Live Attenuated Herpes Simplex Virus 2 Glycoprotein E Deletion Mutant as a Vaccine Candidate Defective in Neuronal Spread
Live Attenuated Herpes Simplex Virus 2 Glycoprotein E Deletion Mutant as a Vaccine Candidate Defective in Neuronal Spread
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DOI：
10.1128/jvi.07203-11
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发表时间：
2012-04-01
影响因子：
5.4
通讯作者：
Friedman, Harvey M.
中科院分区：
文献类型：
--
作者：
Awasthi, Sita;Zumbrun, Elizabeth E.;Friedman, Harvey M.
评价了单纯疱疹病毒2型（HSV-2）糖蛋白E缺失突变体（gE 2-del病毒）作为可复制的减毒活病毒候选疫苗。gE 2-del病毒在上皮细胞到轴突的传播和从神经元细胞体到轴突末端的顺行运输中是有缺陷的。在BALB/c和SCID小鼠中，gE 2-del病毒在阴道、血管内或肌肉内接种后未引起死亡或疾病，并且当直接接种到脑中时，其毒性比野生型病毒低5个数量级。在多种途径接种后，从背根神经节（DRG）中未回收感染性gE 2-del病毒;然而，通过PCR在一些小鼠的腰骶DRG中以低拷贝数检测到gE 2-del DNA。重要的是，在免疫豚鼠中未检测到gE 2-del DNA的复发性阴道脱落。肌肉内免疫优于皮下免疫的所有参数进行评价，虽然个体差异不显着，两个肌肉内免疫比一个更具有保护性。免疫动物的阴道疾病、阴道滴度、DRG感染、复发性生殖器病变和复发性HSV-2 DNA阴道脱落减少;然而，保护不完全。在豚鼠中使用活病毒和HSV-2糖蛋白C和D亚单位抗原的联合免疫不能完全消除HSV-2 DNA的复发性病变或复发性阴道脱落。在先前HSV-2感染的豚鼠中用作免疫抑制疫苗的gE 2-del病毒大大降低了复发性生殖器病变的频率。因此，gE 2-del病毒是安全的，除了当以高滴度注射到脑中时，并且作为预防性和免疫性疫苗是有效的。
A herpes simplex virus 2 (HSV-2) glycoprotein E deletion mutant (gE2-del virus) was evaluated as a replication-competent, attenuated live virus vaccine candidate. The gE2-del virus is defective in epithelial cell-to-axon spread and in anterograde transport from the neuron cell body to the axon terminus. In BALB/c and SCID mice, the gE2-del virus caused no death or disease after vaginal, intravascular, or intramuscular inoculation and was 5 orders of magnitude less virulent than wild-type virus when inoculated directly into the brain. No infectious gE2-del virus was recovered from dorsal root ganglia (DRG) after multiple routes of inoculation; however, gE2-del DNA was detected by PCR in lumbosacral DRG at a low copy number in some mice. Importantly, no recurrent vaginal shedding of gE2-del DNA was detected in immunized guinea pigs. Intramuscular immunization outperformed subcutaneous immunization in all parameters evaluated, although individual differences were not significant, and two intramuscular immunizations were more protective than one. Immunized animals had reduced vaginal disease, vaginal titers, DRG infection, recurrent genital lesions, and recurrent vaginal shedding of HSV-2 DNA; however, protection was incomplete. A combined modality immunization using live virus and HSV-2 glycoprotein C and D subunit antigens in guinea pigs did not totally eliminate recurrent lesions or recurrent vaginal shedding of HSV-2 DNA. The gE2-del virus used as an immunotherapeutic vaccine in previously HSV-2-infected guinea pigs greatly reduced the frequency of recurrent genital lesions. Therefore, the gE2-del virus is safe, other than when injected at high titer into the brain, and is efficacious as a prophylactic and immunotherapeutic vaccine.