Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom.
Division of Infection & Immunity, University College London, London, United Kingdom.
mBio. 2022 Jun 28;13(3):e0026922. doi: 10.1128/mbio.00269-22. Epub 2022 Apr 21.
Prolonged virologic failure on 2nd-line protease inhibitor (PI)-based antiretroviral therapy (ART) without emergence of major protease mutations is well recognized and provides an opportunity to study within-host evolution in long-term viremic individuals. Using next-generation sequencing and haplotype reconstruction, we analyzed whole-genome sequences from longitudinal plasma samples of eight chronically infected HIV-1-positive individuals failing 2nd-line regimens from the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) trial. On nonsuppressive ART, there were large fluctuations in synonymous and nonsynonymous variant frequencies despite stable viremia. Reconstructed haplotypes provided evidence for selective sweeps during periods of partial adherence, and viral haplotype competition, during periods of low drug exposure. Drug resistance mutations in reverse transcriptase (RT) were used as markers of viral haplotypes in the reservoir, and their distribution over time indicated recombination. We independently observed linkage disequilibrium decay, indicative of recombination. These data highlight dramatic changes in virus population structure that occur during stable viremia under nonsuppressive ART. HIV-1 infections are most commonly initiated with a single founder virus and are characterized by extensive inter- and intraparticipant genetic diversity. However, existing literature on HIV-1 intrahost population dynamics is largely limited to untreated infections, predominantly in subtype B-infected individuals. The manuscript characterizes viral population dynamics in long-term viremic treatment-experienced individuals, which has not been previously characterized. These data are particularly relevant for understanding HIV dynamics but can also be applied to other RNA viruses. With this unique data set we propose that the virus is highly unstable, and we have found compelling evidence of HIV-1 within-host viral diversification, recombination, and haplotype competition during nonsuppressive ART.
在二线蛋白酶抑制剂（PI）为基础的抗逆转录病毒治疗（ART）中出现病毒学失败而没有出现主要蛋白酶突变是众所周知的，这为研究长期病毒血症个体中的体内进化提供了机会。使用下一代测序和单倍型重建，我们分析了来自法国国家艾滋病和肝炎研究机构（ANRS）12249 治疗作为预防（TasP）试验中失败二线方案的 8 名慢性感染 HIV-1 阳性个体的纵向血浆样本的全基因组序列。在非抑制性 ART 治疗下，尽管病毒血症稳定，但同义和非同义变异频率仍有很大波动。重建的单倍型提供了在部分依从性期间发生选择清除的证据，以及在药物暴露低的时期发生病毒单倍型竞争的证据。逆转录酶（RT）中的耐药突变被用作储库中病毒单倍型的标记，其随时间的分布表明存在重组。我们独立观察到连锁不平衡衰减，表明存在重组。这些数据突出了在非抑制性 ART 下稳定病毒血症期间病毒种群结构的剧烈变化。HIV-1 感染通常由单个起始病毒引发，并具有广泛的个体间和个体内遗传多样性。然而，关于 HIV-1 宿主内种群动态的现有文献主要限于未经治疗的感染，主要是在感染 B 亚型的个体中。本文描述了长期病毒血症治疗经验丰富个体中的病毒种群动态，这在以前尚未得到描述。这些数据对于理解 HIV 动力学特别重要，但也可以应用于其他 RNA 病毒。通过这个独特的数据集，我们提出病毒高度不稳定，并且我们已经找到了令人信服的证据，证明在非抑制性 ART 期间 HIV-1 存在于宿主内病毒多样化、重组和单倍型竞争。
