Role Of Viral Reservoirs In Pathogenesis Of HIV Disease

有效的抗病毒治疗的使用迅速和持续地抑制了艾滋病毒的复制，并极大地改善了绝大多数接受最佳治疗的感染者的临床结果。然而，由于各种病毒库的持续存在，在接受有效抗病毒治疗的感染者中根除艾滋病毒是不可能的。其中，静止CD4+ T细胞区室中的潜伏感染细胞池已被广泛研究，并被认为是根除艾滋病毒的主要障碍之一。这种潜伏的HIV病毒库的固有半衰期极长，可能使接受目前可用的抗病毒治疗的患者几乎不可能根除病毒。然而，过去几年进行的研究表明，低水平的正在进行的病毒复制持续存在，从而延长了接受抗病毒治疗的患者的总体HIV半衰期。在过去的一年中，我们调查了一组接受不间断抗病毒治疗长达9.1年的患者中残留HIV的存在和状态；使他们持续病毒血症的疗法。在所有研究对象中，我们证明了复制能力病毒在CD4+ T细胞中的持久性。令人惊讶的是，在我们研究的大多数患者中，与静止的CD4+ T细胞相比，在活化的CD4+ T细胞中发现了更高水平的HIV前病毒DNA。系统发育分析显示静息和活化的CD4+ T细胞区室之间存在交叉感染的证据，这表明潜伏感染、静息CD4+ T细胞的持续再激活和活化的CD4+ T细胞的病毒传播可能发生在这些患者身上。这些事件可能允许持续补充CD4+ T细胞库和重置的半衰期的潜伏感染，休眠CD4+ T细胞，尽管病毒血症的延长。

The use of effective antiviral therapy has led to rapid and sustained suppression of HIV replication and has dramatically improved the clinical outcome in the vast majority of infected individuals who are treated optimally. However, it has not been possible to eradicate HIV in infected individuals receiving effective antiviral therapy mainly due to the persistence of various viral reservoirs. Among those, a pool of latently infected cells in the resting CD4+ T cell compartment has been one of the most extensively studied and is considered to be a major impediment to HIV eradication. The extremely long intrinsic half-life of such a latent HIV reservoir may make eradication of the virus all but impossible in patients receiving currently available antiviral therapy. However, studies conducted over the past several years suggest that low levels of on-going viral replication persist and consequently prolong the overall half-life of HIV in patients receiving antiviral therapy. In the past year, we investigated the presence and status of residual HIV in a cohort of patients who had received uninterrupted antiviral therapy for up to 9.1 years; therapy that rendered them consistently aviremic. We demonstrated the persistence of replication-competent virus in CD4+ T cells in all study subjects. Surprisingly, substantially higher levels of HIV proviral DNA were found in activated CD4+ T cells when compared to resting CD4+ T cells in the majority of patients whom we studied. Phylogenetic analyses revealed evidence for cross-infection between the resting and activated CD4+ T cell compartments, suggesting that on-going reactivation of latently infected, resting CD4+ T cells and spread of virus by activated CD4+ T cells may occur in these patients. Such events may allow continual replenishment of the CD4+ T cell reservoir and resetting of the half-life of the latently infected, resting CD4+ T cells despite prolonged periods of aviremia.