HIV Reservoirs In The Pathogenesis Of HIV Disease

CD8+T细胞介导的抗HIV活性在感染者中一直被描述；然而，这种活性在潜伏感染的静止的CD4+T细胞库中控制HIV复制的作用尚不清楚。使用体外系统，我们检测了自体CD8+T细胞在控制HIV复制中的作用，相对于疾病的阶段，以及开始抗逆转录病毒治疗的状态和时机。我们证明，在感染的、未经治疗的长期无进展(LTNPs)患者以及HAART成功控制病毒复制的患者中，自体CD8+T细胞有效地抑制了潜伏的CD4+T细胞库中HIV的复制。相反，自体CD8+T细胞抑制病毒复制的程度要小得多，在潜伏感染的、来自某些血浆病毒血症水平相当高的慢性感染患者的静息CD4+T细胞中。在共培养环境中，自体CD8+T细胞抑制病毒复制的能力与这些感染者外周血中HIV特异性CD8+T细胞的总频率之间缺乏相关性，提示HIV的抑制机制不依赖于细胞毒CD8+T淋巴细胞(CTL)。当检测可溶性CD8+T细胞衍生因子的抗病毒作用时，我们发现CC趋化因子在一些LTNPs和接受HAART的患者的潜伏的CD4+T细胞库中发挥了主要的病毒复制抑制作用，但在没有接受抗逆转录病毒治疗的慢性感染患者中没有发挥作用。除CC趋化因子外，CD8+T细胞衍生的可溶性因子显示出强大的抗病毒活性，这种活性主要在HIV感染急性期后不久启动HAART的感染者身上发现。这些结果表明，CD8+T细胞通过直接细胞接触在潜伏感染的静止的CD4+T细胞库中提供了强大的抑制HIV复制的活性，这不主要依赖于CTL活性，并且这种细胞介导的抗病毒活性在自然感染LTNPs的患者或接受HAART治疗的患者中最为深刻。此外，在HIV感染急性期后不久开始HAART的感染患者中，除了CC趋化因子外，可溶性CD8因子对CD4+T细胞库中病毒复制的抑制作用最强。这些数据表明，通过早期开始治疗来保存这种艾滋病毒抑制机制，可能在中断治疗后遏制感染患者的病毒复制方面发挥重要作用。

CD8+ T cell-mediated antiviral activity against HIV has been described consistently in infected individuals; however, the role of this activity in controlling replication of HIV in the latently infected, resting CD4+ T cell reservoir has been unclear. Using an ex vivo system, we examined the role of autologous CD8+ T cells in controlling HIV replication in this pool of cells relative to stage of disease and the status and timing of initiation of antiretroviral therapy. We demonstrated that replication of HIV in the latent CD4+ T cell reservoir was effectively suppressed by autologous CD8+ T cells in infected, untreated long-term nonprogressors (LTNPs) and in those patients whose viral replication was successfully controlled by HAART. In contrast, autologous CD8+ T cells suppressed virus replication to a much lesser extent in latently infected, resting CD4+ T cells from certain chronically infected patients who had substantial levels of plasma viremia. There was a lack of correlation between the capacity of autologous CD8+ T cells to suppress viral replication in the coculture setting and the overall frequency of HIV-specific CD8+ T cells in the peripheral blood compartment of these infected patients, suggesting that the mechanism of inhibition of HIV was independent of cytotoxic CD8+ T lymphocytes (CTL). When the antiviral role of soluble CD8+ T cell-derived factors was examined, we found that CC-chemokines played a major role in inhibition of viral replication in the latent CD4+ T cell reservoir in some LTNPs and in patients receiving HAART, but not in chronically infected patients who were not receiving antiretroviral therapy. Potent antiviral activity was exhibited by CD8+ T cell-derived soluble factors, other than CC-chemokines, and this activity was found mainly in infected individuals in whom HAART was initiated shortly after the acute phase of HIV infection. These results indicate that CD8+ T cells provide potent suppressive activity against HIV replication in the latently infected, resting CD4+ T cell reservoir via direct cellular contact, which is not dependent predominantly on CTL activity, and that this cell-mediated antiviral activity is most profound in patients who are naturally LTNPs or in those who are treated with HAART. Furthermore, soluble CD8 factors other than CC-chemokines showed the most profound suppressive activity against viral replication in the CD4+ T cell reservoir in infected patients who began HAART soon after the acute phase of HIV infection. These data suggest that preservation of this HIV-suppressive mechanism by early initiation of therapy may play an important role in containment of viral replication in infected patients following interruption of therapy.