Role of HIV Reservoirs in the Pathogenesis of HIV Disease

在接受高效抗逆转录病毒治疗(HAART)并成功抑制血浆病毒血症的人类免疫缺陷病毒(HIV)感染者中，已有很好的证据表明，携带有复制能力的HIV的潜伏感染、静止的CD4+T细胞池持续存在。由于其较长的半衰期和现有药物在消除这些感染细胞方面的无效，这种潜在的病毒储库被认为是接受HAART的感染者彻底根除艾滋病毒的主要障碍；然而，这种病毒储库的致病意义以及它在停止HAART后血浆病毒血症反弹中的作用在很大程度上尚不清楚。我们先前已经证明，在长期成功抑制血浆病毒血症的感染者中，停止HAART后病毒在血浆中反弹的动力学与停止治疗前潜伏的HIV宿主的大小之间没有相关性。使用异源双链迁移率和跟踪分析，我们在这项研究中证明，可检测到的潜伏感染的静止CD4+T细胞池并不能完全解释停止HAART的感染者早期血浆HIV的反弹。在大多数接受检查的患者中，在可检测到的潜伏感染、静止的CD4+T细胞池中，反弹血浆病毒在基因上与细胞相关的HIV RNA和复制能力强的病毒不同。这些结果表明，在HAART停止后，存在其他持续的HIV储备库，可能会促使血浆病毒血症迅速出现，并强调了开发针对此类感染细胞群体的治疗方法的必要性。

The persistence of a pool of latently infected, resting CD4+ T cells carrying replication-competent HIV has been well documented in human immunodeficiency virus (HIV)-infected individuals who are receiving highly active antiretroviral therapy (HAART) and in whom successful suppression of plasma viremia has been achieved. This latent viral reservoir is considered to be a major impediment to complete eradication of HIV in infected individuals receiving HAART due to its long half-life and the ineffectiveness of currently available drugs in eliminating these infected cells; however, the pathogenic significance of this viral reservoir as well as its role in the rebound of plasma viremia following discontinuation of HAART is largely unknown. We have previously demonstrated that there was no correlation between the kinetics of viral rebound in plasma upon cessation of HAART and the size of the latent HIV reservoir prior to discontinuation of therapy in infected individuals in whom prolonged periods of successful suppression of plasma viremia had been achieved. Using heteroduplex mobility and tracking assays, we demonstrate in this study that the detectable pool of latently infected, resting CD4+ T cells does not account entirely for the early rebounding plasma HIV in infected individuals in whom HAART has been discontinued. The rebounding plasma virus was genetically distinct from both the cell-associated HIV RNA and replication-competent virus within the detectable pool of latently infected, resting CD4+ T cells in the majority of patients examined. These results suggest the existence of other persistent HIV reservoirs that could prompt rapid emergence of plasma viremia following cessation of HAART and underscore the necessity to develop therapies directed toward such populations of infected cells.