Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
AIDS Res Hum Retroviruses. 2020 Oct;36(10):835-841. doi: 10.1089/AID.2020.0064. Epub 2020 Aug 3.
The efficacy of combined antiretroviral therapy (cART) against HIV-1 is evidenced by reduction of plasma viremia, disease progression, viral transmission, and mortality. However, major challenges still remain in HIV-1 management, especially the emergence of resistant strains and the persistence of viral reservoirs, apparent after cART treatment interruption. Efforts are ongoing to explore the most effective means to intensify cART and successfully control residual viral replication. We anticipate that the reduction by cART of HIV-1 reservoirs could be further enhanced by combining cART with entry inhibitors and drugs that silence CCR5 expression. CCR5-targeting drugs are attractive option because of their low side effects when combined with other antiretroviral drugs. The concept that their inclusion would be effective has been supported by the reduction in two long terminal repeat unintegrated circular DNA, a marker for new infections, when CCR5-targeting drugs are added to standard antiretroviral treatment. This study is, in part, an extension of our previous study demonstrating greater preservation of human CD4+ T-cells and CD4+/CD8+ cell ratios in HIV-infected CD34+ NSG mice when CCR5-targeting drugs were included with standard cART. In this study, we treated HIV-1-infected cell cultures with cART or cART plus CCR5-targeting drugs (maraviroc and rapamycin). We found that treatment intensification with CCR5-targeting drugs led to a significant reduction of HIV-1 replication in peripheral blood ononuclear cells (PBMCs), as judged by measured viral DNA copies and p24 levels. Our data provide proof of principle for the benefit of adding CCR5-targeting drugs to traditional, standard cART to further lower viremia and subsequently reduce viral reservoirs in clinical settings, while potentially lowering side effects by reducing cART concentrations.
联合抗逆转录病毒疗法（cART）对 HIV-1 的疗效体现在降低血浆病毒载量、疾病进展、病毒传播和死亡率上。然而，HIV-1 管理仍面临重大挑战，特别是在 cART 治疗中断后，耐药株的出现和病毒库的持续存在。目前正在努力探索最有效的方法来加强 cART，以成功控制残留的病毒复制。我们预计，通过将 cART 与进入抑制剂和沉默 CCR5 表达的药物联合使用，可以进一步增强 cART 对 HIV-1 储库的降低作用。由于 CCR5 靶向药物与其他抗逆转录病毒药物联合使用时副作用较低，因此它们是一种有吸引力的选择。当 CCR5 靶向药物被添加到标准抗逆转录病毒治疗中时，两个长末端重复未整合环状 DNA（一种新感染的标志物）减少，这支持了它们的包含将是有效的概念。这项研究部分是对我们之前研究的扩展，该研究表明，当 CCR5 靶向药物与标准 cART 一起使用时，HIV 感染的 CD34+ NSG 小鼠中的人类 CD4+T 细胞和 CD4+/CD8+细胞比例得到了更好的保留。在这项研究中，我们用 cART 或 cART 加 CCR5 靶向药物（马拉维若和雷帕霉素）处理 HIV-1 感染的细胞培养物。我们发现，用 CCR5 靶向药物强化治疗可显著降低外周血单个核细胞（PBMCs）中的 HIV-1 复制，这可通过测量病毒 DNA 拷贝和 p24 水平来判断。我们的数据为在传统的标准 cART 中添加 CCR5 靶向药物以进一步降低病毒血症并随后降低临床环境中的病毒库提供了原理证明，同时通过降低 cART 浓度潜在降低副作用。
