Data from: Exploring an alternative explanation for the second phase of viral decay: infection of short-lived cells in a drug-limited compartment during HAART

Most HIV-infected patients who initiate combination antiretroviral therapy experience a viral load decline in several phases. These phases are characterized by different rates of viral load decay that decrease when transitioning from one phase to the next. There is no consensus as to the origin of these phases. One hypothesis put forward is that short- and long-lived infected cells are responsible for the first and second phases of decay, respectively. However, significant differences in drug concentrations are observed in monocytes from various tissues, suggesting the first two phases of decay in viral loads could instead be attributed to short-lived cells being differently exposed to drugs. Compared to a well-exposed compartment, new cell infection can be expected in a compartment with limited drug exposure, thus leading to a slower viral load decay with potential virologic failure and drug resistance. In the current study, the latter hypothesis was investigated using a model of viral kinetics. Empirical datasets were involved in model elaboration and parameter estimation. In particular, susceptibility assay data was used for an in vitro to in vivo extrapolation based on the expected drug concentrations inside physiological compartments. Results from numerical experiments of the short-term evolution of viral loads can reproduce the first two phases of viral decay when allowing new short-lived cell infections in an unidentified drug-limited compartment. Model long-term predictions are however less consistent with clinical observations. For the hypothesis to hold, efavirenz, tenofovir and emtricitabine drug exposure in the drug-limited compartment would have to be very low compared to exposure in peripheral blood. This would lead to significant long-term viral growth and the frequent development of resistant strains, a prediction not supported by clinical observations. This suggests that the existence of a drug-limited anatomical compartment is unlikely, by itself, to explain the second phase of viral load decay.多数接受联合抗逆转录病毒治疗（combination antiretroviral therapy）的人类免疫缺陷病毒（HIV, Human Immunodeficiency Virus）感染者，其病毒载量（viral load）会经历多阶段下降过程。这些阶段以不同的病毒载量衰减速率为特征，且各阶段间切换时衰减速率会逐渐降低。目前学界对于这些阶段的起源尚未达成共识。有研究者提出假说认为，病毒载量衰减的第一、第二阶段分别由短寿命感染细胞与长寿命感染细胞介导。然而，现有研究发现不同组织来源的单核细胞（monocytes）内药物浓度存在显著差异，这提示病毒载量衰减的前两个阶段或许可归因于短寿命感染细胞所接触的药物暴露水平存在差异。与药物暴露充足的生理隔室（physiological compartments）相比，药物暴露受限的生理隔室中仍可能发生新的细胞感染，进而导致病毒载量衰减速度放缓，并可能引发病毒学失败（virologic failure）与耐药性（drug resistance）产生。本研究针对后一种假说展开探究，采用病毒动力学模型开展相关分析。建模与参数估计过程均采用了经验数据集。具体而言，研究基于生理隔室预期药物浓度，采用敏感性试验（susceptibility assay）数据完成体外-体内外推（in vitro to in vivo extrapolation）分析。数值实验结果显示，若假设在一个未被识别的药物受限隔室中存在短寿命细胞的新感染事件，则可复现病毒载量短期演变过程中的前两个衰减阶段。然而，模型的长期预测结果与临床观测数据吻合度欠佳。若要使该假说成立，则药物受限隔室中依非韦伦（efavirenz）、替诺福韦（tenofovir）与恩曲他滨（emtricitabine）的药物暴露水平需远低于外周血中的暴露水平。这一情况将导致病毒出现显著的长期增殖，并频繁产生耐药毒株，而该预测并未得到临床观测数据的支持。这表明，仅靠药物受限解剖隔室的存在，无法单独解释病毒载量衰减的第二阶段。