Acute antagonism in three-drug combinations for vaginal HIV prevention in humanized mice.
Acute antagonism in three-drug combinations for vaginal HIV prevention in humanized mice.
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DOI：
10.1038/s41598-023-31695-5
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发表时间：
2023-03-21
影响因子：
4.6
通讯作者：
Baum, Marc M.
中科院分区：
文献类型：
--
作者：
Gallay, Philippe A.;Ramirez, Christina M.;Baum, Marc M.
低收入和中等收入国家的少女和年轻妇女感染艾滋病毒-1的风险格外高。旨在克服这一全球健康挑战的新的非疫苗生物医学产品需要在递送一种或多种抗病毒化合物的基础上提供一系列安全、有效和谨慎的剂型。总体策略包括通过插入物/片剂、凝胶、薄膜和阴道内环进行阴道给药。这种方法的吸引力来自于对女性的控制和局部治疗，从而潜在地减少了对药物及其代谢物的全身暴露。以富马酸替诺福韦二氧吡酯（TDF）和恩曲他滨（FTC）为基础的口服方案在HIV-1暴露前预防（PrEP）中是有效的，并为阴道PrEP奠定了良好的基础。本研究采用骨髓/肝脏/胸腺人源化小鼠，测量单药和联合抗病毒药物阴道应用对HIV-1的体内疗效，并利用Chou-Talalay数学模型分析数据，研究剂量效应特征。出乎意料的是，在由TDF-FTC与使用不同作用模式的第三种药物联合组成的药物组合中观察到强烈的拮抗作用。当TDF从方案中省略时，拮抗作用得到补救。我们的方法为预防HIV-1和其他病毒性疾病的药物组合的临床前、合理和系统评估提供了一个翻译模板。
Adolescent girls and young women in low- to middle-income countries are disproportionately at risk of becoming HIV-1 infected. New non-vaccine biomedical products aimed at overcoming this global health challenge need to provide a range of safe, effective, and discreet dosage forms based on the delivery of one or more antiviral compounds. An overarching strategy involves vaginal drug administration through inserts/tablets, gels, films, and intravaginal rings. The approach derives its appeal from being women-controlled and topical, there-by potentially minimizing systemic exposure to the agents and their metabolites. Oral regimens based on tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are established and effective in HIV-1 pre-exposure prophylaxis (PrEP), and form a promising basis for vaginal PrEP. Here, we used bone marrow/liver/thymus humanized mice to measure the in vivo efficacy against HIV-1 of single and combination antiviral compounds applied vaginally, coupled with data analysis using the Chou-Talalay mathematical model to study the dose–effect characteristics. Unexpectedly, strong antagonism was observed in drug combinations composed of TDF-FTC coupled with a third agent using a different mode of action against HIV-1. The antagonistic effect was remedied when TDF was omitted from the regimen. Our approach provides a translational template for the preclinical, rational, and systematic evaluation of drug combinations for the prevention of HIV-1, and other viral diseases.
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影响因子：
3.8
作者：
Lal, Manjari;Lai, Manshun;Zydowsky, Thomas
通讯作者：
Zydowsky, Thomas
DOI：
10.1073/pnas.0801388105
发表时间：
2008-04-08
影响因子：
11.1
作者：
Bobardt, Michael D.;Cheng, Guofeng;Gallay, Philippe A.
通讯作者：
Gallay, Philippe A.
影响因子：
6
作者：
Montgomery, Elizabeth T.;Beksinska, Mags;van der Straten, Ariane
通讯作者：
van der Straten, Ariane
影响因子：
4.6
作者：
Baum, Marc M.;Ramirez, Christina M.;Gallay, Philippe A.
通讯作者：
Gallay, Philippe A.
DOI：
10.2174/1874357901812010001
发表时间：
2018-01-01
期刊：
The open virology journal
影响因子：
--
作者：
Gallay, Philippe A;Chatterji, Udayan;Moss, John A
通讯作者：
Moss, John A