潜在HIV-1 DNA储层的建立及其稳定性
Establishment and stability of the latent HIV-1 DNA reservoir
摘要：
HIV-1感染目前无法治愈，因为尽管多年的抑制性抗逆转录病毒治疗（ART），病毒仍作为整合的前病毒DNA存在于长寿细胞中。为了表征病毒DNA储库的建立、周转和进化，我们对来自10名患者的3-18年抑制性ART后获得的样本中HIV-1基因组的p17 gag区域进行了深度测序。对于这些患者中的每一个，ART开始前HIV-1 RNA群体的全基因组深度测序数据可从跨越5-8年未治疗感染的6-12个纵向血浆样本中获得。这使得在ART过程中前病毒DNA的动力学和起源的详细分析成为可能。由于G-至-A超突变，14%（范围0-42%）的p17 gag DNA序列的中值明显缺陷。其余的序列非常相似，以前观察到的RNA序列，并没有表现出多年的抑制性ART进化的证据。大多数序列从DNA水库非常相似的病毒在血浆中活跃复制（RNA序列）开始前不久的ART。结果不支持持续的HIV-1复制作为一种机制，以维持HIV-1水库在抑制治疗。相反，数据表明，只要患者未经治疗，病毒DNA变异就会发生逆转，而抑制性ART会阻止这种逆转。
英文摘要：
HIV-1 infection currently cannot be cured because the virus persists as integrated proviral DNA in long-lived cells despite years of suppressive antiretroviral therapy (ART). To characterize establishment, turnover, and evolution of viral DNA reservoirs we deep-sequenced the p17gag region of the HIV-1 genome from samples obtained after 3-18 years of suppressive ART from 10 patients. For each of these patients, whole genome deep-sequencing data of HIV-1 RNA populations before onset of ART were available from 6-12 longitudinal plasma samples spanning 5-8 years of untreated infection. This enabled a detailed analysis of the dynamics and origin of proviral DNA during ART. A median of 14% (range 0-42%) of the p17gag DNA sequences were overtly defective due to G-to-A hypermutation. The remaining sequences were remarkably similar to previously observed RNA sequences and showed no evidence of evolution over many years of suppressive ART. Most sequences from the DNA reservoirs were very similar to viruses actively replicating in plasma (RNA sequences) shortly before start of ART. The results do not support persistent HIV-1 replication as a mechanism to maintain the HIV-1 reservoir during suppressive therapy. Rather, the data indicate that viral DNA variants are turning over as long as patients are untreated and that suppressive ART halts this turnover.
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