REPLICATION, ESTABLISHMENT OF LATENCY, AND INDUCED REACTIVATION OF HERPES-SIMPLEX VIRUS-GAMMA(1) 34.5 DELETION MUTANTS IN RODENT MODELS
REPLICATION, ESTABLISHMENT OF LATENCY, AND INDUCED REACTIVATION OF HERPES-SIMPLEX VIRUS-GAMMA(1) 34.5 DELETION MUTANTS IN RODENT MODELS
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DOI：
10.1172/jci116527
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发表时间：
1993-06-01
影响因子：
15.9
通讯作者：
ROIZMAN, B
中科院分区：
文献类型：
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作者：
WHITLEY, RJ;KERN, ER;ROIZMAN, B
先前的研究表明，单纯疱疹病毒1型DNA L成分的倒置重复序列中的基因定位，指定为gamma(1)34.5，对于培养细胞的生长是必不可少的，但缺失突变体（R3616）和每个基因拷贝中含有停止密码子的突变体（R4009）无法在小鼠中枢神经系统（CNS）中复制。缺失序列的恢复恢复了野生型病毒的表型。我们在这里报告了γ(1)34.5突变病毒（R3616和R4009）在两种不同的小鼠和豚鼠的阴道中复制，尽管这两种病毒的滴度都比野生型和恢复型病毒低，持续时间也短。R3616和R4009在Balb/C小鼠或Swiss Webster小鼠鼻内接种后的角膜中均不能复制或引起显著病理。对接种部位的感觉三叉神经节和背根神经节的分析表明，R3616和R4009病毒感染小鼠的潜伏期建立或潜伏期再激活的发生率显著低于野生型或恢复型病毒感染小鼠。因此，γ(1)34.5基因的选择性缺失消除了病毒从外周粘膜部位扩散到中枢神经系统或在中枢神经系统中复制的能力，并降低了病毒在粘膜部位复制的能力，从而建立潜伏期，或能够在体外被重新激活。我们的研究结果可能对基因工程单纯疱疹病毒疫苗的开发有直接的影响。
Previous studies have shown that a gene mapping in the inverted repeats of the L component of herpes simplex virus, type 1 DNA, designated as gamma(1)34.5, was dispensable for growth in cells in culture but that the deletion mutant (R3616) and a mutant containing a stop codon (R4009) in each copy of the gene were incapable of replicating in the central nervous systems (CNS) of mice. Restoration of the deleted sequences restored the wild type virus phenotype. We report here that the gamma(1)34.5 mutant viruses (R3616 and R4009) replicated in the vaginal tract of two different strains of mice and guinea pig, although both viruses were shed at lower titer and for fewer days than the wild type and restored viruses. Both R3616 and R4009 failed to replicate or cause significant pathology in the cornea of Balb/C mice or following intranasal inoculation of Swiss Webster mice. Analyses of sensory trigeminal and dorsal root ganglia innervating the site of inoculation indicated that the incidence of establishment of latency or reactivation from latency by R3616 and R4009 viruses was significantly lower than that determined for mice infected with wild type or restored virus. Thus, selective deletion of gamma(1)34.5 gene abolished the capacity of the virus to spread from peripheral mucosal sites to the CNS or replicate in the CNS, and diminished the capacity of the virus to replicate at mucosal sites and, subsequently, establish latency, or be able to be reactivated ex vivo. The results of our studies may have direct implications for the development of genetically engineered herpes simplex virus vaccines.