HIV Reservoirs In The Pathogenesis Of HIV Disease

CD 8 + T细胞介导的抗HIV抗病毒活性在感染个体中一直被描述;然而，这种活性在潜伏感染的静息CD 4 + T细胞库中控制HIV复制的作用尚不清楚。使用离体系统，我们研究了自体CD 8 + T细胞在控制HIV复制中的作用，相对于疾病的阶段和抗逆转录病毒治疗的开始状态和时间。我们证明，在感染、未治疗的长期无进展者（LTNP）和HAART成功控制病毒复制的患者中，自体CD 8 + T细胞可有效抑制潜伏性CD 4 + T细胞库中的HIV复制。相比之下，自体CD 8 + T细胞抑制病毒复制的程度要小得多的潜伏感染，静息的CD 4 + T细胞从某些慢性感染的患者谁有大量的血浆病毒血症水平。自体CD 8 + T细胞在共培养环境中抑制病毒复制的能力与这些感染患者外周血中HIV特异性CD 8 + T细胞的总体频率之间缺乏相关性，这表明抑制HIV的机制与细胞毒性CD 8 + T淋巴细胞（CTL）无关。当可溶性CD 8 + T细胞衍生因子的抗病毒作用进行了检查，我们发现，CC-趋化因子发挥了重要作用，抑制病毒复制的潜伏性CD 4 + T细胞水库在一些LTNP和接受HAART的患者，但不是在慢性感染的患者谁没有接受抗逆转录病毒治疗。有效的抗病毒活性表现为CD 8 + T细胞衍生的可溶性因子，而不是CC-趋化因子，这种活性主要发现在感染的个体，其中HAART开始后不久，艾滋病毒感染的急性期。这些结果表明，CD 8 + T细胞通过直接细胞接触提供了对潜伏感染的静息CD 4 + T细胞库中HIV复制的有效抑制活性，这主要不依赖于CTL活性，并且这种细胞介导的抗病毒活性在天然LTNP的患者或用HAART治疗的患者中最显著。此外，在HIV感染急性期后不久开始HAART的感染患者中，除CC趋化因子外的可溶性CD 8因子显示出对CD 4 + T细胞库中病毒复制的最深刻的抑制活性。这些数据表明，通过早期启动治疗来保护这种HIV抑制机制可能在中断治疗后感染患者的病毒复制遏制中发挥重要作用。

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.