Human papillomavirus (HPV) is a strongly conserved DNA virus, high-risk types of which can cause cervical cancer in persistent infections. The most common type found in HPV-attributable cancer is HPV16, which can be subdivided into four lineages (A to D) with different carcinogenic properties. Studies have shown HPV16 sequence diversity in different geographical areas, but only limited information is available regarding HPV16 diversity within a population, especially at the whole-genome level. We analyzed HPV16 major variant diversity and conservation in persistent infections and performed a single nucleotide polymorphism (SNP) comparison between persistent and clearing infections. Materials were obtained in the Netherlands from a cohort study with longitudinal follow-up for up to 3 years. Our analysis shows a remarkably large variant diversity in the population. Whole-genome sequences were obtained for 57 persistent and 59 clearing HPV16 infections, resulting in 109 unique variants. Interestingly, persistent infections were completely conserved through time. One reinfection event was identified where the initial and follow-up samples clustered differently. Non-A1/A2 variants seemed to clear preferentially (P = 0.02). Our analysis shows that population-wide HPV16 sequence diversity is very large. In persistent infections, the HPV16 sequence was fully conserved. Sequencing can identify HPV16 reinfections, although occurrence is rare. SNP comparison identified no strongly acting effect of the viral genome affecting HPV16 infection clearance or persistence in up to 3 years of follow-up. These findings suggest the progression of an early HPV16 infection could be host related.

IMPORTANCE Human papillomavirus 16 (HPV16) is the predominant type found in cervical cancer. Progression of initial infection to cervical cancer has been linked to sequence properties; however, knowledge of variants circulating in European populations, especially with longitudinal follow-up, is limited. By sequencing a number of infections with known follow-up for up to 3 years, we gained initial insights into the genetic diversity of HPV16 and the effects of the viral genome on the persistence of infections. A SNP comparison between sequences obtained from clearing and persistent infections did not identify strongly acting DNA variations responsible for these infection outcomes. In addition, we identified an HPV16 reinfection event where sequencing of initial and follow-up samples showed different HPV16 variants. Based on conventional genotyping, this infection would incorrectly be considered a persistent HPV16 infection. In the context of vaccine efficacy and monitoring studies, such infections could potentially cause reduced reported efficacy or efficiency.

人乳头瘤病毒（HPV）是一种高度保守的DNA病毒，其高风险类型可在持续感染中引起宫颈癌。在HPV归因的癌症中发现的最常见类型是HPV16，可分为具有不同致癌特性的四个谱系（A到D）。研究表明，HPV16序列在不同地理区域的多样性，但是关于人群中HPV16多样性的信息非常有限，尤其是在全基因组水平上。我们分析了HPV16主要变异的多样性和持续感染的保守性，并在持续感染和清除感染之间进行了单核苷酸多态性（SNP）比较。资料来自荷兰的一项队列研究，进行了长达3年的纵向随访。我们的分析表明，人口中的变异性非常大。获得了57个持续感染和59个清除HPV16感染的全基因组序列，产生109个独特变体。有趣的是，随着时间的流逝，持久性感染得以完全保留。确定了一次重新感染事件，其中初始样本和后续样本的聚类不同。非A1 / A2变体似乎优先清除（P = 0.02）。我们的分析表明，整个人群的HPV16序列多样性非常大。在持续性感染中，HPV16序列是完全保守的。测序可以识别HPV16再感染，尽管这种情况很少发生。SNP比较发现在长达3年的随访中，病毒基因组没有强烈作用影响HPV16感染的清除或持久性。这些发现表明，早期HPV16感染的进展可能与宿主有关。

重要性人乳头瘤病毒16（HPV16）是在宫颈癌中发现的主要类型。最初感染子宫颈癌的进展与序列特性有关。然而，对欧洲人群中流行的变体的了解有限，尤其是在纵向随访中。通过对多达3年已知随访的多种感染进行测序，我们初步了解了HPV16的遗传多样性以及病毒基因组对感染持续性的影响。从清除感染和持续感染中获得的序列之间的SNP比较未发现导致这些感染结果的作用强烈的DNA变异。此外，我们确定了HPV16再感染事件，其中初始样本和后续样本的测序显示出不同的HPV16变体。根据传统的基因分型，该感染将被错误地视为持续性HPV16感染。在疫苗功效和监测研究的背景下，此类感染可能会导致报告的功效或效率降低。