Institute of Virology and Antiviral Therapy, German Reference Laboratory for HSV and VZV, Jena University Hospital, Jena, Germany.
Virulence. 2010 Nov-Dec;1(6):555-7. doi: 10.4161/viru.1.6.13806. Epub 2010 Nov 1.
Herpes simplex virus (HSV) infections can be treated efficiently by the application of antiviral compounds. Several drugs on the basis of acyclovir (ACV), penciclovir (PCV) and foscarnet (FOS) have been approved. Resistant viral isolates can be observed especially in immunocompromised patients, who are treated with antivirals for long time intervals. That is why methods for analysis of HSV resistance to antiviral drugs have to be available in virological laboratories. We analyzed HSV type 1 (HSV-1) and type 2 (HSV-2) isolates resistant to ACV for correlation between phenotypic and genotypic drug resistance using tetrazolium reduction assay as well as sequencing of thymidine kinase (TK) and DNA polymerase (pol) genes. All strains were characterized as cross-resistant to PCV, brivudin and susceptible to cidofovir. In addition, three sequential isolates were resistant to FOS. Genotypic analysis revealed high polymorphism of TK among HSV-1 isolates and high polymorphism of DNA pol among both HSV-1- and 2 isolates. In nearly half of ACV-resistant strains, nucleotide insertions and deletions, responsible for a frameshift and the synthesis of a non-functional TK could be related to resistance. In the remaining strains, there were non-synonymous nucleotide substitutions which were not known as part of gene polymorphism. In conclusion, for reliable interpretation of genotypic resistance, a database of non-synonymous mutations has to be established.
单纯疱疹病毒（HSV）感染可以通过应用抗病毒化合物来有效治疗。几种以阿昔洛韦（ACV）、喷昔洛韦（PCV）和膦甲酸钠（FOS）为基础的药物已获得批准。特别是在接受抗病毒药物长时间治疗的免疫功能低下的患者中，会观察到耐药的病毒分离株。这就是为什么在病毒学实验室中必须具备分析 HSV 对抗病毒药物耐药性的方法。我们使用噻唑蓝还原测定法以及胸苷激酶（TK）和 DNA 聚合酶（pol）基因测序分析了对 ACV 耐药的 HSV 1 型（HSV-1）和 2 型（HSV-2）分离株的表型和基因型耐药相关性。所有菌株均表现为对 PCV、溴夫定交叉耐药，对更昔洛韦敏感。此外，有三个连续分离株对 FOS 耐药。基因分析显示 HSV-1 分离株的 TK 高度多态性，以及 HSV-1 和 2 分离株的 pol 高度多态性。在近一半的 ACV 耐药株中，核苷酸插入和缺失可导致移码和非功能 TK 的合成，这与耐药性有关。在其余的菌株中，存在非同义核苷酸取代，它们不属于基因多态性的一部分。总之，为了可靠地解释基因型耐药性，必须建立一个非同义突变的数据库。
