Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Phys Rev Lett. 2020 Sep 18;125(12):128101. doi: 10.1103/PhysRevLett.125.128101.
The efficiency of a virus to establish its infection in host cells varies broadly among viruses. It remains unclear if there is a key step in this process that controls viral infectivity. To address this question, we use single-particle tracking and Brownian dynamics simulation to examine human immunodeficiency virus type 1 (HIV-1) infection in cell culture. We find that the frequency of viral-cell encounters is consistent with diffusion-limited interactions. However, even under the most favorable conditions, only 1% of the viruses can become immobilized on cell surface and subsequently enter the cell. This is a result of weak interaction between viral surface gp120 and CD4 receptor, which is insufficient to form a stable complex the majority of the time. We provide the first direct quantitation for efficiencies of these events relevant to measured HIV-1 infectivity and demonstrate that immobilization on host cell surface post-virion-diffusion is the key step in viral infection. Variation of its probability controls the efficiency of a virus to infect its host cells. These results explain the low infectivity of cell-free HIV-1 in vitro and offer a potential rationale for the pervasive high efficiency of cell-to-cell transmission of animal viruses.
病毒在宿主细胞中建立感染的效率在病毒之间有很大的差异。目前尚不清楚这个过程中是否存在控制病毒感染力的关键步骤。为了解决这个问题，我们使用单颗粒跟踪和布朗动力学模拟来研究细胞培养中的人类免疫缺陷病毒 1（HIV-1）感染。我们发现病毒与细胞的接触频率与扩散限制相互作用一致。然而，即使在最有利的条件下，也只有 1%的病毒能够固定在细胞表面上，随后进入细胞。这是由于病毒表面 gp120 和 CD4 受体之间的相互作用较弱，大多数时候不足以形成稳定的复合物。我们首次直接定量了与测量的 HIV-1 感染力相关的这些事件的效率，并证明病毒扩散后的固定在宿主细胞表面是病毒感染的关键步骤。其概率的变化控制着病毒感染宿主细胞的效率。这些结果解释了无细胞 HIV-1 在体外的低感染力，并为动物病毒细胞间传播的普遍高效率提供了潜在的解释。
