INSERM U1016, Institut Cochin, Paris, France.
CNRS, UMR8104, Paris, France.
J Virol. 2017 Nov 30;91(24). doi: 10.1128/JVI.01237-17. Print 2017 Dec 15.
HIV-1-infected macrophages participate in virus dissemination and establishment of virus reservoirs in host tissues, but the mechanisms for virus cell-to-cell transfer to macrophages remain unknown. Here, we reveal the mechanisms for cell-to-cell transfer from infected T cells to macrophages and virus spreading between macrophages. We show that contacts between infected T lymphocytes and macrophages lead to cell fusion for the fast and massive transfer of CCR5-tropic viruses to macrophages. Through the merge of viral material between T cells and macrophages, these newly formed lymphocyte-macrophage fused cells acquire the ability to fuse with neighboring noninfected macrophages. Together, these two-step envelope-dependent cell fusion processes lead to the formation of highly virus-productive multinucleated giant cells reminiscent of the infected multinucleated giant macrophages detected in HIV-1-infected patients and simian immunodeficiency virus-infected macaques. These mechanisms represent an original mode of virus transmission for viral spreading and a new model for the formation of macrophage virus reservoirs during infection. We reveal a very efficient mechanism involved in cell-to-cell transfer from infected T cells to macrophages and subsequent virus spreading between macrophages by a two-step cell fusion process. Infected T cells first establish contacts and fuse with macrophage targets. The newly formed lymphocyte-macrophage fused cells then acquire the ability to fuse with surrounding uninfected macrophages, leading to the formation of infected multinucleated giant cells that can survive for a long time, as evidenced in lymphoid organs and the central nervous system. This route of infection may be a major determinant for virus dissemination and the formation of macrophage virus reservoirs in host tissues during HIV-1 infection.
HIV-1 感染的巨噬细胞参与病毒在宿主组织中的传播和病毒库的建立，但病毒细胞间转移到巨噬细胞的机制仍不清楚。在这里，我们揭示了从感染的 T 细胞到巨噬细胞的细胞间转移和巨噬细胞之间病毒传播的机制。我们表明，感染的淋巴细胞和巨噬细胞之间的接触导致细胞融合，从而快速和大量地将 CCR5 嗜性病毒转移到巨噬细胞中。通过 T 细胞和巨噬细胞之间的病毒物质融合，这些新形成的淋巴细胞-巨噬细胞融合细胞获得了与邻近未感染的巨噬细胞融合的能力。这两个依赖包膜的细胞融合过程共同导致形成具有高度病毒产生能力的多核巨细胞，类似于在 HIV-1 感染患者和感染猴免疫缺陷病毒的猕猴中检测到的感染多核巨细胞。这些机制代表了病毒传播的一种原始的病毒传输方式，也是感染过程中形成巨噬细胞病毒库的新模型。我们揭示了一种非常有效的机制，涉及从感染的 T 细胞到巨噬细胞的细胞间转移，以及通过两步细胞融合过程在巨噬细胞之间随后的病毒传播。感染的 T 细胞首先建立接触并与巨噬细胞靶细胞融合。新形成的淋巴细胞-巨噬细胞融合细胞然后获得与周围未感染的巨噬细胞融合的能力，导致形成感染的多核巨细胞，这些细胞可以长时间存活，正如在淋巴器官和中枢神经系统中所证明的那样。这种感染途径可能是 HIV-1 感染期间病毒在宿主组织中传播和形成巨噬细胞病毒库的主要决定因素。
