AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
Nat Commun. 2024 Jun 14;15(1):5093. doi: 10.1038/s41467-024-49369-9.
The capacity of HIV-1 to replicate during optimal antiretroviral therapy (ART) is challenging to assess directly. To gain greater sensitivity to detect evolution on ART, we used a nonhuman primate (NHP) model providing precise control over the level of pre-ART evolution and more comprehensive analyses than are possible with clinical samples. We infected 21 rhesus macaques (RMs) with the barcoded virus SIVmac239M and initiated ART early to minimize baseline genetic diversity. RMs were treated for 285-1200 days. We used several tests of molecular evolution to compare 1352 near-full-length (nFL) SIV DNA single genome sequences from PBMCs, lymph nodes, and spleen obtained near the time of ART initiation and those present after long-term ART, none of which showed significant changes to the SIV DNA population during ART in any animal. To investigate the possibility of ongoing replication in unsampled putative tissue sanctuaries during ART, we discontinued treatment in four animals and confirmed that none of the 336 nFL SIV RNA sequences obtained from rebound plasma viremia showed evidence of evolution. The rigorous nature of our analyses reinforced the emerging consensus of a lack of appreciable ongoing replication on effective ART and validates the relevance of this NHP model for cure studies.
在最佳抗逆转录病毒疗法 (ART) 期间，HIV-1 的复制能力难以直接评估。为了更灵敏地检测 ART 过程中的进化，我们使用了一种非人类灵长类动物（NHP）模型，该模型可以精确控制 ART 前的进化水平，并进行比临床样本更全面的分析。我们用带有条码的 SIVmac239M 病毒感染了 21 只恒河猴（RMs），并尽早开始 ART 治疗，以最大程度地减少基线遗传多样性。RMs 接受了 285-1200 天的治疗。我们使用了几种分子进化测试，比较了在 ART 开始时和长期 ART 后从 PBMCs、淋巴结和脾脏中获得的 1352 个接近全长（nFL）SIV DNA 单基因组序列，在任何动物中，这些序列都没有显示出在 ART 期间 SIV DNA 群体有显著变化。为了研究在 ART 期间未取样的假定组织避难所中是否存在持续复制的可能性，我们停止了 4 只动物的治疗，并确认从反弹血浆病毒血症中获得的 336 个 nFL SIV RNA 序列中没有任何一个显示出进化的证据。我们分析的严格性强化了在有效的 ART 上没有明显持续复制的共识，并验证了这种 NHP 模型对于治愈研究的相关性。
