Department of Medicine, Yale University, New Haven, Connecticut, United States of America.
Gladstone Institute of Virology and Immunology, San Francisco, California, United States of America.
PLoS One. 2014 Jan 21;9(1):e85613. doi: 10.1371/journal.pone.0085613. eCollection 2014.
The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve despite effective ART. CD4∶CD8 ratio was evaluated in HIV-infected subjects with viral loads >10,000 copies/µl ("non-controllers", n = 42), those with undetectable viral loads on ART ("ART-suppressed", n = 53), and HIV-uninfected subjects (n = 22). In addition, T cell phenotype and function were examined in 25 non-controllers, 18 ART-suppressed, and 7 HIV-uninfected subjects. CD4∶CD8 ratio in non-controllers, ART-suppressed, and HIV-uninfected subjects was 0.25, 0.48, and 1.95 respectively (P<0.0001 for all comparisons). The increased ratio in ART-suppressed compared to non-controllers was driven by an increase of CD4+ T cells, with no change in the expanded CD8+ T cell population. Expansion of differentiated (CD28-CD27-CD45RA+/-CCR7-) T cell subpopulations persisted despite ART and minimal changes were noted in naïve T cell frequencies over time. Increased number of CD8+CD28- T cells and increased CD8+ CMV-specific T cell responses were associated with a decreased CD4∶CD8 ratio. Measures of T cell function demonstrated persistence of high frequencies of CD8+ T cells producing IFN-γ. Lastly, though all CD8+ subpopulations demonstrated significantly lower Ki67 expression in ART-suppressed subjects, CD4+ T cell subpopulations did not consistently show this decrease, thus demonstrating different proliferative responses in the setting of T cell depletion. In summary, this study demonstrated that CD4∶CD8 ratios remained significantly decreased and naïve T cell numbers were slow to increase despite long-term viral suppression on ART. In addition, there is a evidence of differential regulation of the CD4+ and CD8+ T cell subpopulations, suggesting independent homeostatic regulation of the two compartments.
尽管抗逆转录病毒疗法（ART）可重建 HIV 感染者的正常免疫系统，但仍存在不确定性。本研究旨在描述尽管接受了有效的 ART，各种 T 细胞亚群的数量和质量仍未得到改善的特征。在病毒载量＞10,000 拷贝/µl 的 HIV 感染者中（“非控制者”，n = 42），评估了 CD4∶CD8 比值，这些感染者的病毒载量在 ART 下无法检测到（“ART 抑制者”，n = 53），以及 HIV 未感染者（n = 22）。此外，还在 25 名非控制者、18 名 ART 抑制者和 7 名 HIV 未感染者中检查了 T 细胞表型和功能。非控制者、ART 抑制者和 HIV 未感染者的 CD4∶CD8 比值分别为 0.25、0.48 和 1.95（所有比较均 P＜0.0001）。与非控制者相比，ART 抑制者的比值增加是由 CD4+ T 细胞增加引起的，而扩展的 CD8+ T 细胞群没有变化。尽管进行了 ART，但分化（CD28-CD27-CD45RA+/-CCR7-）T 细胞亚群的扩增仍然存在，并且随着时间的推移，幼稚 T 细胞频率的变化很小。增加的 CD8+CD28- T 细胞数量和增加的 CD8+CMV 特异性 T 细胞反应与 CD4∶CD8 比值降低有关。T 细胞功能的测量表明，高水平产生 IFN-γ的 CD8+ T 细胞的频率仍然很高。最后，尽管所有 CD8+亚群在 ART 抑制者中表现出明显降低的 Ki67 表达，但 CD4+ T 细胞亚群并未始终表现出这种降低，因此在 T 细胞耗竭的情况下显示出不同的增殖反应。总之，本研究表明，尽管长期接受 ART 治疗病毒得到抑制，但 CD4∶CD8 比值仍显著降低，幼稚 T 细胞数量增加缓慢。此外，有证据表明 CD4+和 CD8+ T 细胞亚群的调节存在差异，这表明两个亚群的稳态调节是独立的。
