BACKGROUND The HIV-1 proviral genome harbors multiple CpG islands (CpGIs), both in the promoter and intragenic regions. DNA methylation in the promoter region has been shown to be heavily involved in HIV-1 latency regulation in cultured cells. However, its exact role in proviral transcriptional regulation in infected individuals is poorly understood or characterized. Moreover, methylation at intragenic CpGIs has never been studied in depth. RESULTS A large, well-characterized HIV-1 patient cohort (n = 72), consisting of 17 long-term non-progressors and 8 recent seroconverters (SRCV) without combination antiretroviral therapy (cART), 15 early cART-treated, and 32 late cART-treated patients, was analyzed using a next-generation bisulfite sequencing DNA methylation method. In general, we observed low level of promoter methylation and higher levels of intragenic methylation. Additionally, SRCV showed increased promoter methylation and decreased intragenic methylation compared with the other patient groups. This data indicates that increased intragenic methylation could be involved in proviral transcriptional regulation. CONCLUSIONS Contrasting in vitro studies, our results indicate that intragenic hypermethylation of HIV-1 proviral DNA is an underestimated factor in viral control in HIV-1-infected individuals, showing the importance of analyzing the complete proviral genome in future DNA methylation studies.

中文翻译：

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基因内HIV-1 DNA甲基化对感染个体中病毒转录的影响被低估。

背景技术HIV-1前病毒基因组在启动子和基因内区域均具有多个CpG岛（CpGIs）。已显示启动子区域中的DNA甲基化与培养细胞中HIV-1潜伏期的调控密切相关。但是，其在受感染个体中前病毒转录调控中的确切作用了解甚少或特征化。此外，从未深入研究内源性CpGI的甲基化。结果大型，特征明确的HIV-1患者队列（n = 72），由17位长期非进展患者和8位近期未使用抗逆转录病毒疗法（cART）的近期血清转化者（SRCV），15位经过cART早期治疗的患者和32位组成使用新一代的亚硫酸氢盐测序DNA甲基化方法分析了晚期cART治疗的患者。一般来说，我们观察到低水平的启动子甲基化和较高水平的基因内甲基化。此外，与其他患者组相比，SRCV显示出启动子甲基化增强和基因内甲基化降低。该数据表明增加的基因内甲基化可能参与前病毒的转录调控。结论与体外研究相反，我们的结果表明HIV-1前病毒DNA的基因内高甲基化是HIV-1感染者病毒控制中被低估的因素，显示了在将来的DNA甲基化研究中分析完整前病毒基因组的重要性。该数据表明增加的基因内甲基化可能参与前病毒的转录调控。结论与体外研究相反，我们的结果表明HIV-1前病毒DNA的基因内超甲基化是HIV-1感染者病毒控制中被低估的因素，显示了在未来DNA甲基化研究中分析完整前病毒基因组的重要性。该数据表明增加的基因内甲基化可能参与前病毒的转录调控。结论与体外研究相反，我们的结果表明HIV-1前病毒DNA的基因内超甲基化是HIV-1感染者病毒控制中被低估的因素，显示了在未来DNA甲基化研究中分析完整前病毒基因组的重要性。