Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy
Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy
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DOI：
10.1038/nature10347
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发表时间：
2011-09-01
期刊：
影响因子：
64.8
通讯作者：
Baltimore, David
中科院分区：
文献类型：
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作者：
Sigal, Alex;Kim, Jocelyn T.;Baltimore, David
潜伏期和持续复制（1）都被提出来解释药物不敏感的人类免疫缺陷病毒（HIV）的水库维持在抗逆转录病毒治疗。在这里，我们探索了在抗逆转录病毒药物面前艾滋病毒持续复制的新机制。我们提出了一个模型，其中每个细胞的多个感染（2，3）导致药物敏感性降低，而不需要耐药突变，并通过实验验证该模型使用无细胞HIV在药物替诺福韦的存在下，每个细胞的多个感染。然后，我们研究了HIV细胞间传播的药物敏感性（4-7），这是一种HIV传播模式，可导致每个靶细胞发生多起感染事件（8-10）。在抗逆转录病毒药物替诺福韦和依法韦仑的存在下，无细胞病毒引起的感染大大减少，而涉及细胞间传播的感染对药物的敏感性明显降低。敏感性的降低足以防止多轮感染在药物存在下终止。我们研究复制从细胞到细胞的传播中存在的临床药物浓度使用随机感染模型，发现复制是间歇性的，没有大量的突变积累。如果细胞间传播在体内具有相同的特性，则可能对免疫系统产生不良后果（11-13），导致具有风险因素的个体治疗失败（14），并可能导致病毒持续存在，因此成为治愈HIV感染的障碍。
Latency and ongoing replication(1) have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections(2,3) per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV(4-7), a mode of HIV transmission that can lead to multiple infection events per target cell(8-10). Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system(11-13), lead to therapy failure in individuals with risk factors(14), and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.