资金，合同号为75N91019D00024/HHSN261201500003I；NIH授予R01AI078788号。版权所有©2023 The Author(s)。由Elsevier B.V.出版。保留所有权利。

Long-acting subcutaneous lenacapavir (LEN), a first-in-class HIV capsid inhibitor approved by the US FDA for the treatment of multidrug-resistant HIV-1 with twice yearly dosing, is under investigation for HIV-1 pre-exposure prophylaxis (PrEP). We previously derived a simian-tropic HIV-1 clone (stHIV-A19) that encodes an HIV-1 capsid and replicates to high titres in pigtail macaques (PTM), resulting in a nonhuman primate model well-suited for evaluating LEN PrEP in vivo.Lenacapavir potency against stHIV-A19 in PTM peripheral blood mononuclear cells in vitro was determined and subcutaneous LEN pharmacokinetics were evaluated in naïve PTMs in vivo. To evaluate the protective efficacy of LEN PrEP, naïve PTMs received either a single subcutaneous injection of LEN (25 mg/kg, N = 3) or vehicle (N = 4) 30 days before a high-dose intravenous challenge with stHIV-A19, or 7 daily subcutaneous injections of a 3-drug control PrEP regimen starting 3 days before stHIV-A19 challenge (N = 3).In vitro, LEN showed potent antiviral activity against stHIV-A19, comparable to its potency against HIV-1. In vivo, subcutaneous LEN displayed sustained plasma drug exposures in PTMs. Following stHIV-A19 challenge, while all vehicle control animals became productively infected, all LEN and 3-drug control PrEP animals were protected from infection.These findings highlight the utility of the stHIV-A19/PTM model and support the clinical development of long-acting LEN for PrEP in humans.Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab; federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I; NIH grant R01AI078788.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.