Flamand L, Stefanescu I, Ablashi D V, Menezes J
Laboratory of Immunovirology, Ste-Justine Hospital, Montreal, Canada.
J Virol. 1993 Nov;67(11):6768-77. doi: 10.1128/JVI.67.11.6768-6777.1993.
One common attribute of herpesviruses is the ability to establish latent, life-long infections. The role of virus-virus interaction in viral reactivation between or among herpesviruses has not been studied. Preliminary experiments in our laboratory had indicated that infection of Epstein-Barr virus (EBV) genome-positive human lymphoid cell lines with human herpesvirus 6 (HHV-6) results in EBV reactivation in these cells. To further our knowledge of this complex phenomenon, we investigated the effect of HHV-6 infection on expression of the viral lytic cycle proteins of EBV. Our results indicate that HHV-6 upregulates, by up to 10-fold, expression of the immediate-early Zebra antigen and the diffuse and restricted (85 kDa) early antigens (EA-D and EA-R, respectively) in both EBV producer and nonproducer cell lines (i.e., P3HR1, Akata, and Raji). Maximal EA-D induction was observed at 72 h post-HHV-6 infection. Furthermore, expression of late EBV gene products, namely, the viral capsid antigen (125 kDa) and viral membrane glycoprotein gp350, was also increased in EBV producer cells (P3HR1 and Akata) following infection by HHV-6. By using dual-color membrane immunofluorescence, it was found that most of the cells expressing viral membrane glycoprotein gp350 were also positive for HHV-6 antigens, suggesting a direct effect of HHV-6 replication on induction of the EBV replicative cycle. No expression of late EBV antigens was observed in Raji cells following infection by HHV-6, implying a lack of functional complementation between the deleted form of EBV found in Raji cells and the superinfecting HHV-6. The susceptibility of the cell lines to infection by HHV-6 correlated with increased expression of various EBV proteins in that B95-8 cells, which are not susceptible to HHV-6 infection, did not show an increase in expression of EBV antigens following treatment with HHV-6. Moreover, UV light-irradiated or heat-inactivated HHV-6 had no upregulating effect on the Zebra antigen or EA-D in Raji cells, indicating that infectious virus is required for the observed effects of HHV-6 on these EBV products. These results show that HHV-6, another lymphotropic human herpesvirus, can activate EBV replication and may thus contribute to the pathogenesis of EBV-associated diseases.
疱疹病毒的一个共同特性是能够建立潜伏性的终身感染。疱疹病毒之间病毒 - 病毒相互作用在病毒再激活中的作用尚未得到研究。我们实验室的初步实验表明，用人疱疹病毒6型（HHV - 6）感染爱泼斯坦 - 巴尔病毒（EBV）基因组阳性的人淋巴母细胞系会导致这些细胞中EBV重新激活。为了进一步了解这一复杂现象，我们研究了HHV - 6感染对EBV病毒裂解周期蛋白表达的影响。我们的结果表明，HHV - 6在EBV产生细胞系和非产生细胞系（即P3HR1、Akata和Raji）中，将立即早期Zebra抗原以及弥漫性和局限性（85 kDa）早期抗原（分别为EA - D和EA - R）的表达上调了多达10倍。在HHV - 6感染后72小时观察到EA - D的最大诱导。此外，在HHV - 6感染后，EBV晚期基因产物，即病毒衣壳抗原（125 kDa）和病毒膜糖蛋白gp350在EBV产生细胞（P3HR1和Akata）中的表达也增加。通过双色膜免疫荧光法发现，大多数表达病毒膜糖蛋白gp350的细胞也对HHV - 6抗原呈阳性，这表明HHV - 6复制对EBV复制周期的诱导有直接影响。在HHV - 6感染后，Raji细胞中未观察到EBV晚期抗原的表达，这意味着在Raji细胞中发现的缺失形式的EBV与超感染的HHV - 6之间缺乏功能互补。细胞系对HHV - 6感染的易感性与各种EBV蛋白表达的增加相关，因为对HHV - 6感染不敏感的B95 - 8细胞在用HHV - 6处理后未显示出EBV抗原表达的增加。此外，紫外线照射或热灭活的HHV - 6对Raji细胞中的Zebra抗原或EA - D没有上调作用，这表明观察到的HHV - 6对这些EBV产物的影响需要有感染性的病毒。这些结果表明，另一种嗜淋巴细胞的人疱疹病毒HHV - 6可以激活EBV复制，因此可能有助于EBV相关疾病的发病机制。
