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.

中文翻译：

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CCR5 靶向药物增强了原代细胞中标准联合抗逆转录病毒疗法的抗 HIV 活性。

血浆病毒血症、疾病进展、病毒传播和死亡率的减少证明了联合抗逆转录病毒疗法 (cART) 对 HIV-1 的疗效。然而，在 HIV-1 管理方面仍然存在重大挑战，尤其是耐药菌株的出现和病毒库的持续存在，这在 cART 治疗中断后很明显。正在努力探索加强 cART 并成功控制残留病毒复制的最有效方法。我们预计，通过将 cART 与进入抑制剂和沉默 CCR5 表达的药物相结合，可以进一步增强 cART 对 HIV-1 储库的减少。CCR5 靶向药物与其他抗逆转录病毒药物联合使用时副作用小，因此是有吸引力的选择。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的环状 DNA（一种新感染的标志物）的减少支持了它们的包含将是有效的概念。这项研究在一定程度上是我们之前研究的延伸，证明当 CCR5 靶向药物包含在标准 cART 中时，在 HIV 感染的 CD34+ NSG 小鼠中，人类 CD4+ T 细胞和 CD4+/CD8+ 细胞比率得到更好的保存。在这项研究中，我们用 cART 或 cART 加 CCR5 靶向药物（马拉韦罗和雷帕霉素）处理感染 HIV-1 的细胞培养物。我们发现，根据测量的病毒 DNA 拷贝数和 p24 水平判断，使用 CCR5 靶向药物强化治疗导致外周血核细胞 (PBMC) 中 HIV-1 复制显着减少。