Role of Viral Reservoirs in the Pathogenesis of HIV Disease

在过去的几年里，我们一直在研究潜伏感染的静息CD 4 + T细胞和持续的病毒复制在HIV感染发病机制中的作用，以及这种储存库对HIV感染者治疗的影响。我们以前证明，潜伏的病毒水库在休息的CD 4 + T细胞区室坚持在几乎所有感染的个人接受有效的抗病毒治疗。因此，这种病毒库是体内根除HIV的主要障碍。此外，我们认识到，在接受有效抗病毒治疗的慢性感染者中，HIV持续以低水平复制，这使他们在很长一段时间内持续出现病毒血症。在过去的一年里，我们的研究重点是：1）描述艾滋病毒在接受有效抗逆转录病毒治疗的感染者中持续存在的机制，2）检查强化抗逆转录病毒治疗对临床成功药物治疗的感染者中病毒储存库的衰减和大小的影响。 首先，我们研究了在不同时间段内接受有效抗逆转录病毒治疗的个体中残留HIV的存在和状态，并研究了HIV在这些个体的静息CD 4 + T细胞中持续存在的潜在机制。已经提出，存在于感染的静息CD 4 + T细胞中的HIV在病毒学上是静止的。我们证明，与接受有效抗逆转录病毒治疗的感染个体血液中的PD-1阴性静息CD 4 + T细胞相比，表达程序性死亡（PD）-1基因的静息CD 4 + T细胞亚群携带显著更高水平的HIV前病毒DNA。大多数PD-1+静息CD 4 + T细胞表达组织归巢受体CXCR 3，这表明这些细胞可能最近从各种组织部位迁移到外周血室中。来自临床上成功的抗逆转录病毒治疗的大多数患者的PD-1+静息CD 4 + T细胞在没有任何激活刺激的情况下自发释放HIV。这表明这些细胞在生理上不同于未分级的潜伏感染的静息CD 4 + T细胞。综上所述，我们的数据表明，PD-1+静息CD 4 + T细胞代表了一种独特的感染细胞群体，在感染个体的抗逆转录病毒治疗期间持续存在，并且可能需要一种新的治疗方法才能实现体内病毒的完全清除。 第二，在过去的一年里，我们启动了一项临床试验，以研究抗逆转录病毒治疗强化如何影响已接受临床成功药物治疗超过3年的感染者的病毒储存库的衰变。尽管治疗策略取得了成功，但在接受有效抗逆转录病毒治疗的受感染者中，主要由于各种病毒储存库的持续存在，尚不可能根除艾滋病毒。我们最近证明了HIV在活化和静息CD 4 + T细胞中的持久性，并为接受长达9.1年有效抗逆转录病毒治疗的病毒血症患者中这些细胞区室之间的交叉感染提供了证据。这表明潜伏感染的静息CD 4 + T细胞的持续再活化和病毒在体内的传播。为了降低残余病毒复制水平，并设计有效的抗逆转录病毒策略，旨在根除病毒，我们正在研究共同管理的效果，一种新开发的抗逆转录病毒药物，整合酶抑制剂雷特格韦，对病毒库的衰减在外周血和肠道相关淋巴组织的感染者谁正在接受有效的抗逆转录病毒治疗一段时间。我们即将完成上述临床试验（96周），并将在未来几个月内对各种免疫学和病毒学参数进行分析。

For the past several years, we have been investigating the role of latently infected, resting CD4+ T cells and persistent viral replication in the pathogenesis of HIV infection and the impact of this reservoir on the treatment of HIV-infected individuals. We previously demonstrated that the latent viral reservoir in the resting CD4+ T cell compartment persists in virtually all infected individuals receiving effective antiviral therapy. Consequently, this viral reservoir is a major impediment to the eradication of HIV in vivo. In addition, we realized that HIV continually replicates at low levels in chronically infected individuals who are receiving effective antiviral therapy that renders them consistently aviremic for prolonged periods of time. Over the past year, we have focused our research on: 1) delineating the mechanisms by which HIV persists in infected individuals receiving effective antiretroviral therapy for extended periods of time and 2) examining the effect of intensifying antiretroviral therapy on the decay and size of viral reservoirs in infected individuals who had been on clinically successful drug regimens. First, we investigated the presence and status of residual HIV in individuals who had received effective antiretroviral therapy for varying periods of time and we examined the underlying mechanisms by which HIV persists in resting CD4+ T cells of such individuals. It has been proposed that the HIV present in infected resting CD4+ T cells is virologically quiescent. We demonstrated that a subset of resting CD4+ T cells that express the programmed death (PD)-1 gene carry substantially higher levels of HIV proviral DNA compared to PD-1-negative resting CD4+ T cells in the blood of infected individuals receiving effective antiretroviral therapy. The majority of PD-1+ resting CD4+ T cells express CXCR3, a tissue homing receptor, which suggests that these cells may have recently migrated out of various tissue sites into the peripheral blood compartment. PD-1+ resting CD4+ T cells from the majority of patients on clinically successful antiretroviral therapy spontaneously released HIV in the absence of any activating stimuli. This suggests that these cells are physiologically distinct from unfractionated latently infected, resting CD4+ T cells. Taken together, our data suggest that PD-1+ resting CD4+ T cells represent a unique population of infected cells that persists during antiretroviral therapy in infected individuals and that may require a novel therapeutic approach in order to achieve complete clearance of virus in vivo. Second, over the past year, we initiated a clinical trial to examine how antiretroviral therapy intensification affects the decay of viral reservoirs in infected individuals who had been on clinically successful drug regimens for greater than 3 years. Despite the success of therapeutic strategies, it has not been possible to eradicate HIV in infected individuals receiving effective antiretroviral therapy mainly due to the persistence of various viral reservoirs. We have recently demonstrated the persistence of HIV in activated as well as resting CD4+ T cells and provided evidence for cross-infection between these cellular compartments in aviremic patients receiving up to 9.1 years of effective antiretroviral therapy. This suggests ongoing reactivation of latently infected, resting CD4+ T cells and spread of virus in vivo. In order to decrease levels of residual viral replication and to design effective antiretroviral strategies aimed at eradicating virus, we are examining the effect of co-administering a newly developed antiretroviral drug, the integrase inhibitor raltegravir, on the decay of the viral reservoir in peripheral blood and gut-associated lymphoid tissues of infected individuals who are receiving effective antiretroviral therapy for some time. We are near the completion of the above clinical trial (96 weeks) and will conduct analyses of various immunologic and virologic parameters in the coming months.