Di Mascio Michele, Sereti Irini, Matthews Lynn T, Natarajan Ven, Adelsberger Joseph, Lempicki Richard, Yoder Christian, Jones Elizabeth, Chow Catherine, Metcalf Julia A, Sidorov Igor A, Dimitrov Dimiter S, Polis Michael A, Kovacs Joseph A
National Institute of Allergy and Infectious Diseases, National Institutes of Health, 6700 B Rockledge Drive, MSC 7609, Bethesda, MD 20892, USA.
J Virol. 2006 Mar;80(6):2665-74. doi: 10.1128/JVI.80.6.2665-2674.2006.
Both naïve CD4+ and naïve CD8+ T cells are depleted in individuals with human immunodeficiency virus type 1 (HIV-1) infection by unknown mechanisms. Analysis of their dynamics prior to and after highly active antiretroviral therapy (HAART) could reveal possible mechanisms of depletion. Twenty patients were evaluated with immunophenotyping, intracellular Ki67 staining, T-cell receptor excision circle (TREC) quantitation in sorted CD4 and CD8 cells, and thymic computed tomography scans prior to and approximately 6 and approximately 18 months after initiation of HAART. Naïve T-cell proliferation decreased significantly during the first 6 months of therapy (P < 0.01) followed by a slower decline. Thymic indices did not change significantly over time. At baseline, naïve CD4+ T-cell numbers were lower than naive CD8+ T-cell numbers; after HAART, a greater increase in naïve CD4+ T cells than naïve CD8+ T cells was observed. A greater relative change (n-fold) in the number of TREC+ T cells/mul than in naïve T-cell counts was observed at 6 months for both CD4+ (median relative change [n-fold] of 2.2 and 1.7, respectively; P < 0.01) and CD8+ T cell pools (1.4 and 1.2; P < 0.01). A more pronounced decrease in the proliferation than the disappearance rate of naïve T cells after HAART was observed in a second group of six HIV-1-infected patients studied by in vivo pulse labeling with bromodeoxyuridine. These observations are consistent with a mathematical model where the HIV-1-induced increase in proliferation of naïve T cells is mostly explained by a faster recruitment into memory cells.
在人类免疫缺陷病毒1型（HIV-1）感染个体中，初始CD4⁺和初始CD8⁺T细胞均以未知机制耗竭。分析高效抗逆转录病毒疗法（HAART）前后它们的动态变化可能揭示耗竭的潜在机制。对20例患者在开始HAART之前、开始HAART后约6个月和约18个月时进行免疫表型分析、细胞内Ki67染色、分选的CD4和CD8细胞中的T细胞受体切除环（TREC）定量以及胸腺计算机断层扫描。在治疗的前6个月，初始T细胞增殖显著下降（P<0.01），随后下降速度减慢。胸腺指数随时间无显著变化。基线时，初始CD4⁺T细胞数量低于初始CD8⁺T细胞数量；HAART后，观察到初始CD4⁺T细胞的增加幅度大于初始CD8⁺T细胞。在6个月时，CD4⁺（中位数相对变化[n倍]分别为2.2和1.7；P<0.01）和CD8⁺T细胞库（1.4和1.2；P<0.01）中，TREC⁺T细胞数量/微升的相对变化（n倍）大于初始T细胞计数。在第二组6例接受溴脱氧尿苷体内脉冲标记研究的HIV-1感染患者中，观察到HAART后初始T细胞的增殖下降比消失速率更明显。这些观察结果与一个数学模型一致，即HIV-1诱导的初始T细胞增殖增加主要由更快地招募到记忆细胞中解释。
