Espirito-Santo Maria, Santos-Costa Quirina, Calado Marta, Dorr Patrick, Azevedo-Pereira J Miguel
Centro de Patogénese Molecular, Unidade de Retrovírus e Infecções Associadas, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, Lisbon, Portugal.
AIDS Res Hum Retroviruses. 2012 May;28(5):478-85. doi: 10.1089/AID.2011.0124. Epub 2011 Oct 3.
Human immunodeficiency virus (HIV) entry into susceptible cells involves the interaction between viral envelope glycoproteins with CD4 and a chemokine receptor (coreceptor), namely CCR5 and CXCR4. This interaction has been studied to enable the discovery of a new class of antiretroviral drugs that targets the envelope glycoprotein-coreceptor interaction. However, very few data exist regarding HIV-2 susceptibility to these coreceptor inhibitors. With this work we aimed to identify this susceptibility in order to assess the potential use of these molecules to treat HIV-2-infected patients and to further understand the molecular basis of HIV-2 envelope glycoprotein interactions with CCR5 and CXCR4. We found that CCR5-using HIV-2 isolates are readily inhibited by maraviroc, TAK-779, and PF-227153, while monoclonal antibody 2D7 shows only residual or no inhibitory effects. The anti-HIV-2 activity of CXCR4-targeted molecules reveals that SDF-1α/CXCL12 inhibited all HIV-2 tested except one, while mAb 12G5 inhibited the replication of only two isolates, showing residual inhibitory effects with all the other CXCR4-using viruses. A major conclusion from our results is that infection by HIV-2 primary isolates is readily blocked in vitro by maraviroc, at concentrations similar to those required for HIV-1. The susceptibility to maraviroc was independent of CD4(+) T cell counts or clinical stage of the patient from which the virus was obtained. These findings indicate that maraviroc could constitute a reliable therapeutic alternative for HIV-2-infected patients, as long as they are infected with CCR5-using variants, and this may have direct implications for the clinical management of HIV-2-infected patients.
人类免疫缺陷病毒（HIV）进入易感细胞涉及病毒包膜糖蛋白与CD4以及一种趋化因子受体（共受体）之间的相互作用，该共受体即CCR5和CXCR4。对这种相互作用进行了研究，以发现一类针对包膜糖蛋白 - 共受体相互作用的新型抗逆转录病毒药物。然而，关于HIV - 2对这些共受体抑制剂的敏感性的数据非常少。通过这项工作，我们旨在确定这种敏感性，以便评估这些分子用于治疗HIV - 2感染患者的潜在用途，并进一步了解HIV - 2包膜糖蛋白与CCR5和CXCR4相互作用的分子基础。我们发现，使用CCR5的HIV - 2分离株很容易被马拉维若、TAK - 779和PF - 227153抑制，而单克隆抗体2D7仅显示出残余或无抑制作用。靶向CXCR4的分子的抗HIV - 2活性表明，SDF - 1α/CXCL12抑制了除一种之外的所有测试的HIV - 2，而单克隆抗体12G5仅抑制了两种分离株的复制，对所有其他使用CXCR4的病毒显示出残余抑制作用。我们结果的一个主要结论是，HIV - 2原代分离株的感染在体外很容易被马拉维若阻断，其浓度与HIV - 1所需的浓度相似。对马拉维若的敏感性与获得病毒的患者的CD4(+) T细胞计数或临床阶段无关。这些发现表明，只要HIV - 2感染患者感染的是使用CCR5的变体，马拉维若就可以构成一种可靠的治疗选择，这可能对HIV - 2感染患者的临床管理有直接影响。
