Musick Andrew, Spindler Jonathan, Boritz Eli, Pérez Liliana, Crespo-Vélez Daniel, Patro Sean C, Sobolewski Michele D, Bale Michael J, Reid Carolyn, Keele Brandon F, Capoferri Adam, Shao Wei, Wiegand Ann, Simonetti Francesco R, Mellors John W, Hughes Stephen H, Coffin John M, Maldarelli Frank, Kearney Mary F
Human Immunodeficiency Virus (HIV) Dynamics and Replication Program, Center for Cancer Research (CCR), National Cancer Institute (NCI)-Frederick, Frederick, MD, United States.
Virus Persistence and Dynamics Section, Vaccine Research Center, National Institute for Allergies and Infectious Diseases (NIAID), Bethesda, MD, United States.
Front Microbiol. 2019 Oct 1;10:2204. doi: 10.3389/fmicb.2019.02204. eCollection 2019.
BACKGROUND: HIV-1 proviruses can persist during ART in clonally-expanded populations of CD4+ T cells. To date, few examples of an expanded clones containing replication-competent proviruses exist, although it is suspected to be common. One such clone, denoted AMBI-1 (Maldarelli et al., 2014), was also a source of persistent viremia on ART, begging the question of how the AMBI-1 clone can survive despite infection with a replication-competent, actively-expressing provirus. We hypothesized that only a small fraction of cells within the AMBI-1 clone are activated to produce virus particles during cell division while the majority remain latent despite division, ensuring their survival. To address this question, we determined the fraction of HIV-1 proviruses within the AMBI-1 clone that expresses unspliced cell-associated RNA during ART and compared this fraction to 33 other infected T cell clones within the same individual. RESULTS: In total, 34 different clones carrying either intact or defective proviruses in "Patient 1" from Maldarelli et al. (2014) were assessed. We found that 2.3% of cells within the AMBI-1 clone contained unspliced HIV-1 RNA. Highest levels of HIV-1 RNA were found in the effector memory (EM) T cell subset. The fraction of cells within clones that contained HIV-1 RNA was not different in clones with intact (median 2.3%) versus defective (median 3.5%) proviruses ( = 0.2). However, higher fractions and levels of RNA were found in cells with proviruses containing multiple drug resistance mutations, including those contributing to rebound viremia. CONCLUSION: These findings show that the vast majority of HIV-1 proviruses within expanded T cell clones, including intact proviruses, may be transcriptionally silent at any given time, implying that infected T cells may be able to be activated to proliferate without inducing the expression of the integrated provirus or, alternatelively, may be able to proliferate without cellular activation. The results of this study suggest that the long, presumed correlation between the level of cellular and proviral activation may not be accurate and, therefore, requires further investigation.
背景：在抗逆转录病毒治疗（ART）期间，HIV-1前病毒可在CD4+T细胞的克隆扩增群体中持续存在。尽管人们怀疑这种情况很常见，但迄今为止，含有具有复制能力前病毒的扩增克隆的例子很少。其中一个这样的克隆，称为AMBI-1（Maldarelli等人，2014年），也是ART期间持续性病毒血症的一个来源，这就引出了一个问题：尽管感染了具有复制能力、活跃表达的前病毒，AMBI-1克隆是如何存活下来的。我们假设，在细胞分裂过程中，AMBI-1克隆中只有一小部分细胞被激活以产生病毒颗粒，而大多数细胞尽管发生了分裂仍保持潜伏状态，从而确保它们的存活。为了解决这个问题，我们确定了在ART期间AMBI-1克隆中表达未剪接的细胞相关RNA的HIV-1前病毒的比例，并将这一比例与同一个体内的其他33个受感染T细胞克隆进行了比较。 结果：总共评估了来自Maldarelli等人（2014年）“患者1”的34个携带完整或缺陷前病毒的不同克隆。我们发现，AMBI-1克隆中2.3%的细胞含有未剪接的HIV-1 RNA。在效应记忆（EM）T细胞亚群中发现了最高水平的HIV-1 RNA。在含有完整（中位数2.3%）与缺陷（中位数3.5%）前病毒的克隆中，含有HIV-1 RNA的细胞比例没有差异（P = 0.2）。然而，在含有多个耐药突变的前病毒的细胞中，发现了更高比例和水平的RNA，包括那些导致病毒血症反弹的突变。 结论：这些发现表明，在扩增的T细胞克隆中，绝大多数HIV-1前病毒，包括完整的前病毒，在任何给定时间可能都是转录沉默的，这意味着受感染的T细胞可能能够在不诱导整合前病毒表达的情况下被激活以增殖, 或者，可能能够在没有细胞激活的情况下增殖。这项研究的结果表明，长期以来假定的细胞激活水平与前病毒激活水平之间的相关性可能不准确，因此需要进一步研究。
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