Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy
dankan 添加于 2011-8-18 14:13:09 118次阅读 | 0次推荐 | 0个评论
Latency and ongoing replication1 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 infections2, 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 HIV4, 5, 6, 7, a mode of HIV transmission that can lead to multiple infection events per target cell8, 9, 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 system11, 12, 13, lead to therapy failure in individuals with risk factors14, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.
作 者：Alex Sigal; Jocelyn T. Kim; Alejandro B. Balazs; Erez Dekel; Avi Mayo; Ron Milo; David Baltimore
期刊名称： Nature
期卷页： 2011-08-17 第卷 第期 ~页
学科领域：生命科学 » 微生物学 » 病毒学
添加人是否为作者: 否
原文链接：http://www.nature.com/nature/jou ... bs/nature10347.html
DOI： doi:10.1038/nature10347
ISBN： 0028-0836
关键词： Virology, Computing science, Mathematics, Statistics, Cell biology
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