HIV rebounds from latently infected cells, rather than from continuing low-level replication
HIV rebounds from latently infected cells, rather than from continuing low-level replication
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DOI：
10.1073/pnas.0804192105
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发表时间：
2008-10-28
影响因子：
11.1
通讯作者：
Guenthard, Huldrych F.
中科院分区：
文献类型：
--
作者：
Joos, Beda;Fischer, Marek;Guenthard, Huldrych F.
在中断长期联合抗逆转录病毒治疗（cART）后，患者血浆病毒血症的快速反弹表明低水平复制细胞的持续存在或潜伏感染细胞的快速再活化。为了进一步表征反弹病毒，我们对HIV env C2-V3-C3区域进行了广泛的纵向克隆进化研究，并利用了20例经历多次2周结构化治疗中断（STI）的慢性HIV-1感染患者中反弹血浆病毒与预处理序列的时间关系。在短期STI反弹病毒是同质的，这表明单克隆或寡克隆的起源在重新激活。没有证据表明，在预处理序列方面的反弹病毒的时间结构被发现。此外，在不同的STI周期出现不同的谱系的扩展。总之，这些发现意味着来自长寿命潜伏感染细胞的不同克隆的随机再活化，而不是在低水平复制的病毒群体的扩增。处理停止后，多样性稳步增加，但预处理的多样性，平均而言，只有超过2.5年后，STI开始时，从先前存在的准种也出现了显着的分歧。总之，我们的研究结果反对持续低水平复制的抑制性cART患者。此外，治疗中断后治疗前病毒多样性恢复的长期延迟证明了间断抗逆转录病毒治疗引起的令人惊讶的持续进化瓶颈。
Rapid rebound of plasma viremia in patients after interruption of long-term combination antiretroviral therapy (cART) suggests persistence of low-level replicating cells or rapid reactivation of latently infected cells. To further characterize rebounding virus, we performed extensive longitudinal clonal evolutionary studies of HIV env C2-V3-C3 regions and exploited the temporal relationships of rebounding plasma viruses with regard to pretreatment sequences in 20 chronically HIV-1-infected patients having undergone multiple 2-week structured treatment interruptions (STI). Rebounding virus during the short STI was homogeneous, suggesting mono- or oligoclonal origin during reactivation. No evidence for a temporal structure of rebounding virus in regard to pretreatment sequences was found. Furthermore, expansion of distinct lineages at different STI cycles emerged. Together, these findings imply stochastic reactivation of different clones from long-lived latently infected cells rather than expansion of viral populations replicating at low levels. After treatment was stopped, diversity increased steadily, but pretreatment diversity was, on average, achieved only >2.5 years after the start of STI when marked divergence from preexisting quasispecies also emerged. In summary, our results argue against persistence of ongoing low-level replication in patients on suppressive cART. Furthermore, a prolonged delay in restoration of pretreatment viral diversity after treatment interruption demonstrates a surprisingly sustained evolutionary bottleneck induced by punctuated antiretroviral therapy.