Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C/ Dr. Esquerdo 46, 28007 Madrid, Spain.
Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C/ Dr. Esquerdo 46, 28007 Madrid, Spain; Unidad de cultivos celulares, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), C/ Dr. Esquerdo 46, 28007 Madrid, Spain.
Antiviral Res. 2015 Nov;123:163-71. doi: 10.1016/j.antiviral.2015.09.014. Epub 2015 Sep 30.
Although an effective combination of antiretroviral therapy (cART) controls HIV-1 viraemia in infected patients, viral latency established soon after infection hinders HIV-1 eradication. It has been shown that bryostatin-1 (BRY) inhibits HIV-infection in vitro and reactivates the latent virus through the protein kinase C-NF-κB pathway. We determined the in vitro potential effect of BRY in combination with currently used antiretroviral drugs. BRY alone or in combination with maraviroc (MVC)/Atripla (ATP) was tested for its capacity to reactivate latent virus and inhibit new infections. JLTRG-R5 cells and two latent HIV-1-infected cell lines, J89GFP and THP89GFP, were used as latency models. To quantify HIV infection, the reporter cell line TZM-bl was used. We found that BRY reactivates HIV-1 even in combination with MVC or ATP. Antiretroviral combinations with BRY do not interfere with BRY activity (i.e., the reactivation of latently infected cells) or with the antiviral activity of antiretroviral drugs. In addition, BRY-mediated down-modulation of surface CD4 and CXCR4 was not affected when it was used in combination with other antiretrovirals, and no hyperactivation or high-proliferation effects were observed in primary T cells. Moreover, the BRY treatment was able to reactivate HIV-1 in CD4+ T cells from HIV-1-infected patients under cART. Thus, we propose the use of BRY to purge the viral reservoir and recommend its combination with current antiretroviral treatments.
尽管有效的抗逆转录病毒疗法（cART）可控制感染患者的 HIV-1 病毒血症，但感染后不久建立的病毒潜伏期阻碍了 HIV-1 的清除。已经表明，原海绵素-1（BRY）可抑制 HIV 体外感染，并通过蛋白激酶 C-NF-κB 途径激活潜伏病毒。我们确定了 BRY 与目前使用的抗逆转录病毒药物联合使用的体外潜在效果。单独使用 BRY 或与马拉维若（MVC）/Atripla（ATP）联合使用，测试其激活潜伏病毒和抑制新感染的能力。JLTRG-R5 细胞和两种潜伏 HIV-1 感染的细胞系，J89GFP 和 THP89GFP，被用作潜伏期模型。为了定量 HIV 感染，使用报告细胞系 TZM-bl。我们发现 BRY 可重新激活 HIV-1，即使与 MVC 或 ATP 联合使用也是如此。与 BRY 联合使用的抗逆转录病毒药物组合不会干扰 BRY 活性（即潜伏感染细胞的激活）或抗逆转录病毒药物的抗病毒活性。此外，当与其他抗逆转录病毒药物联合使用时，BRY 介导的表面 CD4 和 CXCR4 下调不受影响，并且在原代 T 细胞中未观察到过度激活或高增殖效应。此外，BRY 治疗能够在接受 cART 的 HIV-1 感染患者的 CD4+T 细胞中重新激活 HIV-1。因此，我们建议使用 BRY 清除病毒库，并建议将其与当前的抗逆转录病毒治疗相结合。
