Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia.
Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia.
复制标题
自体干细胞移植会破坏猿猴/人类免疫缺陷病毒病毒血症反弹期间的适应性免疫反应。
DOI：
10.1128/jvi.00095-17
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发表时间：
2017
影响因子：
5.4
通讯作者：
Schiffer,JoshuaT
中科院分区：
文献类型：
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作者：
Reeves,DanielB;Peterson,ChristopherW;Kiem,Hans-Peter;Schiffer,JoshuaT
原发性HIV-1感染诱导病毒特异性适应性/细胞溶解免疫反应，影响血浆病毒载量设定点和艾滋病进展率。抗逆转录病毒联合治疗（cART）将血浆病毒血症抑制到无法检测的水平，并在cART治疗中断后反弹。在cART停药后，与原发感染相比，病毒特异性适应性免疫反应的记忆成分可能改善病毒控制。在这里，利用猴/人免疫缺陷病毒（SHIV）感染猕猴的初次感染和治疗中断数据，我们观察到病毒载量的峰值较低，但病毒反弹期间的病毒设定点不变。在cART停药前加入自体干细胞移植改变了病毒动力学：我们发现与原发感染相比，反弹设定点更高，但峰值病毒载量相似。计算基本免疫参数的数据的数学建模实现了对异质病毒载量的极好拟合。对模型输出的分析表明，治疗中断后的快速记忆免疫反应并不能最终导致更好的病毒遏制。移植降低了cART停药和病毒反弹后适应性免疫反应的持久性。我们的模型结果强调了内源性适应性免疫反应在原发性SHIV感染期间的影响。此外，由于我们捕获了适应性免疫记忆和移植的影响，该模型将为受柏林病人启发的治疗策略的进一步研究提供见解。中断抗逆转录病毒联合治疗（cART）的hiv患者最终会经历病毒反弹，病毒载量恢复到治疗前的水平。然而，“柏林病人”在停止抗逆转录病毒治疗十多年后仍然没有出现艾滋病毒反弹。他的治愈归功于白血病治疗，其中包括抗hiv干细胞移植。受此病例启发，我们研究了干细胞移植对猕猴/HIV （SHIV）系统的影响。利用机械数学模型，我们发现，虽然原发性感染产生适应性免疫记忆反应，但干细胞移植破坏了这种习得性免疫。这一结果对基于干细胞移植的HIV治疗方案具有启示意义。
Primary HIV-1 infection induces a virus-specific adaptive/cytolytic immune response that impacts the plasma viral load set point and the rate of progression to AIDS. Combination antiretroviral therapy (cART) suppresses plasma viremia to undetectable levels that rebound upon cART treatment interruption. Following cART withdrawal, the memory component of the virus-specific adaptive immune response may improve viral control compared to primary infection. Here, using primary infection and treatment interruption data from macaques infected with simian/human immunodeficiency virus (SHIV), we observe a lower peak viral load but an unchanged viral set point during viral rebound. The addition of an autologous stem cell transplant before cART withdrawal alters viral dynamics: we found a higher rebound set point but similar peak viral loads compared to the primary infection. Mathematical modeling of the data that accounts for fundamental immune parameters achieves excellent fit to heterogeneous viral loads. Analysis of model output suggests that the rapid memory immune response following treatment interruption does not ultimately lead to better viral containment. Transplantation decreases the durability of the adaptive immune response following cART withdrawal and viral rebound. Our model's results highlight the impact of the endogenous adaptive immune response during primary SHIV infection. Moreover, because we capture adaptive immune memory and the impact of transplantation, this model will provide insight into further studies of cure strategies inspired by the Berlin patient.IMPORTANCEHIV patients who interrupt combination antiretroviral therapy (cART) eventually experience viral rebound, the return of viral loads to pretreatment levels. However, the “Berlin patient” remained free of HIV rebound over a decade after stopping cART. His cure is attributed to leukemia treatment that included an HIV-resistant stem cell transplant. Inspired by this case, we studied the impact of stem cell transplantation in a macaque simian/HIV (SHIV) system. Using a mechanistic mathematical model, we found that while primary infection generates an adaptive immune memory response, stem cell transplantation disrupts this learned immunity. The results have implications for HIV cure regimens based on stem cell transplantation.