Virology Unit, Microbiology Group, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Antwerp, Belgium.
PLoS One. 2012;7(5):e37792. doi: 10.1371/journal.pone.0037792. Epub 2012 May 30.
Upon interruption of antiretroviral therapy, HIV-infected patients usually show viral load rebound to pre-treatment levels. Four patients, hereafter referred to as secondary controllers (SC), were identified who initiated therapy during chronic infection and, after stopping treatment, could control virus replication at undetectable levels for more than six months. In the present study we set out to unravel possible viral and immune parameters or mechanisms of this phenomenon by comparing secondary controllers with elite controllers and non-controllers, including patients under HAART. As candidate correlates of protection, virus growth kinetics, levels of intracellular viral markers, several aspects of HIV-specific CD4+ and CD8+ T cell function and HIV neutralizing antibodies were investigated. As expected all intracellular viral markers were lower in aviremic as compared to viremic subjects, but in addition both elite and secondary controllers had lower levels of viral unspliced RNA in PBMC as compared to patients on HAART. Ex vivo cultivation of the virus from CD4+ T cells of SC consistently failed in one patient and showed delayed kinetics in the three others. Formal in vitro replication studies of these three viruses showed low to absent growth in two cases and a virus with normal fitness in the third case. T cell responses toward HIV peptides, evaluated in IFN-γ ELISPOT, revealed no significant differences in breadth, magnitude or avidity between SC and all other patient groups. Neither was there a difference in polyfunctionality of CD4+ or CD8+ T cells, as evaluated with intracellular cytokine staining. However, secondary and elite controllers showed higher proliferative responses to Gag and Pol peptides. SC also showed the highest level of autologous neutralizing antibodies. These data suggest that higher T cell proliferative responses and lower replication kinetics might be instrumental in secondary viral control in the absence of treatment.
在中断抗逆转录病毒治疗后，HIV 感染患者的病毒载量通常会反弹到治疗前水平。本研究中我们发现了 4 名患者，他们在慢性感染期开始接受治疗，停药后能将病毒复制控制在不可检测水平超过 6 个月，被称为继发性控制者（SC）。为了揭示这种现象的可能的病毒和免疫参数或机制，我们将继发性控制者与精英控制者和非控制者（包括接受 HAART 的患者）进行了比较。作为保护的候选相关因素，我们研究了病毒生长动力学、细胞内病毒标志物水平、HIV 特异性 CD4+和 CD8+T 细胞功能的几个方面以及 HIV 中和抗体。正如预期的那样，所有的细胞内病毒标志物在无病毒血症患者中均低于病毒血症患者，但精英控制者和继发性控制者的外周血单核细胞（PBMC）中未剪接的病毒 RNA 水平也低于接受 HAART 的患者。在一名患者中，从 SC 的 CD4+T 细胞中体外培养病毒的实验始终失败，在另外 3 名患者中病毒培养的动力学延迟。对这三种病毒的体外复制研究表明，两种情况下病毒的生长较低或不存在，第三种情况下病毒的适应性正常。在 IFN-γ ELISPOT 中评估针对 HIV 肽的 T 细胞反应，在广度、幅度或亲和力方面，SC 和所有其他患者组之间没有显著差异。CD4+或 CD8+T 细胞的多功能性也没有差异，通过细胞内细胞因子染色进行评估。然而，继发性和精英控制者对 Gag 和 Pol 肽的增殖反应更高。SC 还表现出最高水平的自体中和抗体。这些数据表明，在没有治疗的情况下，更高的 T 细胞增殖反应和更低的复制动力学可能有助于继发性病毒控制。
