Effros R B, Allsopp R, Chiu C P, Hausner M A, Hirji K, Wang L, Harley C B, Villeponteau B, West M D, Giorgi J V
Department of Pathology and Laboratory Medicine, University of California Los Angeles (UCLA) School of Medicine 90095-1745, USA.
AIDS. 1996 Jul;10(8):F17-22. doi: 10.1097/00002030-199607000-00001.
To test the hypothesis that the expanded population of non-proliferative CD28-CD8+ T cells in HIV disease have shortened telomeres, thereby providing evidence that increased rounds of CD8+ cell division occur during HIV disease, possibly leading to replicative senescence and exhaustion of CD8+ T-cell responses.
CD8+ cells play a central role in control of HIV infection. In late HIV disease, an expanded population of CD28-CD8+ cells with reduced proliferative potential has been documented. A similar population of CD28-CD8+ cells has been identified in ageing humans, where telomere length measurements have suggested that these cells have reached the irreversible state of replicative senescence.
CD8+ cells from HIV-infected and control subjects were sorted by flow cytometry into CD28+ and CD28- fractions. Telomere lengths were determined as mean terminal restriction fragment (TRF) lengths by Southern hybridization.
The TRF lengths of sorted CD28-CD8+ cells in HIV-infected subjects ranged between 5 and 7 kilobases (kb) and were significantly shorter than TRF lengths of CD28-CD8+ cells in uninfected subjects (P = 0.003). The TRF length in CD28-CD8+ cells from HIV-infected subjects was the same as that observed for centenarian peripheral blood mononuclear cells and is compatible with a state of replicative senescence.
The shortened telomeres in the CD28-CD8+ cells in HIV-infected subjects and the poor proliferative potential of these cells identifies CD8+ cell replicative senescence as a newly described feature of HIV disease. Our results provide a mechanism for the loss of CD8+ cell control of viral replication that accompanies advanced HIV disease. Replicative senescence may contribute to exhaustion of the T-cell response as a result of chronic HIV disease. Whether this phenomenon occurs in other chronic viral infections is unknown.
检验以下假说，即HIV疾病中增殖能力受限的CD28-CD8+ T细胞群体端粒缩短，从而证明HIV疾病期间CD8+细胞分裂轮次增加，这可能导致CD8+ T细胞反应的复制性衰老和耗竭。
CD8+细胞在控制HIV感染中起核心作用。在HIV疾病晚期，已记录到具有降低增殖潜能的CD28-CD8+细胞群体扩大。在老年人中也鉴定出了类似的CD28-CD8+细胞群体，端粒长度测量表明这些细胞已达到复制性衰老的不可逆状态。
通过流式细胞术将HIV感染受试者和对照受试者的CD8+细胞分选成CD28+和CD28-亚群。通过Southern杂交将端粒长度确定为平均末端限制片段（TRF）长度。
HIV感染受试者中经分选的CD28-CD8+细胞的TRF长度在5至7千碱基（kb）之间，明显短于未感染受试者中CD28-CD8+细胞的TRF长度（P = 0.003）。HIV感染受试者的CD28-CD8+细胞中的TRF长度与百岁老人外周血单个核细胞中观察到的长度相同，并且与复制性衰老状态相符。
HIV感染受试者中CD28-CD8+细胞的端粒缩短以及这些细胞的增殖潜能较差，将CD8+细胞复制性衰老确定为HIV疾病新描述的特征。我们的结果为晚期HIV疾病伴随的CD8+细胞对病毒复制控制丧失提供了一种机制。复制性衰老可能由于慢性HIV疾病导致T细胞反应耗竭。这种现象是否发生在其他慢性病毒感染中尚不清楚。
