Chen Zigui, Ho Wendy C S, Boon Siaw Shi, Law Priscilla T Y, Chan Martin C W, DeSalle Rob, Burk Robert D, Chan Paul K S
Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
Stanley Ho Center for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
J Virol. 2017 Oct 13;91(21). doi: 10.1128/JVI.01285-17. Print 2017 Nov 1.
Human papillomavirus 58 (HPV58) is found in 10 to 18% of cervical cancers in East Asia but is rather uncommon elsewhere. The distribution and oncogenic potential of HPV58 variants appear to be heterogeneous, since the E7 T20I/G63S variant is more prevalent in East Asia and confers a 7- to 9-fold-higher risk of cervical precancer and cancer. However, the underlying genomic mechanisms that explain the geographic and carcinogenic diversity of HPV58 variants are still poorly understood. In this study, we used a combination of phylogenetic analyses and bioinformatics to investigate the deep evolutionary history of HPV58 complete genome variants. The initial splitting of HPV58 variants was estimated to occur 478,600 years ago (95% highest posterior density [HPD], 391,000 to 569,600 years ago). This divergence time is well within the era of speciation between and Neanderthals/Denisovans and around three times longer than the modern divergence times. The expansion of present-day variants in Eurasia could be the consequence of viral transmission from Neanderthals/Denisovans to non-African modern human populations through gene flow. A whole-genome sequence signature analysis identified 3 amino acid changes, 16 synonymous nucleotide changes, and a 12-bp insertion strongly associated with the E7 T20I/G63S variant that represents the A3 sublineage and carries higher carcinogenetic potential. Compared with the capsid proteins, the oncogenes E7 and E6 had increased substitution rates indicative of higher selection pressure. These data provide a comprehensive evolutionary history and genomic basis of HPV58 variants to assist further investigation of carcinogenic association and the development of diagnostic and therapeutic strategies. Papillomaviruses (PVs) are an ancient and heterogeneous group of double-stranded DNA viruses that preferentially infect the cutaneous and mucocutaneous epithelia of vertebrates. Persistent infection by specific oncogenic human papillomaviruses (HPVs), including HPV58, has been established as the primary cause of cervical cancer. In this work, we reveal the complex evolutionary history of HPV58 variants that explains the heterogeneity of oncogenic potential and geographic distribution. Our data suggest that HPV58 variants may have coevolved with archaic hominins and dispersed across the planet through host interbreeding and gene flow. Certain genes and codons of HPV58 variants representing higher carcinogenic potential and/or that are under positive selection may have important implications for viral host specificity, pathogenesis, and disease prevention.
人乳头瘤病毒58型（HPV58）在东亚地区10%至18%的宫颈癌中被发现，但在其他地区则较为罕见。HPV58变异体的分布和致癌潜力似乎存在异质性，因为E7 T20I/G63S变异体在东亚更为普遍，且使宫颈癌前病变和癌症的风险提高了7至9倍。然而，解释HPV58变异体地理和致癌多样性的潜在基因组机制仍知之甚少。在本研究中，我们结合系统发育分析和生物信息学方法，研究HPV58完整基因组变异体的深层进化历史。HPV58变异体的初始分化估计发生在478,600年前（95%最高后验密度[HPD]，391,000至569,600年前）。这个分化时间恰好在智人与尼安德特人/丹尼索瓦人物种形成的时代范围内，大约是现代智人分化时间的三倍。当今欧亚大陆变异体的扩张可能是病毒通过基因流动从尼安德特人/丹尼索瓦人传播到非洲以外现代人类群体的结果。全基因组序列特征分析确定了3个氨基酸变化、16个同义核苷酸变化以及一个与代表A3亚谱系且具有更高致癌潜力的E7 T20I/G63S变异体强烈相关的12碱基插入。与衣壳蛋白相比，致癌基因E7和E6的替换率增加，表明选择压力更高。这些数据提供了HPV58变异体的全面进化历史和基因组基础，有助于进一步研究致癌关联以及开发诊断和治疗策略。乳头瘤病毒（PVs）是一类古老且异质的双链DNA病毒，优先感染脊椎动物的皮肤和黏膜上皮。包括HPV58在内的特定致癌性人乳头瘤病毒（HPVs）的持续感染已被确定为宫颈癌的主要原因。在这项工作中，我们揭示了HPV58变异体复杂的进化历史，解释了致癌潜力和地理分布的异质性。我们的数据表明，HPV58变异体可能与古代人类共同进化，并通过宿主杂交和基因流动在全球传播。代表更高致癌潜力和/或处于正选择下的HPV58变异体的某些基因和密码子可能对病毒宿主特异性、发病机制和疾病预防具有重要意义。
