Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+ T-Cell Responses
Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+ T-Cell Responses
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DOI：
10.1128/jvi.03723-14
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发表时间：
2015-04-01
影响因子：
5.4
通讯作者：
Vaslin, Bruno
中科院分区：
文献类型：
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作者：
Bruel, Timothee;Hamimi, Chiraz;Vaslin, Bruno
人类和猿猴免疫缺陷病毒（HIV/SIV）的自发控制通常与特定的主要组织相容性复合体（MHC） I类等位基因和有效的CD8(+) t细胞应答有关，但许多控制者尽管具有非保护性MHC背景和弱CD8(+) t细胞应答，但仍保持病毒控制。因此，这种反应对维持长期病毒控制的贡献尚不清楚。为了解决这个问题，我们短暂地耗尽了5只siv感染的食蟹猕猴的CD8(+) T细胞，这些猕猴具有长期的病毒控制和弱CD8(+) T细胞反应。其中只有一个携带保护性MHC等位基因H6。耗尽后，5个控制者中的4个经历了短暂的病毒血症反弹。回到无法检测到的病毒血症时，体内缺乏有效SIV抑制能力的SIV特异性CD8(+) T细胞仅适度扩增。相反，耗竭与与病毒反弹相关的CD4(+) T细胞的稳态激活/扩增有关。在一只猕猴体内，尽管CD8（+）细胞高效耗竭和CD4(+) T细胞诱导SIV复制，但病毒血症仍然检测不到。总之，我们的研究结果表明，CD8(+) T细胞并不是SIV控制模型中长期维持低病毒血症的唯一贡献者，其他机制，如弱病毒库或激活控制，可能在控制中发挥重要作用。自发控制HIV-1到检测不到的水平与有效的抗hiv CD8(+) t细胞反应有关。然而，在某些情况下，这种反应随着时间的推移而减弱，尽管病毒控制得以维持，并且许多HIV控制者（弱应答者）具有非常低的HIV特异性CD8(+) T细胞频率。在这些病例中，CD8 T细胞在维持HIV-1控制中的重要性值得怀疑。我们开发了一种非人类灵长类动物持久SIV控制模型，其免疫特征与弱应答者相似。CD8（+）细胞的短暂耗竭诱导了病毒载量的上升。然而，病毒血症与CD8（+）细胞耗竭后CD4(+) t细胞活化相关。病毒控制恢复到耗尽前水平与CD8(+) T细胞抗siv能力的恢复无关。我们的研究结果表明，CD8(+) T细胞可能不参与维持弱应答者的病毒控制，并强调了不应低估其他机制的事实。
The spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8(+) T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8(+) T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8(+) T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8(+) T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8(+) T cells that lacked efficient SIV suppression capacity ex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4(+) T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8(+) cell depletion and inducible SIV replication from its CD4(+) T cells in vitro. Altogether, our results suggest that CD8(+) T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control.IMPORTANCESpontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8(+) T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8(+) T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8(+) cells induced a rise in the viral load. However, viremia was correlated with CD4(+) T-cell activation subsequent to CD8(+) cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8(+) T cells. Our results suggest that CD8(+) T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.