Neurovirulence and Latency of Drug-Resistant Clinical Herpes Simplex Viruses in Animal Models
Neurovirulence and Latency of Drug-Resistant Clinical Herpes Simplex Viruses in Animal Models
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DOI：
10.1002/jmv.21773
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发表时间：
2010-06-01
影响因子：
12.7
通讯作者：
Boivin, Guy
中科院分区：
文献类型：
--
作者：
Dambrosi, Sarah;Martin, Melanie;Boivin, Guy
单纯疱疹病毒（HSV）对阿昔洛韦或膦甲酸的耐药性源于病毒胸苷激酶（TK）和/或DNA聚合酶（pol）基因的突变。使用小鼠脑炎和棉鼠生殖器感染模型评估TK和/或DNA pol临床突变体的复制动力学和毒力。DNA pol突变株（L 850 I）和TK/DNA pol突变株（C467缺失/A912 V）在Vero细胞中的复制能力显著低于无关野生型（WT），而双DNA pol突变株（S724 N/P920 S）表现出与WT相似的复制动力学。或未改变的（高M.O I.）与WT病毒相比，这取决于病毒接种物。与用WT HSV-1或-2病毒鼻内感染的小鼠的6%的存活率相比，G439 5add、C467缺失/A912 V和L 850 I毒株与100%的存活率相关（P < 0.05），而用S724 N/P920 S突变体感染的小鼠的存活率为33%（P = 0.08）。在感染WT HSV-1或-2毒株和双DNA pol突变体的小鼠中，脑病毒滴度更高。除DNA聚合酶突变体L 850 I外，所有菌株都能在棉鼠背根神经节中建立潜伏期。通常发现DNA pol突变体的复制动力学与其在小鼠中的神经毒力潜力之间存在良好的相关性，而TK突变体的这种相关性并不直接。医学病毒学杂志82：1000-1006，2010. (C)2010年威利-利斯。Inc
Herpes simplex virus (HSV) resistance to acyclovir or foscarnet results from mutations in viral thymidine kinase (TK) and/or DNA polymerase (pol) genes. Replication kinetics and virulence of TK and/or DNA pol clinical mutants were assessed using models of mouse encephalitis and cotton rat genital infection. Replication capacities in Vero cells of a DNA pol altered strain (L850I) and a TK/DNA pol mutant (C467deletion/A912V) were significantly lower than those of unrelated wild-type (WT) strains, while a double DNA pol mutant (S724N/P920S) demonstrated replication kinetics similar to the WT The replication of a TK-deficient mutant (G439.5addition) was impaired (low m.o.i.) or unaltered (high m.o i.) compared to that of a WT virus depending on the viral inoculum. Compared to a survival rate of 6% for mice infected intranasally with WT HSV-1 or -2 viruses, G439 5add, C467deletion/A912V and L850I strains were associated with survival rates of 100% (P < 0.05) whereas mice infected with the S724N/P920S mutant had a survival rate of 33% (P = 0.08). Brain viral titers were higher in mice infected with WT HSV-1 or -2 strains and the double DNA pol mutant. All strains except the DNA pol mutant L850I were able to establish latency in the dorsal root ganglia of cotton rats. A good correlation was generally found between replication kinetics of DNA pol mutants and their neurovirulence potential in mice whereas such correlation was not straightforward for TK mutants. J. Med. Virol. 82:1000-1006, 2010. (C) 2010 Wiley-Liss. Inc