Wood Charles E, Chen Zigui, Cline J Mark, Miller Brigitte E, Burk Robert D
Department of Pathology/Section on Comparative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040, USA.
J Virol. 2007 Jun;81(12):6339-45. doi: 10.1128/JVI.00233-07. Epub 2007 Apr 11.
Cervical cancer is one of the leading causes of cancer mortality in women worldwide, yet few suitable animal models currently exist for study of this disease. Virtually all cases of cervical cancer in women are caused by specific types of genital human papillomavirus (HPV). In this study, we investigated naturally occurring genital PVs in female cynomolgus macaques (Macaca fascicularis) without breeding contact for at least 3.5 years. Exfoliated cervicovaginal cells from 19 of 54 animals tested positive for at least one PV. Seven different PVs were identified, including four novel genotypes and two genotypes (RhPV-d and RhPV-a) previously identified in rhesus macaques (Macaca mulatta). Four PV types were associated with cervical intraepithelial neoplasia (CIN), which resembled human CIN by endoscopy, cervical cytology, histology, and immunohistochemistry. The presence of CIN was highly associated with PV infection (P<0.0001). The most prevalent virus type was RhPV-d, which was identified in 60% of animals with CIN. An RhPV-d genome sequenced from a high-grade CIN lesion was found to be phylogenetically related to the highly oncogenic HPV16. Transfer of cervical cytobrush samples from donor animals naturally carrying RhPV-d resulted in new infections in 4 of 12 previously virus-free animals and abnormal cytology and histology in 1 of 4 infected animals after 18 weeks of infection. Experimental transmission was confirmed by E1/\E4 reverse transcription-PCR products and RhPV-d sequence identity with the donor variant. These findings identify key similarities between macaque and human oncogenic PVs which should prove useful in the study of viral persistence, carcinogenesis, and therapeutic development.
宫颈癌是全球女性癌症死亡的主要原因之一，但目前几乎没有适合研究这种疾病的动物模型。实际上，女性宫颈癌的所有病例都是由特定类型的生殖器人乳头瘤病毒（HPV）引起的。在本研究中，我们调查了至少3.5年没有繁殖接触的雌性食蟹猴（食蟹猴）自然存在的生殖器PV。在54只接受测试的动物中，有19只的宫颈阴道脱落细胞至少对一种PV呈阳性。鉴定出七种不同的PV，包括四种新基因型和两种先前在恒河猴（恒河猴）中鉴定出的基因型（RhPV-d和RhPV-a）。四种PV类型与宫颈上皮内瘤变（CIN）相关，通过内窥镜检查、宫颈细胞学、组织学和免疫组织化学，其与人类CIN相似。CIN的存在与PV感染高度相关（P<0.0001）。最常见的病毒类型是RhPV-d，在60%的CIN动物中被鉴定出来。从高级别CIN病变中测序的RhPV-d基因组在系统发育上与高度致癌的HPV16相关。将自然携带RhPV-d的供体动物的宫颈细胞刷样本转移，导致12只先前无病毒的动物中有4只出现新感染，感染18周后，4只感染动物中有1只出现异常细胞学和组织学变化。通过E1/E4逆转录PCR产物和RhPV-d与供体变体的序列同一性证实了实验性传播。这些发现确定了猕猴和人类致癌PV之间的关键相似性，这在病毒持续性、致癌作用和治疗开发研究中应该会很有用。
