Pinzone Marilia Rita, Graf Erin, Lynch Lindsay, McLaughlin Brigit, Hecht Frederick M, Connors Mark, Migueles Stephen A, Hwang Wei-Ting, Nunnari Giuseppe, O'Doherty Una
Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Virol. 2016 Nov 14;90(23):10436-10445. doi: 10.1128/JVI.00242-16. Print 2016 Dec 1.
The dynamics of HIV reservoir accumulation off antiretroviral therapy (ART) is underexplored. Levels of integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) were longitudinally monitored before and after antiviral therapy. HIV integration increased over time in both elite controllers (ECs; n = 8) and noncontrollers (NCs; n = 6) before ART, whereas integration remained stable in patients on ART (n = 4). The median annual fold change was higher in NCs than in ECs and negatively correlated with CD4/CD8 T-cell ratio. Cytotoxic T lymphocyte (CTL) function as assessed by infected CD4 T-cell elimination (ICE) and granzyme B activity did not significantly change over time in ECs, suggesting that the gradual increase in integrated HIV DNA observed in ECs was not a result of progressive loss of immune-mediated control. Also, acutely infected (n = 7) but not chronically infected (n = 6) patients exhibited a significant drop in integrated HIV DNA 12 months after ART initiation. In conclusion, in the absence of ART, integrated HIV accumulates over time both in NCs and in ECs, at variable individual rates. Starting ART early in infection leads to a greater drop in integrated HIV DNA than does initiating treatment after years of infection. The increase in integrated HIV DNA over time suggests that early treatment may be of benefit in limiting HIV reservoirs.
The establishment of a latent reservoir represents a barrier to cure among HIV-infected individuals. The dynamics of HIV reservoir accumulation over time in patients before antiviral therapy is underexplored, in large part because it is difficult to accurately and reproducibly measure the size of HIV reservoir in this setting. In our study, we compared the dynamics of integrated HIV DNA over time in ECs and NCs before and after ART was initiated. We found that integrated HIV DNA levels progressively increase over time in the absence of ART, but with a higher, albeit variable, rate in NCs compared to ECs. In addition, integrated HIV DNA declines more dramatically when ART is initiated in acute rather than chronic HIV infection, suggesting important differences between acute and chronic infection. Our study highlights the role of HIV replication and CTL control in reservoir accumulation in sanctuary sites and why ART appears to be more effective in acute infection.
抗逆转录病毒疗法（ART）停用后HIV储存库积累的动态变化尚未得到充分研究。在抗病毒治疗前后，对外周血单核细胞（PBMC）中整合型HIV DNA的水平进行了纵向监测。在接受ART治疗前，精英控制者（ECs；n = 8）和非控制者（NCs；n = 6）的HIV整合均随时间增加，而接受ART治疗的患者（n = 4）中整合情况保持稳定。NCs的年中位数变化倍数高于ECs，且与CD4/CD8 T细胞比率呈负相关。通过感染的CD4 T细胞清除（ICE）和颗粒酶B活性评估的细胞毒性T淋巴细胞（CTL）功能在ECs中随时间未发生显著变化，这表明在ECs中观察到的整合型HIV DNA的逐渐增加并非免疫介导控制逐渐丧失的结果。此外，急性感染患者（n = 7）而非慢性感染患者（n = 6）在开始ART治疗12个月后，整合型HIV DNA出现显著下降。总之，在未进行ART治疗的情况下，NCs和ECs中的整合型HIV均会随时间积累，但个体速率各不相同。在感染早期开始ART治疗比在感染数年之后开始治疗，导致整合型HIV DNA下降幅度更大。整合型HIV DNA随时间增加表明早期治疗可能有助于限制HIV储存库。
潜伏储存库的建立是HIV感染者治愈的障碍。抗病毒治疗前患者中HIV储存库随时间积累的动态变化尚未得到充分研究，很大程度上是因为在此情况下难以准确且可重复地测量HIV储存库的大小。在我们的研究中，我们比较了开始ART治疗前后ECs和NCs中整合型HIV DNA随时间的动态变化。我们发现，在未进行ART治疗的情况下，整合型HIV DNA水平随时间逐渐升高，但与ECs相比，NCs中的升高速率更高，尽管存在个体差异。此外，在急性而非慢性HIV感染中开始ART治疗时，整合型HIV DNA下降更为显著，这表明急性和慢性感染之间存在重要差异。我们的研究突出了HIV复制和CTL控制在 sanctuary 部位储存库积累中的作用，以及为什么ART在急性感染中似乎更有效。
