Stroop W G, Banks M C, Qavi H, Chodosh J, Brown S M
Ophthalmology Research Laboratory, Houston Department of Veterans Affairs Medical Center, Texas.
J Med Virol. 1994 Jul;43(3):297-309. doi: 10.1002/jmv.1890430319.
The incidence of herpetic keratitis following intranasal or direct ocular infection with thymidine kinase-negative (TK-) strains of herpes simplex virus (HSV)-2 has not been well studied, and the role of the TK gene in the establishment of latency and virus reactivation is controversial. To determine whether a TK- strain of HSV-2 could establish trigeminal ganglionic latency and be reactivated in vivo to produce recurrent keratitis or nervous system infection, an animal model of acute and recurrent infection was utilized. Rabbits were infected by the intranasal or ocular routes, and latency was reactivated by immunosuppression. Virus shedding in nasal and ocular secretions was monitored, and the eyes were examined for the presence of corneal epithelial lesions during acute and reactivated infections. Central nervous system (CNS) and trigeminal ganglionic tissues were assayed by histologic, virologic, and in situ hybridization techniques. All rabbits intranasally infected shed virus in both ocular and nasal secretions, whereas only 30% of rabbits infected in the eyes shed virus in nasal secretions. Virus was recovered from cocultivation cultures, but not from cell-free homogenates, of trigeminal ganglionic and CNS tissues from animals inoculated by both routes. The incidence of keratitis was much greater after direct ocular inoculation, although both routes of inoculation produced CNS and ganglionic inflammatory lesions. Keratitis healed in 92% of the animals infected by the ocular route by 26 days post infection. Of rabbits initially infected in the eyes and then subjected to drug-induced reactivation, only 30% shed virus, which was limited to a 24 hour period; there was no reappearance of epithelial keratitis, no animal became blind, and none died. In contrast, latently infected control rabbits uniformly reactivated. These studies show that this TK-HSV-2 strain (i) replicates in the eye, (ii) is neuroinvasive but non-neurovirulent following intranasal and direct ocular infection; (iii) sheds in the eye more frequently and for longer periods after ocular than after intranasal inoculation; (iv) induces epithelial keratitis that usually heals spontaneously; (v) establishes latency in trigeminal ganglionic neurons, but no other ganglionic cells; and, (vi) reactivates in a small proportion of animals, but does not produce recurrent ocular lesions following drug-induced immunosuppression. Thus, the TK gene appears directly involved in HSV latency and reactivation in vivo.
鼻内或直接眼部感染单纯疱疹病毒2型（HSV-2）胸苷激酶阴性（TK-）毒株后疱疹性角膜炎的发病率尚未得到充分研究，且TK基因在潜伏建立和病毒再激活中的作用存在争议。为了确定HSV-2的TK-毒株是否能在三叉神经节建立潜伏并在体内再激活以产生复发性角膜炎或神经系统感染，利用了急性和复发性感染的动物模型。通过鼻内或眼部途径感染兔子，并通过免疫抑制激活潜伏。监测鼻和眼分泌物中的病毒排出情况，并在急性和再激活感染期间检查眼睛是否存在角膜上皮病变。通过组织学、病毒学和原位杂交技术检测中枢神经系统（CNS）和三叉神经节组织。所有经鼻内感染的兔子在眼和鼻分泌物中均排出病毒，而仅30%经眼部感染的兔子在鼻分泌物中排出病毒。从两种途径接种动物的三叉神经节和CNS组织的共培养物中回收了病毒，但未从无细胞匀浆中回收。直接眼部接种后角膜炎的发病率要高得多，尽管两种接种途径均产生了CNS和神经节炎性病变。感染后26天时，92%经眼部途径感染的动物角膜炎愈合。最初经眼部感染然后接受药物诱导再激活的兔子中，仅30%排出病毒，且仅限于24小时；角膜上皮炎未再次出现，没有动物失明，也没有动物死亡。相比之下，潜伏感染的对照兔子均发生了再激活。这些研究表明该TK-HSV-2毒株（i）在眼中复制，（ii）经鼻内和直接眼部感染后具有神经侵袭性但无神经毒性；（iii）眼部接种后比鼻内接种后更频繁且更长时间地在眼中排出；（iv）诱导通常可自发愈合的上皮性角膜炎；（v）在三叉神经节神经元中建立潜伏，但不在其他神经节细胞中建立；并且，（vi）在一小部分动物中再激活，但在药物诱导的免疫抑制后不产生复发性眼部病变。因此，TK基因似乎直接参与了HSV在体内的潜伏和再激活。
