Siglec-1 initiates formation of the virus-containing compartment and enhances macrophage-to-T cell transmission of HIV-1

HIV-1 particles assemble and bud from the plasma membrane of infected T lymphocytes. Infected macrophages, in contrast, accumulate particles within an apparent intracellular compartment known as the virus-containing compartment or VCC. Many aspects of the formation and function of the VCC remain unclear. Here we demonstrate that VCC formation does not actually require infection of the macrophage, but can be reproduced through the exogenous addition of non-infectious virus-like particles or infectious virions to macrophage cultures. Particles were captured by Siglec-1, a prominent cell surface lectin that attaches to gangliosides on the lipid envelope of the virus. VCCs formed within infected macrophages were readily targeted by the addition of ganglioside-containing virus-like particles to the extracellular media. Depletion of Siglec-1 from the macrophage or depletion of gangliosides from viral particles prevented particle uptake into the VCC and resulted in substantial reductions of VCC volume. Furthermore, Siglec-1-mediated virion capture and subsequent VCC formation was required for efficient trans-infection of autologous T cells. Our results help to define the nature of this intracellular compartment, arguing that it is a compartment formed by particle uptake from the periphery, and that this compartment can readily transmit virus to target T lymphocytes. Inhibiting or eliminating the VCC may be an important component of strategies to reduce HIV transmission and to eradicate HIV reservoirs.

HIV-1病毒颗粒（HIV-1 particles）于受感染T淋巴细胞的质膜上组装并出芽。与之形成鲜明对比的是，受感染的巨噬细胞会将病毒颗粒蓄积于一个被称为含病毒区室（virus-containing compartment，VCC）的疑似细胞内区室中。目前VCC的形成与功能的诸多方面仍未明确。本研究证实，VCC的形成实际上并不依赖巨噬细胞的感染，而是可通过向巨噬细胞培养物中外源添加非感染性病毒样颗粒（virus-like particles，VLPs）或感染性病毒粒子得以重现。病毒颗粒可被Siglec-1捕获——这是一种主要的细胞表面凝集素，能够结合病毒脂质包膜上的神经节苷脂。向胞外培养基中添加含神经节苷脂的病毒样颗粒，即可靶向标记受感染巨噬细胞内形成的VCC。若巨噬细胞缺失Siglec-1，或病毒颗粒缺失神经节苷脂，均可阻断病毒颗粒向VCC的摄取，并导致VCC体积显著减小。此外，Siglec-1介导的病毒粒子捕获及后续VCC形成，是高效完成自体T淋巴细胞转感染的必要条件。本研究结果有助于明确该细胞内区室的本质：其为通过外周颗粒摄取形成的细胞内区室，且该结构可高效将病毒传播至靶T淋巴细胞。抑制或消除VCC，或可成为减少HIV传播、根除HIV病毒储存库策略的重要组成部分。