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反义寡核苷酸对1型人类免疫缺陷病毒复制的特异性抑制：一种治疗的体外模型

Specific inhibition of human immunodeficiency virus type 1 replication by antisense oligonucleotides: an in vitro model for treatment.

作者信息

Lisziewicz J, Sun D, Klotman M, Agrawal S, Zamecnik P, Gallo R

机构信息

Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

出版信息

Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11209-13. doi: 10.1073/pnas.89.23.11209.

DOI:10.1073/pnas.89.23.11209
PMID:1454800
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC50519/
Abstract

We have developed a culture system, simulating in vivo conditions of human immunodeficiency virus type 1 (HIV-1) infection, to evaluate the long-term efficacy of antisense oligonucleotide treatment. Five oligonucleotide phosphorothioates (28-mers), complementary to different regions of HIV-1 RNA, blocked replication of the virus in a sequence-specific manner at 1 microM concentration. Variations in antiviral activity were seen among the different oligonucleotides, revealing an effect of target selection. Mismatched or random oligonucleotide phosphorothioates delayed, but did not completely inhibit, HIV-1 replication. In the case of inhibition by a splice-acceptor-site antisense oligodeoxynucleotide, a break-through phenomenon occurred after 25 days of treatment, suggesting the development of an "escape mutant." This result did not occur when the inhibitory oligodeoxynucleotides were complementary to the primary-sequence areas of the rev-responsive element and rev-1 genes. Sequential treatment of HIV-1-infected cells with a combination of different antisense oligonucleotides, each administered once, also prevented the development of escape mutants. Our results suggest that chemotherapy based on specifically targeted antisense-oligonucleotide phosphorothioates may be an effective method for reducing the viral burden in HIV-1-infected individuals at clinically achievable oligonucleotide concentrations.

摘要

我们开发了一种模拟人类免疫缺陷病毒1型（HIV-1）感染体内条件的培养系统，以评估反义寡核苷酸治疗的长期疗效。五种与HIV-1 RNA不同区域互补的硫代磷酸寡核苷酸（28聚体）在1 microM浓度下以序列特异性方式阻断了病毒的复制。不同寡核苷酸之间观察到抗病毒活性的差异，揭示了靶点选择的影响。错配或随机硫代磷酸寡核苷酸延迟但未完全抑制HIV-1复制。在用剪接受体位点反义寡脱氧核苷酸抑制的情况下，治疗25天后出现了突破现象，提示“逃逸突变体”的产生。当抑制性寡脱氧核苷酸与rev反应元件和rev-1基因的一级序列区域互补时，未出现此结果。用不同反义寡核苷酸组合依次处理HIV-1感染细胞（每种只给药一次），也可防止逃逸突变体的产生。我们的结果表明，基于特异性靶向硫代磷酸反义寡核苷酸的化疗可能是在临床可达到的寡核苷酸浓度下降低HIV-1感染个体病毒载量的有效方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ca1/50519/7818ba1755a6/pnas01097-0114-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ca1/50519/1cbce09fd36d/pnas01097-0114-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ca1/50519/7818ba1755a6/pnas01097-0114-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ca1/50519/1cbce09fd36d/pnas01097-0114-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ca1/50519/7818ba1755a6/pnas01097-0114-b.jpg

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