Sambaturu Narmada, Fray Emily J, Hariharan Vivek, Wu Fengting, Zitzmann Carolin, Simonetti Francesco R, Barouch Dan H, Siliciano Janet D, Siliciano Robert F, Ribeiro Ruy M, Perelson Alan S, Molina-París Carmen, Leitner Thomas
Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA; School of Systems Science and Industrial Engineering, State University of New York at Binghamton, Binghamton, NY, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Rep. 2025 May 27;44(5):115663. doi: 10.1016/j.celrep.2025.115663. Epub 2025 May 5.
The human immunodeficiency virus (HIV) can persist in a latent form as integrated DNA (provirus) in resting CD4 T cells unaffected by antiretroviral therapy. Despite being a major obstacle for eradication efforts, it remains unclear which infected cells survive, persist, and ultimately enter the long-lived reservoir. Here, we determine the genetic divergence and integration times of simian immunodeficiency virus (SIV) envelope sequences collected from infected macaques. We show that the proviral divergence and the phylogenetically estimated integration times display a biphasic decline over time. Investigating the dynamics of the mutational distributions, we show that SIV genomes in short-lived cells are, on average, more diverged, while long-lived cells contain less diverged virus. The change in the mutational distributions over time explains the observed biphasic decline in the divergence of the proviruses. This suggests that long-lived cells harbor viruses deposited earlier in infection, while short-lived cells predominantly harbor more recent viruses.
人类免疫缺陷病毒（HIV）可以以整合DNA（前病毒）的潜伏形式存在于静息CD4 T细胞中，不受抗逆转录病毒疗法的影响。尽管这是根除努力的主要障碍，但仍不清楚哪些受感染细胞能够存活、持续存在并最终进入长期储存库。在这里，我们确定了从感染猕猴中收集的猿猴免疫缺陷病毒（SIV）包膜序列的遗传差异和整合时间。我们表明，前病毒差异和系统发育估计的整合时间随时间呈双相下降。研究突变分布的动态变化，我们发现短寿命细胞中的SIV基因组平均差异更大，而长寿命细胞中所含病毒的差异较小。随着时间的推移，突变分布的变化解释了观察到的前病毒差异的双相下降。这表明长寿命细胞中含有感染早期沉积的病毒，而短寿命细胞中主要含有较新的病毒。
