Hermonat P L, Meyers C, Parham G P, Santin A D
Department of Obstetrics and Gynecology, University of Arkansas for Medical Science, Little Rock 72205, USA.
Virology. 1998 Aug 1;247(2):240-50. doi: 10.1006/viro.1998.9256.
Infection by adeno-associated virus (AAV) is associated with lower cervical cancer rates. We have been investigating the hypothesis that AAV interacts with and inhibits the role of human papillomaviruses (HPV) in cervical cancer. We have been studying the response of bovine papillomavirus type 1 (BPV) oncogenic transformation and DNA replication to AAV as a prototype system. The AAV Rep 78 gene product is responsible for this inhibition. Here, it is demonstrated that in two assay systems, focus formation of C127 cells and chloramphenicol acetyl-transferase (CAT, measuring P89 promoter expression) assays, the smaller the time interval between AAV introduction relative to BPV introduction, the higher the level of inhibition resulted. Preinfection with AAV was also effective in inhibiting BPV, but the effectiveness also decreased with increasing time intervals. These differences in inhibition demonstrate that the efficiency of AAV's inhibition of BPV changes dramatically with time (as much as 10(4) when delaying AAV infection) and possibly reflect temporal changes in viral gene expression by AAV, BPV, or both, which affect the AAV-papillomavirus interaction. It is further found that two different chimeric BPV/AAV genomes, equivalent to a specific simultaneous infection by these viruses at a specific ratio (which can't be duplicated by virus infection), were fully defective for oncogenic transformation and DNA replication. These chimeric BPV/AAV genomes were also able to trans-inhibit the wild-type BPV genome. Finally, and surprisingly, C127 cells with resident AAV Rep78 positive provirus were found to have increased sensitivity to oncogenic transformation by BPV. These data define the conditions under which an inhibitory affect of the AAV Rep78 gene on BPV phentotypes can be expected. However, under certain conditions AAV appears able to stimulate BPV oncogenic transformation. This final observation is not totally unexpected as Rep78 is a transcription factor known to both stimulate or repress AAV's own gene expression depending upon adenovirus coinfection.
腺相关病毒（AAV）感染与较低的宫颈癌发病率相关。我们一直在研究AAV与人类乳头瘤病毒（HPV）相互作用并抑制其在宫颈癌中作用的假说。我们一直在以牛乳头瘤病毒1型（BPV）的致癌转化和DNA复制对AAV的反应作为一个原型系统进行研究。AAV Rep 78基因产物负责这种抑制作用。在此表明，在两种检测系统中，即C127细胞的集落形成和氯霉素乙酰转移酶（CAT，用于测量P89启动子表达）检测中，相对于BPV引入，AAV引入的时间间隔越短，产生的抑制水平越高。AAV预感染在抑制BPV方面也有效，但随着时间间隔增加，有效性也降低。这些抑制方面的差异表明，AAV对BPV的抑制效率随时间急剧变化（延迟AAV感染时可达10⁴倍），这可能反映了AAV、BPV或两者病毒基因表达的时间变化，这些变化影响了AAV - 乳头瘤病毒的相互作用。进一步发现，两种不同的嵌合BPV/AAV基因组，等同于这些病毒以特定比例同时感染（这无法通过病毒感染复制），在致癌转化和DNA复制方面完全有缺陷。这些嵌合BPV/AAV基因组也能够反式抑制野生型BPV基因组。最后，令人惊讶的是，发现带有常驻AAV Rep78阳性前病毒的C127细胞对BPV的致癌转化敏感性增加。这些数据确定了可预期AAV Rep78基因对BPV表型产生抑制作用的条件。然而，在某些条件下，AAV似乎能够刺激BPV致癌转化。这一最终观察结果并非完全出乎意料，因为Rep78是一种已知根据腺病毒共感染情况既刺激又抑制AAV自身基因表达的转录因子。
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